TY  - JOUR
AU  - Petrović, Jelena
AU  - Radovanović, Ljiljana
AU  - Šaponjić, Jasna
PY  - 2021
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0166432820306562
UR  - http://www.ncbi.nlm.nih.gov/pubmed/33038348
UR  - https://radar.ibiss.bg.ac.rs/123456789/3908
AB  - We investigated the prodromal alterations of local sleep, particularly the motor cortical and hippocampal sleep, along with spontaneous locomotor activity in the rat models of Parkinson's disease (PD). We performed our experiments in adult, male Wistar rats, chronically implanted for sleep recording and divided into four experimental groups: the control (implanted controls), the bilateral pedunculopontine tegmental nucleus (PPT) lesions (PD cholinopathy), the unilateral substantia nigra pars compacta (SNpc) lesions (hemiparkinsonism) and the unilateral SNpc/bilateral PPT lesions (hemiparkinsonism with PD cholinopathy). We followed their sleep, basal locomotor activity and spatial habituation for 14 days following the surgical procedures. Severe prodromal local sleep disturbances in the hemiparkinsonian rats were expressed as sleep fragmentation and distinct local NREM/REM EEG microstructure alterations in both the motor cortex and the hippocampus. Alongside the state-unrelated role of the dopaminergic control of theta oscillations and NREM/REM related sigma and beta oscillations, we demonstrated that the REM neurochemical regulatory substrate is particularly important in the dopaminergic control of beta oscillations. In addition, hippocampal prodromal sleep disorders in the hemiparkinsonian rats were expressed as NREM/REM fragmentation and the opposite impact of dopaminergic versus cholinergic control of the NREM delta and beta oscillation amplitudes in the hippocampus, likewise in the motor cortex versus the hippocampus. All these distinct prodromal local sleep disorders and the dopaminergic vs. cholinergic impact on NREM/REM EEG microstructure alterations are of fundamental importance for the further development and follow-up of PD-modifying therapies, and for the identification of patients who are at risk of developing PD.
PB  - Elsevier
T2  - Behavioural Brain Research
T1  - Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy.
VL  - 397
DO  - 10.1016/j.bbr.2020.112957
SP  - 112957
ER  - 

@article{
author = "Petrović, Jelena and Radovanović, Ljiljana and Šaponjić, Jasna",
year = "2021",
abstract = "We investigated the prodromal alterations of local sleep, particularly the motor cortical and hippocampal sleep, along with spontaneous locomotor activity in the rat models of Parkinson's disease (PD). We performed our experiments in adult, male Wistar rats, chronically implanted for sleep recording and divided into four experimental groups: the control (implanted controls), the bilateral pedunculopontine tegmental nucleus (PPT) lesions (PD cholinopathy), the unilateral substantia nigra pars compacta (SNpc) lesions (hemiparkinsonism) and the unilateral SNpc/bilateral PPT lesions (hemiparkinsonism with PD cholinopathy). We followed their sleep, basal locomotor activity and spatial habituation for 14 days following the surgical procedures. Severe prodromal local sleep disturbances in the hemiparkinsonian rats were expressed as sleep fragmentation and distinct local NREM/REM EEG microstructure alterations in both the motor cortex and the hippocampus. Alongside the state-unrelated role of the dopaminergic control of theta oscillations and NREM/REM related sigma and beta oscillations, we demonstrated that the REM neurochemical regulatory substrate is particularly important in the dopaminergic control of beta oscillations. In addition, hippocampal prodromal sleep disorders in the hemiparkinsonian rats were expressed as NREM/REM fragmentation and the opposite impact of dopaminergic versus cholinergic control of the NREM delta and beta oscillation amplitudes in the hippocampus, likewise in the motor cortex versus the hippocampus. All these distinct prodromal local sleep disorders and the dopaminergic vs. cholinergic impact on NREM/REM EEG microstructure alterations are of fundamental importance for the further development and follow-up of PD-modifying therapies, and for the identification of patients who are at risk of developing PD.",
publisher = "Elsevier",
journal = "Behavioural Brain Research",
title = "Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy.",
volume = "397",
doi = "10.1016/j.bbr.2020.112957",
pages = "112957"
}

Petrović, J., Radovanović, L.,& Šaponjić, J.. (2021). Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy.. in Behavioural Brain Research
Elsevier., 397, 112957.
https://doi.org/10.1016/j.bbr.2020.112957

Petrović J, Radovanović L, Šaponjić J. Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy.. in Behavioural Brain Research. 2021;397:112957.
doi:10.1016/j.bbr.2020.112957 .

Petrović, Jelena, Radovanović, Ljiljana, Šaponjić, Jasna, "Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy." in Behavioural Brain Research, 397 (2021):112957,
https://doi.org/10.1016/j.bbr.2020.112957 . .

TY  - JOUR
AU  - Petrović, Jelena
AU  - Radovanović, Ljiljana
AU  - Šaponjić, Jasna
PY  - 2021
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0166432820306562
UR  - http://www.ncbi.nlm.nih.gov/pubmed/33038348
UR  - https://radar.ibiss.bg.ac.rs/123456789/3908
UR  - https://radar.ibiss.bg.ac.rs/123456789/3909
AB  - We investigated the prodromal alterations of local sleep, particularly the motor cortical and hippocampal sleep, along with spontaneous locomotor activity in the rat models of Parkinson's disease (PD). We performed our experiments in adult, male Wistar rats, chronically implanted for sleep recording and divided into four experimental groups: the control (implanted controls), the bilateral pedunculopontine tegmental nucleus (PPT) lesions (PD cholinopathy), the unilateral substantia nigra pars compacta (SNpc) lesions (hemiparkinsonism) and the unilateral SNpc/bilateral PPT lesions (hemiparkinsonism with PD cholinopathy). We followed their sleep, basal locomotor activity and spatial habituation for 14 days following the surgical procedures. Severe prodromal local sleep disturbances in the hemiparkinsonian rats were expressed as sleep fragmentation and distinct local NREM/REM EEG microstructure alterations in both the motor cortex and the hippocampus. Alongside the state-unrelated role of the dopaminergic control of theta oscillations and NREM/REM related sigma and beta oscillations, we demonstrated that the REM neurochemical regulatory substrate is particularly important in the dopaminergic control of beta oscillations. In addition, hippocampal prodromal sleep disorders in the hemiparkinsonian rats were expressed as NREM/REM fragmentation and the opposite impact of dopaminergic versus cholinergic control of the NREM delta and beta oscillation amplitudes in the hippocampus, likewise in the motor cortex versus the hippocampus. All these distinct prodromal local sleep disorders and the dopaminergic vs. cholinergic impact on NREM/REM EEG microstructure alterations are of fundamental importance for the further development and follow-up of PD-modifying therapies, and for the identification of patients who are at risk of developing PD.
PB  - Elsevier
T2  - Behavioural Brain Research
T1  - Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy.
VL  - 397
DO  - 10.1016/j.bbr.2020.112957
SP  - 112957
ER  - 

@article{
author = "Petrović, Jelena and Radovanović, Ljiljana and Šaponjić, Jasna",
year = "2021",
abstract = "We investigated the prodromal alterations of local sleep, particularly the motor cortical and hippocampal sleep, along with spontaneous locomotor activity in the rat models of Parkinson's disease (PD). We performed our experiments in adult, male Wistar rats, chronically implanted for sleep recording and divided into four experimental groups: the control (implanted controls), the bilateral pedunculopontine tegmental nucleus (PPT) lesions (PD cholinopathy), the unilateral substantia nigra pars compacta (SNpc) lesions (hemiparkinsonism) and the unilateral SNpc/bilateral PPT lesions (hemiparkinsonism with PD cholinopathy). We followed their sleep, basal locomotor activity and spatial habituation for 14 days following the surgical procedures. Severe prodromal local sleep disturbances in the hemiparkinsonian rats were expressed as sleep fragmentation and distinct local NREM/REM EEG microstructure alterations in both the motor cortex and the hippocampus. Alongside the state-unrelated role of the dopaminergic control of theta oscillations and NREM/REM related sigma and beta oscillations, we demonstrated that the REM neurochemical regulatory substrate is particularly important in the dopaminergic control of beta oscillations. In addition, hippocampal prodromal sleep disorders in the hemiparkinsonian rats were expressed as NREM/REM fragmentation and the opposite impact of dopaminergic versus cholinergic control of the NREM delta and beta oscillation amplitudes in the hippocampus, likewise in the motor cortex versus the hippocampus. All these distinct prodromal local sleep disorders and the dopaminergic vs. cholinergic impact on NREM/REM EEG microstructure alterations are of fundamental importance for the further development and follow-up of PD-modifying therapies, and for the identification of patients who are at risk of developing PD.",
publisher = "Elsevier",
journal = "Behavioural Brain Research",
title = "Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy.",
volume = "397",
doi = "10.1016/j.bbr.2020.112957",
pages = "112957"
}

Petrović, J., Radovanović, L.,& Šaponjić, J.. (2021). Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy.. in Behavioural Brain Research
Elsevier., 397, 112957.
https://doi.org/10.1016/j.bbr.2020.112957

Petrović J, Radovanović L, Šaponjić J. Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy.. in Behavioural Brain Research. 2021;397:112957.
doi:10.1016/j.bbr.2020.112957 .

Petrović, Jelena, Radovanović, Ljiljana, Šaponjić, Jasna, "Prodromal local sleep disorders in a rat model of Parkinson's disease cholinopathy, hemiparkinsonism and hemiparkinsonism with cholinopathy." in Behavioural Brain Research, 397 (2021):112957,
https://doi.org/10.1016/j.bbr.2020.112957 . .

TY  - JOUR
AU  - Petrović, Jelena
AU  - Radovanović, Ljiljana
AU  - Šaponjić, Jasna
PY  - 2020
UR  - https://onlinelibrary.wiley.com/doi/abs/10.1111/jsr.13090
UR  - http://www.ncbi.nlm.nih.gov/pubmed/32472657
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3696
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3707
AB  - We investigated the homogeneity/heterogeneity of spontaneous sleep, simultaneously recorded in the motor cortex and the hippocampus of control rats, and particularly analysed simultaneous and non-simultaneous motor cortical and hippocampal non-rapid eye movement (NREM)/rapid eye movement (REM) sleep. We demonstrate that the sleep architectures of the motor cortex and hippocampus are different in control rats. There was an increase of NREM duration and a decrease of REM duration in the hippocampus versus the motor cortex. In terms of duration, NREM state is the most heterogeneous in the hippocampus, whereas the REM state is the most heterogeneous in the motor cortex. Whereas the hippocampal NREM duration was increased due to the prolongation of NREM episodes, the hippocampal REM duration decreased due to the decreased number of REM episodes. The heterogeneity of sleep in the motor cortex and hippocampus in control rats was particularly expressed through the inverse alteration of sigma amplitude during NREM sleep and beta/gamma amplitudes during REM sleep in the hippocampus, along with the delta, sigma, beta and gamma amplitudes only during non-simultaneous NREM/REM sleep in the hippocampus. We demonstrated the brain structure-related and NREM/REM state-related heterogeneity of the motor cortical and hippocampal local sleep in control rats. The distinctly altered local NREM/REM states, alongside their episode dynamics and electroencephalographic (EEG) microstructures, suggest the importance of both the local neuronal network substrate and the NREM/REM neurochemical substrate in the control mechanisms of sleep.
PB  - Blackwell Publishing Ltd
T2  - Journal of Sleep Research
T1  - Diversity of simultaneous sleep in the motor cortex and hippocampus in rats.
DO  - 10.1111/jsr.13090
SP  - e13090
ER  - 

@article{
author = "Petrović, Jelena and Radovanović, Ljiljana and Šaponjić, Jasna",
year = "2020",
abstract = "We investigated the homogeneity/heterogeneity of spontaneous sleep, simultaneously recorded in the motor cortex and the hippocampus of control rats, and particularly analysed simultaneous and non-simultaneous motor cortical and hippocampal non-rapid eye movement (NREM)/rapid eye movement (REM) sleep. We demonstrate that the sleep architectures of the motor cortex and hippocampus are different in control rats. There was an increase of NREM duration and a decrease of REM duration in the hippocampus versus the motor cortex. In terms of duration, NREM state is the most heterogeneous in the hippocampus, whereas the REM state is the most heterogeneous in the motor cortex. Whereas the hippocampal NREM duration was increased due to the prolongation of NREM episodes, the hippocampal REM duration decreased due to the decreased number of REM episodes. The heterogeneity of sleep in the motor cortex and hippocampus in control rats was particularly expressed through the inverse alteration of sigma amplitude during NREM sleep and beta/gamma amplitudes during REM sleep in the hippocampus, along with the delta, sigma, beta and gamma amplitudes only during non-simultaneous NREM/REM sleep in the hippocampus. We demonstrated the brain structure-related and NREM/REM state-related heterogeneity of the motor cortical and hippocampal local sleep in control rats. The distinctly altered local NREM/REM states, alongside their episode dynamics and electroencephalographic (EEG) microstructures, suggest the importance of both the local neuronal network substrate and the NREM/REM neurochemical substrate in the control mechanisms of sleep.",
publisher = "Blackwell Publishing Ltd",
journal = "Journal of Sleep Research",
title = "Diversity of simultaneous sleep in the motor cortex and hippocampus in rats.",
doi = "10.1111/jsr.13090",
pages = "e13090"
}

Petrović, J., Radovanović, L.,& Šaponjić, J.. (2020). Diversity of simultaneous sleep in the motor cortex and hippocampus in rats.. in Journal of Sleep Research
Blackwell Publishing Ltd., e13090.
https://doi.org/10.1111/jsr.13090

Petrović J, Radovanović L, Šaponjić J. Diversity of simultaneous sleep in the motor cortex and hippocampus in rats.. in Journal of Sleep Research. 2020;:e13090.
doi:10.1111/jsr.13090 .

Petrović, Jelena, Radovanović, Ljiljana, Šaponjić, Jasna, "Diversity of simultaneous sleep in the motor cortex and hippocampus in rats." in Journal of Sleep Research (2020):e13090,
https://doi.org/10.1111/jsr.13090 . .

TY  - JOUR
AU  - Petrović, Jelena
AU  - Radovanović, Ljiljana
AU  - Šaponjić, Jasna
PY  - 2020
UR  - https://onlinelibrary.wiley.com/doi/abs/10.1111/jsr.13090
UR  - http://www.ncbi.nlm.nih.gov/pubmed/32472657
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3696
UR  - https://radar.ibiss.bg.ac.rs/handle/handle/123456789/3707
AB  - We investigated the homogeneity/heterogeneity of spontaneous sleep, simultaneously recorded in the motor cortex and the hippocampus of control rats, and particularly analysed simultaneous and non-simultaneous motor cortical and hippocampal non-rapid eye movement (NREM)/rapid eye movement (REM) sleep. We demonstrate that the sleep architectures of the motor cortex and hippocampus are different in control rats. There was an increase of NREM duration and a decrease of REM duration in the hippocampus versus the motor cortex. In terms of duration, NREM state is the most heterogeneous in the hippocampus, whereas the REM state is the most heterogeneous in the motor cortex. Whereas the hippocampal NREM duration was increased due to the prolongation of NREM episodes, the hippocampal REM duration decreased due to the decreased number of REM episodes. The heterogeneity of sleep in the motor cortex and hippocampus in control rats was particularly expressed through the inverse alteration of sigma amplitude during NREM sleep and beta/gamma amplitudes during REM sleep in the hippocampus, along with the delta, sigma, beta and gamma amplitudes only during non-simultaneous NREM/REM sleep in the hippocampus. We demonstrated the brain structure-related and NREM/REM state-related heterogeneity of the motor cortical and hippocampal local sleep in control rats. The distinctly altered local NREM/REM states, alongside their episode dynamics and electroencephalographic (EEG) microstructures, suggest the importance of both the local neuronal network substrate and the NREM/REM neurochemical substrate in the control mechanisms of sleep.
PB  - Blackwell Publishing Ltd
T2  - Journal of Sleep Research
T1  - Diversity of simultaneous sleep in the motor cortex and hippocampus in rats.
DO  - 10.1111/jsr.13090
SP  - e13090
ER  - 

@article{
author = "Petrović, Jelena and Radovanović, Ljiljana and Šaponjić, Jasna",
year = "2020",
abstract = "We investigated the homogeneity/heterogeneity of spontaneous sleep, simultaneously recorded in the motor cortex and the hippocampus of control rats, and particularly analysed simultaneous and non-simultaneous motor cortical and hippocampal non-rapid eye movement (NREM)/rapid eye movement (REM) sleep. We demonstrate that the sleep architectures of the motor cortex and hippocampus are different in control rats. There was an increase of NREM duration and a decrease of REM duration in the hippocampus versus the motor cortex. In terms of duration, NREM state is the most heterogeneous in the hippocampus, whereas the REM state is the most heterogeneous in the motor cortex. Whereas the hippocampal NREM duration was increased due to the prolongation of NREM episodes, the hippocampal REM duration decreased due to the decreased number of REM episodes. The heterogeneity of sleep in the motor cortex and hippocampus in control rats was particularly expressed through the inverse alteration of sigma amplitude during NREM sleep and beta/gamma amplitudes during REM sleep in the hippocampus, along with the delta, sigma, beta and gamma amplitudes only during non-simultaneous NREM/REM sleep in the hippocampus. We demonstrated the brain structure-related and NREM/REM state-related heterogeneity of the motor cortical and hippocampal local sleep in control rats. The distinctly altered local NREM/REM states, alongside their episode dynamics and electroencephalographic (EEG) microstructures, suggest the importance of both the local neuronal network substrate and the NREM/REM neurochemical substrate in the control mechanisms of sleep.",
publisher = "Blackwell Publishing Ltd",
journal = "Journal of Sleep Research",
title = "Diversity of simultaneous sleep in the motor cortex and hippocampus in rats.",
doi = "10.1111/jsr.13090",
pages = "e13090"
}

Petrović, J., Radovanović, L.,& Šaponjić, J.. (2020). Diversity of simultaneous sleep in the motor cortex and hippocampus in rats.. in Journal of Sleep Research
Blackwell Publishing Ltd., e13090.
https://doi.org/10.1111/jsr.13090

Petrović J, Radovanović L, Šaponjić J. Diversity of simultaneous sleep in the motor cortex and hippocampus in rats.. in Journal of Sleep Research. 2020;:e13090.
doi:10.1111/jsr.13090 .

Petrović, Jelena, Radovanović, Ljiljana, Šaponjić, Jasna, "Diversity of simultaneous sleep in the motor cortex and hippocampus in rats." in Journal of Sleep Research (2020):e13090,
https://doi.org/10.1111/jsr.13090 . .

TY  - JOUR
AU  - Vučićević, Ljubica
AU  - Misirkić Marjanović, Maja
AU  - Ćirić, Darko
AU  - Martinović, Tamara
AU  - Jovanović, Maja
AU  - Isaković, Aleksandra
AU  - Marković, Ivanka
AU  - Šaponjić, Jasna
AU  - Foretz, Marc
AU  - Rabanal-Ruiz, Yoana
AU  - Korolchuk, Viktor I.
AU  - Trajković, Vladimir
PY  - 2020
UR  - http://link.springer.com/10.1007/s00018-019-03356-2
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3528
AB  - We investigated the role of autophagy, a controlled lysosomal degradation of cellular macromolecules and organelles, in glutamate excitotoxicity during nutrient deprivation in vitro. The incubation in low-glucose serum/amino acid-free cell culture medium synergized with glutamate in increasing AMP/ATP ratio and causing excitotoxic necrosis in SH-SY5Y human neuroblastoma cells. Glutamate suppressed starvation-triggered autophagy, as confirmed by diminished intracellular acidification, lower LC3 punctuation and LC3-I conversion to autophagosome-associated LC3-II, reduced expression of proautophagic beclin-1 and ATG5, increase of the selective autophagic target NBR1, and decreased number of autophagic vesicles. Similar results were observed in PC12 rat pheochromocytoma cells. Both glutamate-mediated excitotoxicity and autophagy inhibition in starved SH-SY5Y cells were reverted by NMDA antagonist memantine and mimicked by NMDA agonists D-aspartate and ibotenate. Glutamate reduced starvation-triggered phosphorylation of the energy sensor AMP-activated protein kinase (AMPK) without affecting the activity of mammalian target of rapamycin complex 1, a major negative regulator of autophagy. This was associated with reduced mRNA levels of autophagy transcriptional activators (FOXO3, ATF4) and molecules involved in autophagy initiation (ULK1, ATG13, FIP200), autophagosome nucleation/elongation (ATG14, beclin-1, ATG5), and autophagic cargo delivery to autophagosomes (SQSTM1). Glutamate-mediated transcriptional repression of autophagy was alleviated by overexpression of constitutively active AMPK. Genetic or pharmacological AMPK activation by AMPK overexpression or metformin, as well as genetic or pharmacological autophagy induction by TFEB overexpression or lithium chloride, reduced the sensitivity of nutrient-deprived SH-SY5Y cells to glutamate excitotoxicity. These data indicate that transcriptional inhibition of AMPK-dependent cytoprotective autophagy is involved in glutamate-mediated excitotoxicity during nutrient deprivation in vitro.
T2  - Cellular and Molecular Life Sciences
T1  - Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells.
VL  - 77
DO  - 10.1007/s00018-019-03356-2
SP  - 3383
EP  - 3399
ER  - 

@article{
author = "Vučićević, Ljubica and Misirkić Marjanović, Maja and Ćirić, Darko and Martinović, Tamara and Jovanović, Maja and Isaković, Aleksandra and Marković, Ivanka and Šaponjić, Jasna and Foretz, Marc and Rabanal-Ruiz, Yoana and Korolchuk, Viktor I. and Trajković, Vladimir",
year = "2020",
abstract = "We investigated the role of autophagy, a controlled lysosomal degradation of cellular macromolecules and organelles, in glutamate excitotoxicity during nutrient deprivation in vitro. The incubation in low-glucose serum/amino acid-free cell culture medium synergized with glutamate in increasing AMP/ATP ratio and causing excitotoxic necrosis in SH-SY5Y human neuroblastoma cells. Glutamate suppressed starvation-triggered autophagy, as confirmed by diminished intracellular acidification, lower LC3 punctuation and LC3-I conversion to autophagosome-associated LC3-II, reduced expression of proautophagic beclin-1 and ATG5, increase of the selective autophagic target NBR1, and decreased number of autophagic vesicles. Similar results were observed in PC12 rat pheochromocytoma cells. Both glutamate-mediated excitotoxicity and autophagy inhibition in starved SH-SY5Y cells were reverted by NMDA antagonist memantine and mimicked by NMDA agonists D-aspartate and ibotenate. Glutamate reduced starvation-triggered phosphorylation of the energy sensor AMP-activated protein kinase (AMPK) without affecting the activity of mammalian target of rapamycin complex 1, a major negative regulator of autophagy. This was associated with reduced mRNA levels of autophagy transcriptional activators (FOXO3, ATF4) and molecules involved in autophagy initiation (ULK1, ATG13, FIP200), autophagosome nucleation/elongation (ATG14, beclin-1, ATG5), and autophagic cargo delivery to autophagosomes (SQSTM1). Glutamate-mediated transcriptional repression of autophagy was alleviated by overexpression of constitutively active AMPK. Genetic or pharmacological AMPK activation by AMPK overexpression or metformin, as well as genetic or pharmacological autophagy induction by TFEB overexpression or lithium chloride, reduced the sensitivity of nutrient-deprived SH-SY5Y cells to glutamate excitotoxicity. These data indicate that transcriptional inhibition of AMPK-dependent cytoprotective autophagy is involved in glutamate-mediated excitotoxicity during nutrient deprivation in vitro.",
journal = "Cellular and Molecular Life Sciences",
title = "Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells.",
volume = "77",
doi = "10.1007/s00018-019-03356-2",
pages = "3383-3399"
}

Vučićević, L., Misirkić Marjanović, M., Ćirić, D., Martinović, T., Jovanović, M., Isaković, A., Marković, I., Šaponjić, J., Foretz, M., Rabanal-Ruiz, Y., Korolchuk, V. I.,& Trajković, V.. (2020). Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells.. in Cellular and Molecular Life Sciences, 77, 3383-3399.
https://doi.org/10.1007/s00018-019-03356-2

Vučićević L, Misirkić Marjanović M, Ćirić D, Martinović T, Jovanović M, Isaković A, Marković I, Šaponjić J, Foretz M, Rabanal-Ruiz Y, Korolchuk VI, Trajković V. Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells.. in Cellular and Molecular Life Sciences. 2020;77:3383-3399.
doi:10.1007/s00018-019-03356-2 .

Vučićević, Ljubica, Misirkić Marjanović, Maja, Ćirić, Darko, Martinović, Tamara, Jovanović, Maja, Isaković, Aleksandra, Marković, Ivanka, Šaponjić, Jasna, Foretz, Marc, Rabanal-Ruiz, Yoana, Korolchuk, Viktor I., Trajković, Vladimir, "Transcriptional block of AMPK-induced autophagy promotes glutamate excitotoxicity in nutrient-deprived SH-SY5Y neuroblastoma cells." in Cellular and Molecular Life Sciences, 77 (2020):3383-3399,
https://doi.org/10.1007/s00018-019-03356-2 . .

TY  - JOUR
AU  - Rajković, Nemanja
AU  - Ćirić, Jelena
AU  - Milošević, Nebojša
AU  - Šaponjić, Jasna
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0010482519303518?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3487
AB  - To reveal the best choice of algorithm for parvalbumin-immunostained images of the hippocampal gyrus dentatus in two distinct rat models of Parkinson's disease (PD), particularly in terms of extracting the crucial information from the image, we tested whether the impact of experimentally induced dopaminergic (hemiparkinsonism) vs. cholinergic (PD cholinopathy) innervation impairment on the parvalbumin stained GABA interneurons could be detected using two separate algorithms, the fractal box-count and the gray-level co-occurrence matrix analysis (GLCM) algorithms. For the texture and fractal analysis of the hippocampal gyrus dentatus images, we used.tif images from three experimental groups of adult male Wistar rats: control rats, rats with Parkinson disease (PD) cholinergic neuropathology (with a PPT lesion), and hemiparkinsonian rats (with a SNpc lesion). For the suprapyramidal layer of the gyrus dentatus ASM and Entropy differentiated the images of the SNpc lesion versus the images of the control and the PPT lesion subjects, with significantly higher ASM and lower Entropy, indicating the homogenization of the images and their lower gray-level complexity. The infrapyramidal images of the SNpc group were differentiated versus the images from the control and PPT groups in terms of all the GLCM parameters: they showed lower mean Entropy and Contrast and higher ASM, Correlation and IDM. These results strongly suggest a rise in the uniformity, homogeneity and orderliness in the gray-levels of images from the SNpc group. Our results indicate that GLCM analysis is a more sensitive tool than fractal analysis for the detection of increased dendritic arborization in histological images.
T2  - Computers in Biology and Medicine
T1  - Novel application of the gray-level co-occurrence matrix analysis in the parvalbumin stained hippocampal gyrus dentatus in distinct rat models of Parkinson's disease.
VL  - 115
DO  - 10.1016/j.compbiomed.2019.103482
SP  - 103482
ER  - 

@article{
author = "Rajković, Nemanja and Ćirić, Jelena and Milošević, Nebojša and Šaponjić, Jasna",
year = "2019",
abstract = "To reveal the best choice of algorithm for parvalbumin-immunostained images of the hippocampal gyrus dentatus in two distinct rat models of Parkinson's disease (PD), particularly in terms of extracting the crucial information from the image, we tested whether the impact of experimentally induced dopaminergic (hemiparkinsonism) vs. cholinergic (PD cholinopathy) innervation impairment on the parvalbumin stained GABA interneurons could be detected using two separate algorithms, the fractal box-count and the gray-level co-occurrence matrix analysis (GLCM) algorithms. For the texture and fractal analysis of the hippocampal gyrus dentatus images, we used.tif images from three experimental groups of adult male Wistar rats: control rats, rats with Parkinson disease (PD) cholinergic neuropathology (with a PPT lesion), and hemiparkinsonian rats (with a SNpc lesion). For the suprapyramidal layer of the gyrus dentatus ASM and Entropy differentiated the images of the SNpc lesion versus the images of the control and the PPT lesion subjects, with significantly higher ASM and lower Entropy, indicating the homogenization of the images and their lower gray-level complexity. The infrapyramidal images of the SNpc group were differentiated versus the images from the control and PPT groups in terms of all the GLCM parameters: they showed lower mean Entropy and Contrast and higher ASM, Correlation and IDM. These results strongly suggest a rise in the uniformity, homogeneity and orderliness in the gray-levels of images from the SNpc group. Our results indicate that GLCM analysis is a more sensitive tool than fractal analysis for the detection of increased dendritic arborization in histological images.",
journal = "Computers in Biology and Medicine",
title = "Novel application of the gray-level co-occurrence matrix analysis in the parvalbumin stained hippocampal gyrus dentatus in distinct rat models of Parkinson's disease.",
volume = "115",
doi = "10.1016/j.compbiomed.2019.103482",
pages = "103482"
}

Rajković, N., Ćirić, J., Milošević, N.,& Šaponjić, J.. (2019). Novel application of the gray-level co-occurrence matrix analysis in the parvalbumin stained hippocampal gyrus dentatus in distinct rat models of Parkinson's disease.. in Computers in Biology and Medicine, 115, 103482.
https://doi.org/10.1016/j.compbiomed.2019.103482

Rajković N, Ćirić J, Milošević N, Šaponjić J. Novel application of the gray-level co-occurrence matrix analysis in the parvalbumin stained hippocampal gyrus dentatus in distinct rat models of Parkinson's disease.. in Computers in Biology and Medicine. 2019;115:103482.
doi:10.1016/j.compbiomed.2019.103482 .

Rajković, Nemanja, Ćirić, Jelena, Milošević, Nebojša, Šaponjić, Jasna, "Novel application of the gray-level co-occurrence matrix analysis in the parvalbumin stained hippocampal gyrus dentatus in distinct rat models of Parkinson's disease." in Computers in Biology and Medicine, 115 (2019):103482,
https://doi.org/10.1016/j.compbiomed.2019.103482 . .

TY  - JOUR
AU  - Ćirić, Jelena
AU  - Kapor, Slobodan
AU  - Perović, Milka
AU  - Šaponjić, Jasna
PY  - 2019
UR  - https://www.frontiersin.org/article/10.3389/fnins.2019.00148/full
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6401659
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3294
AB  - Our previous studies in the rat model of Parkinson's disease (PD) cholinopathy demonstrated the sleep-related alterations in electroencephalographic (EEG) oscillations at the cortical and hippocampal levels, cortical drives, and sleep spindles (SSs) as the earliest functional biomarkers preceding hypokinesia. Our aim in this study was to follow the impact of a unilateral substantia nigra pars compacta (SNpc) lesion in rat on the cortical and hippocampal sleep architectures and their EEG microstructures, as well as the cortico-hippocampal synchronizations of EEG oscillations, and the SS and high voltage sleep spindle (HVS) dynamics during NREM and REM sleep. We performed unilateral SNpc lesions using two different concentrations/volumes of 6-hydroxydopamine (6-OHDA; 12 μg/1 μl or 12 μg/2 μl). Whereas the unilateral dopaminergic neuronal loss >50% throughout the overall SNpc rostro-caudal dimension prolonged the Wake state, with no change in the NREM or REM duration, there was a long-lasting theta amplitude augmentation across all sleep states in the motor cortex (MCx), but also in the CA1 hippocampus (Hipp) during both Wake and REM sleep. We demonstrate that SS are the hallmarks of NREM sleep, but that they also occur during REM sleep in the MCx and Hipp of the control rats. Whereas SS are always longer in REM vs. NREM sleep in both structures, they are consistently slower in the Hipp. The dopaminergic neuronal loss increased the density of SS in both structures and shortened them in the MCx during NREM sleep, without changing the intrinsic frequency. Conversely, HVS are the hallmarks of REM sleep in the control rats, slower in the Hipp vs. MCx, and the dopaminergic neuronal loss increased their density in the MCx, but shortened them more consistently in the Hipp during REM sleep. In addition, there was an altered synchronization of the EEG oscillations between the MCx and Hipp in different sleep states, particularly the theta and sigma coherences during REM sleep. We provide novel evidence for the importance of the SNpc dopaminergic innervation in sleep regulation, theta rhythm generation, and SS/HVS dynamics control. We suggest the importance of the underlying REM sleep regulatory substrate to HVS generation and duration and to the cortico-hippocampal synchronizations of EEG oscillations in hemiparkinsonian rats.
T2  - Frontiers in Neuroscience
T1  - Alterations of Sleep and Sleep Oscillations in the Hemiparkinsonian Rat.
VL  - 13
DO  - 10.3389/fnins.2019.00148
SP  - 148
ER  - 

@article{
author = "Ćirić, Jelena and Kapor, Slobodan and Perović, Milka and Šaponjić, Jasna",
year = "2019",
abstract = "Our previous studies in the rat model of Parkinson's disease (PD) cholinopathy demonstrated the sleep-related alterations in electroencephalographic (EEG) oscillations at the cortical and hippocampal levels, cortical drives, and sleep spindles (SSs) as the earliest functional biomarkers preceding hypokinesia. Our aim in this study was to follow the impact of a unilateral substantia nigra pars compacta (SNpc) lesion in rat on the cortical and hippocampal sleep architectures and their EEG microstructures, as well as the cortico-hippocampal synchronizations of EEG oscillations, and the SS and high voltage sleep spindle (HVS) dynamics during NREM and REM sleep. We performed unilateral SNpc lesions using two different concentrations/volumes of 6-hydroxydopamine (6-OHDA; 12 μg/1 μl or 12 μg/2 μl). Whereas the unilateral dopaminergic neuronal loss >50% throughout the overall SNpc rostro-caudal dimension prolonged the Wake state, with no change in the NREM or REM duration, there was a long-lasting theta amplitude augmentation across all sleep states in the motor cortex (MCx), but also in the CA1 hippocampus (Hipp) during both Wake and REM sleep. We demonstrate that SS are the hallmarks of NREM sleep, but that they also occur during REM sleep in the MCx and Hipp of the control rats. Whereas SS are always longer in REM vs. NREM sleep in both structures, they are consistently slower in the Hipp. The dopaminergic neuronal loss increased the density of SS in both structures and shortened them in the MCx during NREM sleep, without changing the intrinsic frequency. Conversely, HVS are the hallmarks of REM sleep in the control rats, slower in the Hipp vs. MCx, and the dopaminergic neuronal loss increased their density in the MCx, but shortened them more consistently in the Hipp during REM sleep. In addition, there was an altered synchronization of the EEG oscillations between the MCx and Hipp in different sleep states, particularly the theta and sigma coherences during REM sleep. We provide novel evidence for the importance of the SNpc dopaminergic innervation in sleep regulation, theta rhythm generation, and SS/HVS dynamics control. We suggest the importance of the underlying REM sleep regulatory substrate to HVS generation and duration and to the cortico-hippocampal synchronizations of EEG oscillations in hemiparkinsonian rats.",
journal = "Frontiers in Neuroscience",
title = "Alterations of Sleep and Sleep Oscillations in the Hemiparkinsonian Rat.",
volume = "13",
doi = "10.3389/fnins.2019.00148",
pages = "148"
}

Ćirić, J., Kapor, S., Perović, M.,& Šaponjić, J.. (2019). Alterations of Sleep and Sleep Oscillations in the Hemiparkinsonian Rat.. in Frontiers in Neuroscience, 13, 148.
https://doi.org/10.3389/fnins.2019.00148

Ćirić J, Kapor S, Perović M, Šaponjić J. Alterations of Sleep and Sleep Oscillations in the Hemiparkinsonian Rat.. in Frontiers in Neuroscience. 2019;13:148.
doi:10.3389/fnins.2019.00148 .

Ćirić, Jelena, Kapor, Slobodan, Perović, Milka, Šaponjić, Jasna, "Alterations of Sleep and Sleep Oscillations in the Hemiparkinsonian Rat." in Frontiers in Neuroscience, 13 (2019):148,
https://doi.org/10.3389/fnins.2019.00148 . .

TY  - JOUR
AU  - Ćirić, Jelena
AU  - Lazić, Katarina
AU  - Kapor, Slobodan
AU  - Perović, Milka
AU  - Petrović, Jelena
AU  - Pešić, Vesna
AU  - Kanazir, Selma
AU  - Šaponjić, Jasna
PY  - 2018
UR  - http://linkinghub.elsevier.com/retrieve/pii/S0166432817312391
UR  - http://www.ncbi.nlm.nih.gov/pubmed/29170000
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3361
AB  - In order to find out the possible earliest biomarkers of Parkinson's disease (PD) cholinopathy, we followed the impact of bilateral pedunculopontine tegmental nucleus (PPT) lesion in rat on: the cortical and hippocampal sleep/wake states architectures, all sleep states related EEG microstructures, sleep spindles, the basal and stimulated locomotor activity. Sleep and basal locomotor activity in adult Wistar rats were followed during their inactive circadian phase, and throughout the same aging period. The bilateral PPT lesions were done by 0.1M ibotenic acid (IBO) during the surgical procedure for implantation of the electroencephalographic (EEG) and electromyographic (EMG) electrodes for chronic sleep recording. The cholinergic neuronal loss was identified by NADPH - diaphorase histochemistry. After all sleep and behavioral recording sessions, the locomotor activity was stimulated by d-amphetamine (d-AMPH) and the neuronal activity of striatum was followed by c-Fos immunolabeling. Impaired cholinergic innervation from the PPT was expressed earlier as sleep disorder then as movement disorder, and it was the earliest and long-lasting at hippocampal and thalamo-cortical level, and followed by a delayed "hypokinesia". This severe impact of a tonically impaired PPT cholinergic innervation was evidenced as the cholinergic interneuronal loss of the caudate putamen and as a suppressed c-Fos expression after stimulation by d-AMPH. In order how they occurred, the hippocampal non rapid eye movement (NREM) sleep disorder, altered high voltage sleep spindle (HVS) dynamics during rapid eye movement (REM) sleep in the hippocampus and motor cortex, and "hypokinesia" may serve as the biomarkers of PD cholinopathy onset and progression.
T2  - Behavioural Brain Research
T1  - Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat
VL  - 339
DO  - 10.1016/j.bbr.2017.11.021
SP  - 79
EP  - 92
ER  - 

@article{
author = "Ćirić, Jelena and Lazić, Katarina and Kapor, Slobodan and Perović, Milka and Petrović, Jelena and Pešić, Vesna and Kanazir, Selma and Šaponjić, Jasna",
year = "2018",
abstract = "In order to find out the possible earliest biomarkers of Parkinson's disease (PD) cholinopathy, we followed the impact of bilateral pedunculopontine tegmental nucleus (PPT) lesion in rat on: the cortical and hippocampal sleep/wake states architectures, all sleep states related EEG microstructures, sleep spindles, the basal and stimulated locomotor activity. Sleep and basal locomotor activity in adult Wistar rats were followed during their inactive circadian phase, and throughout the same aging period. The bilateral PPT lesions were done by 0.1M ibotenic acid (IBO) during the surgical procedure for implantation of the electroencephalographic (EEG) and electromyographic (EMG) electrodes for chronic sleep recording. The cholinergic neuronal loss was identified by NADPH - diaphorase histochemistry. After all sleep and behavioral recording sessions, the locomotor activity was stimulated by d-amphetamine (d-AMPH) and the neuronal activity of striatum was followed by c-Fos immunolabeling. Impaired cholinergic innervation from the PPT was expressed earlier as sleep disorder then as movement disorder, and it was the earliest and long-lasting at hippocampal and thalamo-cortical level, and followed by a delayed "hypokinesia". This severe impact of a tonically impaired PPT cholinergic innervation was evidenced as the cholinergic interneuronal loss of the caudate putamen and as a suppressed c-Fos expression after stimulation by d-AMPH. In order how they occurred, the hippocampal non rapid eye movement (NREM) sleep disorder, altered high voltage sleep spindle (HVS) dynamics during rapid eye movement (REM) sleep in the hippocampus and motor cortex, and "hypokinesia" may serve as the biomarkers of PD cholinopathy onset and progression.",
journal = "Behavioural Brain Research",
title = "Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat",
volume = "339",
doi = "10.1016/j.bbr.2017.11.021",
pages = "79-92"
}

Ćirić, J., Lazić, K., Kapor, S., Perović, M., Petrović, J., Pešić, V., Kanazir, S.,& Šaponjić, J.. (2018). Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat. in Behavioural Brain Research, 339, 79-92.
https://doi.org/10.1016/j.bbr.2017.11.021

Ćirić J, Lazić K, Kapor S, Perović M, Petrović J, Pešić V, Kanazir S, Šaponjić J. Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat. in Behavioural Brain Research. 2018;339:79-92.
doi:10.1016/j.bbr.2017.11.021 .

Ćirić, Jelena, Lazić, Katarina, Kapor, Slobodan, Perović, Milka, Petrović, Jelena, Pešić, Vesna, Kanazir, Selma, Šaponjić, Jasna, "Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat" in Behavioural Brain Research, 339 (2018):79-92,
https://doi.org/10.1016/j.bbr.2017.11.021 . .

TY  - JOUR
AU  - Ćirić, Jelena
AU  - Lazić, Katarina
AU  - Kapor, Slobodan
AU  - Perović, Milka
AU  - Petrović, Jelena
AU  - Pešić, Vesna
AU  - Kanazir, Selma
AU  - Šaponjić, Jasna
PY  - 2018
UR  - http://linkinghub.elsevier.com/retrieve/pii/S0166432817312391
UR  - http://www.ncbi.nlm.nih.gov/pubmed/29170000
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2932
AB  - In order to find out the possible earliest biomarkers of Parkinson's disease (PD) cholinopathy, we followed the impact of bilateral pedunculopontine tegmental nucleus (PPT) lesion in rat on: the cortical and hippocampal sleep/wake states architectures, all sleep states related EEG microstructures, sleep spindles, the basal and stimulated locomotor activity. Sleep and basal locomotor activity in adult Wistar rats were followed during their inactive circadian phase, and throughout the same aging period. The bilateral PPT lesions were done by 0.1M ibotenic acid (IBO) during the surgical procedure for implantation of the electroencephalographic (EEG) and electromyographic (EMG) electrodes for chronic sleep recording. The cholinergic neuronal loss was identified by NADPH - diaphorase histochemistry. After all sleep and behavioral recording sessions, the locomotor activity was stimulated by d-amphetamine (d-AMPH) and the neuronal activity of striatum was followed by c-Fos immunolabeling. Impaired cholinergic innervation from the PPT was expressed earlier as sleep disorder then as movement disorder, and it was the earliest and long-lasting at hippocampal and thalamo-cortical level, and followed by a delayed "hypokinesia". This severe impact of a tonically impaired PPT cholinergic innervation was evidenced as the cholinergic interneuronal loss of the caudate putamen and as a suppressed c-Fos expression after stimulation by d-AMPH. In order how they occurred, the hippocampal non rapid eye movement (NREM) sleep disorder, altered high voltage sleep spindle (HVS) dynamics during rapid eye movement (REM) sleep in the hippocampus and motor cortex, and "hypokinesia" may serve as the biomarkers of PD cholinopathy onset and progression.
T2  - Behavioural Brain Research
T1  - Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat
VL  - 339
DO  - 10.1016/j.bbr.2017.11.021
SP  - 79
EP  - 92
ER  - 

@article{
author = "Ćirić, Jelena and Lazić, Katarina and Kapor, Slobodan and Perović, Milka and Petrović, Jelena and Pešić, Vesna and Kanazir, Selma and Šaponjić, Jasna",
year = "2018",
abstract = "In order to find out the possible earliest biomarkers of Parkinson's disease (PD) cholinopathy, we followed the impact of bilateral pedunculopontine tegmental nucleus (PPT) lesion in rat on: the cortical and hippocampal sleep/wake states architectures, all sleep states related EEG microstructures, sleep spindles, the basal and stimulated locomotor activity. Sleep and basal locomotor activity in adult Wistar rats were followed during their inactive circadian phase, and throughout the same aging period. The bilateral PPT lesions were done by 0.1M ibotenic acid (IBO) during the surgical procedure for implantation of the electroencephalographic (EEG) and electromyographic (EMG) electrodes for chronic sleep recording. The cholinergic neuronal loss was identified by NADPH - diaphorase histochemistry. After all sleep and behavioral recording sessions, the locomotor activity was stimulated by d-amphetamine (d-AMPH) and the neuronal activity of striatum was followed by c-Fos immunolabeling. Impaired cholinergic innervation from the PPT was expressed earlier as sleep disorder then as movement disorder, and it was the earliest and long-lasting at hippocampal and thalamo-cortical level, and followed by a delayed "hypokinesia". This severe impact of a tonically impaired PPT cholinergic innervation was evidenced as the cholinergic interneuronal loss of the caudate putamen and as a suppressed c-Fos expression after stimulation by d-AMPH. In order how they occurred, the hippocampal non rapid eye movement (NREM) sleep disorder, altered high voltage sleep spindle (HVS) dynamics during rapid eye movement (REM) sleep in the hippocampus and motor cortex, and "hypokinesia" may serve as the biomarkers of PD cholinopathy onset and progression.",
journal = "Behavioural Brain Research",
title = "Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat",
volume = "339",
doi = "10.1016/j.bbr.2017.11.021",
pages = "79-92"
}

Ćirić, J., Lazić, K., Kapor, S., Perović, M., Petrović, J., Pešić, V., Kanazir, S.,& Šaponjić, J.. (2018). Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat. in Behavioural Brain Research, 339, 79-92.
https://doi.org/10.1016/j.bbr.2017.11.021

Ćirić J, Lazić K, Kapor S, Perović M, Petrović J, Pešić V, Kanazir S, Šaponjić J. Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat. in Behavioural Brain Research. 2018;339:79-92.
doi:10.1016/j.bbr.2017.11.021 .

Ćirić, Jelena, Lazić, Katarina, Kapor, Slobodan, Perović, Milka, Petrović, Jelena, Pešić, Vesna, Kanazir, Selma, Šaponjić, Jasna, "Sleep disorder and altered locomotor activity as biomarkers of the Parkinson's disease cholinopathy in rat" in Behavioural Brain Research, 339 (2018):79-92,
https://doi.org/10.1016/j.bbr.2017.11.021 . .

TY  - JOUR
AU  - Lazić, Katarina
AU  - Ćirić, Jelena
AU  - Šaponjić, Jasna
PY  - 2018
UR  - http://doi.wiley.com/10.1111/jsr.12758
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3140
AB  - On the basis of our previous studies and the important role of the thalamo-cortical network in states of unconsciousness, such as anaesthesia and sleep, and in sleep spindles generation, we investigated sleep spindles (SS) and high-voltage sleep spindle (HVS) dynamics during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep following different types of general anaesthesia in both physiological controls and in a rat model of Parkinson's disease (PD) cholinopathy, to follow the impact of anaesthesia on post-anaesthesia sleep at the thalamo-cortical level through an altered sleep spindle dynamics. We recorded 6 hr of spontaneous sleep in all rats, both before and 48 hr after ketamine/diazepam or pentobarbital anaesthesia, and we used 1 hr of NREM or REM sleep from each to validate visually the automatically detected SS or HVS for their extraction and analysis. In the controls, SS occurred mainly during NREM, whereas HVS occurred only during REM sleep. Ketamine/diazepam anaesthesia promoted HVS, prolonged SS during NREM, induced HVS of increased frequency during REM, and increased SS/HVS densities during REM versus NREM sleep. Pentobarbital anaesthesia decreased the frequency of SS during NREM and the HVS density during REM sleep. Although the pedunculopontine tegmental nucleus lesion prolonged SS only during NREM sleep, in these rats, ketamine/diazepam anaesthesia suppressed HVS during both sleep states, whereas pentobarbital anaesthesia promoted HVS during REM sleep. The different impacts of two anaesthetic regimens on the thalamo-cortical regulatory network are expressed through their distinct sleep spindle generation and dynamics that are dependent on the NREM and REM state regulatory neuronal substrate.
T2  - Journal of Sleep Research
T1  - Sleep spindle dynamics during NREM and REM sleep following distinct general anaesthesia in control rats and in a rat model of Parkinson’s disease cholinopathy
DO  - 10.1111/jsr.12758
ER  - 

@article{
author = "Lazić, Katarina and Ćirić, Jelena and Šaponjić, Jasna",
year = "2018",
abstract = "On the basis of our previous studies and the important role of the thalamo-cortical network in states of unconsciousness, such as anaesthesia and sleep, and in sleep spindles generation, we investigated sleep spindles (SS) and high-voltage sleep spindle (HVS) dynamics during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep following different types of general anaesthesia in both physiological controls and in a rat model of Parkinson's disease (PD) cholinopathy, to follow the impact of anaesthesia on post-anaesthesia sleep at the thalamo-cortical level through an altered sleep spindle dynamics. We recorded 6 hr of spontaneous sleep in all rats, both before and 48 hr after ketamine/diazepam or pentobarbital anaesthesia, and we used 1 hr of NREM or REM sleep from each to validate visually the automatically detected SS or HVS for their extraction and analysis. In the controls, SS occurred mainly during NREM, whereas HVS occurred only during REM sleep. Ketamine/diazepam anaesthesia promoted HVS, prolonged SS during NREM, induced HVS of increased frequency during REM, and increased SS/HVS densities during REM versus NREM sleep. Pentobarbital anaesthesia decreased the frequency of SS during NREM and the HVS density during REM sleep. Although the pedunculopontine tegmental nucleus lesion prolonged SS only during NREM sleep, in these rats, ketamine/diazepam anaesthesia suppressed HVS during both sleep states, whereas pentobarbital anaesthesia promoted HVS during REM sleep. The different impacts of two anaesthetic regimens on the thalamo-cortical regulatory network are expressed through their distinct sleep spindle generation and dynamics that are dependent on the NREM and REM state regulatory neuronal substrate.",
journal = "Journal of Sleep Research",
title = "Sleep spindle dynamics during NREM and REM sleep following distinct general anaesthesia in control rats and in a rat model of Parkinson’s disease cholinopathy",
doi = "10.1111/jsr.12758"
}

Lazić, K., Ćirić, J.,& Šaponjić, J.. (2018). Sleep spindle dynamics during NREM and REM sleep following distinct general anaesthesia in control rats and in a rat model of Parkinson’s disease cholinopathy. in Journal of Sleep Research.
https://doi.org/10.1111/jsr.12758

Lazić K, Ćirić J, Šaponjić J. Sleep spindle dynamics during NREM and REM sleep following distinct general anaesthesia in control rats and in a rat model of Parkinson’s disease cholinopathy. in Journal of Sleep Research. 2018;.
doi:10.1111/jsr.12758 .

Lazić, Katarina, Ćirić, Jelena, Šaponjić, Jasna, "Sleep spindle dynamics during NREM and REM sleep following distinct general anaesthesia in control rats and in a rat model of Parkinson’s disease cholinopathy" in Journal of Sleep Research (2018),
https://doi.org/10.1111/jsr.12758 . .

TY  - THES
AU  - Lazić, Katarina
PY  - 2017
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=5775
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:17640/bdef:Content/download
UR  - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=1025173682
UR  - http://nardus.mpn.gov.rs/123456789/9462
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3295
AB  - U ovoj doktorskoj disertaciji ispitivan je uticaj ketamin/diazepam i pentobarbital opšte anestezije na EEG mikrostrukturu i obrazac disanja tokom anestezije, kao i na arhitekturu spavanja i strukturu prelaznih stanja, EEG mikrostrukturu i dinamiku epizoda svih faza spavanja nakon anestezije, kako u fiziološkim kontrolama, tako i u eksperimentalnom modelu holinergičke neuropatologije Parkinsonove bolesti (bilateralna lezija PPT jedra).Rezultati ove doktorske disertacije pokazali su da je ketamin/diazepam anestezija operativnog nivoa izazvala ozbiljan poremećaj respiratornog obrasca i EEG mikrostrukture tokom anestezije. Međutim, jednako vreme potrebno za uspostavljanje stabilne anestezije u pacova sa bilateralnom lezijom PPT jedra kao i dugotrajni suprimirajući efekti na povećanu NREM beta i teta amplitudu (elektrofiziološki markeri deficita holinergičkih neurona PPT jedra) nakon anestezije, ukazuju da je ova anestezija potencijalno povoljnija, kako za ulazak u anesteziju, tako i za NREM fazu spavanja nakon operativnih zahvata kod gerijatrijskih pacijenata, kao i pacijenata obolelih od Parkinsonove i Alchajmerove bolesti.Nasuprot ketamin/diazepam anesteziji, pentobarbital anestezija ima povoljnije dejstvo na REM fazu spavanja nakon anestezije, kako kod fizioloških kontrola, tako i u eksperimentalnom modelu holinergičke neuropatologije Parkinsonove bolesti na osnovu: dugotrajnih poremećaja REM spavanja i strukture prelaznih stanja kod fizioloških kontrola koje izaziva ketamin/diazepam anestezija; suprimirajućih efekata obe anestezije operativnog nivoa na produženu REM/REM1 fazu spavanja i poremećaj njihove EEG mikrostrukture kod bilateralne lezije PPT jedra; suprimirajućeg efekta pentobarbital anestezije na povećani broj NREM/REM/NREM prelaza uzrokovanih lezijom PPT jedra; kao i na osnovu EEG mikrostrukture tokom stabilne pentobarbital anestezije, koja se ne razlikuje u poređenju PPT lezije i fiziološke kontrole.
AB  - The aim of this doctoral dissertation was to follow the impact of ketamine/diazepam and pentobarbital anesthesia on the EEG microstructure and respiratory pattern during anesthesia, and on the post-anesthesia sleep/wake states architecture and transition structure, EEG microstructure across sleep, and all the sleep state episodes dynamics in the physiological condition, as well as during the PPT cholinergic neuropathology (the experimental model of Parkinson’s disease cholinergic neuropathology). Ketamine/diazepam anesthesia induces more alterations in the EEG microstructure and respiratory pattern than does the pentobarbital anesthesia in the PPT lesioned rats. In addition, the equal time required to establish an anesthetized state in the PPT lesioned vs. control rats, and the long-term suppressive effect on augmented NREM beta and theta amplitudes (the hallmarks of PPT cholinergic neuronal loss in rat) suggest ketamine/diazepam anesthesia as potentially more beneficial both for anesthesia induction and for post-anesthesia NREM sleep in the surgical procedures of the elderly, and Parkinson’s, and Alzheimer’s patients. In contrast to the ketamine/diazepam anesthesia the pentobarbital anesthesia is much more beneficial for the post-anesthesia REM sleep in physiological conditions as well as during the PPT cholinergic neuropathology on the basis of: the long-lasting REM sleep and transition structure disorders in physiological controls, induced by the ketamine/diazepam; the abolishing effects of both anesthetic regimens on the post-anesthesia prolonged REM/REM1 sleep and on their EEG microstructure disorders in the PPT lesioned rats; the abolishing effect of pentobarbital on the increased NREM/REM/NREM transitions, caused by the PPT lesion; and the equal EEG microstructure during stable pentobarbital anesthesia in the PPT lesioned rats versus controls.
PB  - Belgrade: University of Belgrade, Faculty of Biology
T2  - University of Belgrade, Faculty of Biology
T1  - Uticaj opšte anestezije na spavanje u eksperimentalnom modelu holinergičke neuropatologije Parkinsonove bolesti - mogući rizici postoperativnog oporavka
T1  - Impact of general anesthesia on sleep in the experimental model of Parkison's disease neuropathology - possible risks of postoperative recovery
SP  - 1
EP  - 106
UR  - https://hdl.handle.net/21.15107/rcub_nardus_9462
ER  - 

@phdthesis{
author = "Lazić, Katarina",
year = "2017",
abstract = "U ovoj doktorskoj disertaciji ispitivan je uticaj ketamin/diazepam i pentobarbital opšte anestezije na EEG mikrostrukturu i obrazac disanja tokom anestezije, kao i na arhitekturu spavanja i strukturu prelaznih stanja, EEG mikrostrukturu i dinamiku epizoda svih faza spavanja nakon anestezije, kako u fiziološkim kontrolama, tako i u eksperimentalnom modelu holinergičke neuropatologije Parkinsonove bolesti (bilateralna lezija PPT jedra).Rezultati ove doktorske disertacije pokazali su da je ketamin/diazepam anestezija operativnog nivoa izazvala ozbiljan poremećaj respiratornog obrasca i EEG mikrostrukture tokom anestezije. Međutim, jednako vreme potrebno za uspostavljanje stabilne anestezije u pacova sa bilateralnom lezijom PPT jedra kao i dugotrajni suprimirajući efekti na povećanu NREM beta i teta amplitudu (elektrofiziološki markeri deficita holinergičkih neurona PPT jedra) nakon anestezije, ukazuju da je ova anestezija potencijalno povoljnija, kako za ulazak u anesteziju, tako i za NREM fazu spavanja nakon operativnih zahvata kod gerijatrijskih pacijenata, kao i pacijenata obolelih od Parkinsonove i Alchajmerove bolesti.Nasuprot ketamin/diazepam anesteziji, pentobarbital anestezija ima povoljnije dejstvo na REM fazu spavanja nakon anestezije, kako kod fizioloških kontrola, tako i u eksperimentalnom modelu holinergičke neuropatologije Parkinsonove bolesti na osnovu: dugotrajnih poremećaja REM spavanja i strukture prelaznih stanja kod fizioloških kontrola koje izaziva ketamin/diazepam anestezija; suprimirajućih efekata obe anestezije operativnog nivoa na produženu REM/REM1 fazu spavanja i poremećaj njihove EEG mikrostrukture kod bilateralne lezije PPT jedra; suprimirajućeg efekta pentobarbital anestezije na povećani broj NREM/REM/NREM prelaza uzrokovanih lezijom PPT jedra; kao i na osnovu EEG mikrostrukture tokom stabilne pentobarbital anestezije, koja se ne razlikuje u poređenju PPT lezije i fiziološke kontrole., The aim of this doctoral dissertation was to follow the impact of ketamine/diazepam and pentobarbital anesthesia on the EEG microstructure and respiratory pattern during anesthesia, and on the post-anesthesia sleep/wake states architecture and transition structure, EEG microstructure across sleep, and all the sleep state episodes dynamics in the physiological condition, as well as during the PPT cholinergic neuropathology (the experimental model of Parkinson’s disease cholinergic neuropathology). Ketamine/diazepam anesthesia induces more alterations in the EEG microstructure and respiratory pattern than does the pentobarbital anesthesia in the PPT lesioned rats. In addition, the equal time required to establish an anesthetized state in the PPT lesioned vs. control rats, and the long-term suppressive effect on augmented NREM beta and theta amplitudes (the hallmarks of PPT cholinergic neuronal loss in rat) suggest ketamine/diazepam anesthesia as potentially more beneficial both for anesthesia induction and for post-anesthesia NREM sleep in the surgical procedures of the elderly, and Parkinson’s, and Alzheimer’s patients. In contrast to the ketamine/diazepam anesthesia the pentobarbital anesthesia is much more beneficial for the post-anesthesia REM sleep in physiological conditions as well as during the PPT cholinergic neuropathology on the basis of: the long-lasting REM sleep and transition structure disorders in physiological controls, induced by the ketamine/diazepam; the abolishing effects of both anesthetic regimens on the post-anesthesia prolonged REM/REM1 sleep and on their EEG microstructure disorders in the PPT lesioned rats; the abolishing effect of pentobarbital on the increased NREM/REM/NREM transitions, caused by the PPT lesion; and the equal EEG microstructure during stable pentobarbital anesthesia in the PPT lesioned rats versus controls.",
publisher = "Belgrade: University of Belgrade, Faculty of Biology",
journal = "University of Belgrade, Faculty of Biology",
title = "Uticaj opšte anestezije na spavanje u eksperimentalnom modelu holinergičke neuropatologije Parkinsonove bolesti - mogući rizici postoperativnog oporavka, Impact of general anesthesia on sleep in the experimental model of Parkison's disease neuropathology - possible risks of postoperative recovery",
pages = "1-106",
url = "https://hdl.handle.net/21.15107/rcub_nardus_9462"
}

Lazić, K.. (2017). Uticaj opšte anestezije na spavanje u eksperimentalnom modelu holinergičke neuropatologije Parkinsonove bolesti - mogući rizici postoperativnog oporavka. in University of Belgrade, Faculty of Biology
Belgrade: University of Belgrade, Faculty of Biology., 1-106.
https://hdl.handle.net/21.15107/rcub_nardus_9462

Lazić K. Uticaj opšte anestezije na spavanje u eksperimentalnom modelu holinergičke neuropatologije Parkinsonove bolesti - mogući rizici postoperativnog oporavka. in University of Belgrade, Faculty of Biology. 2017;:1-106.
https://hdl.handle.net/21.15107/rcub_nardus_9462 .

Lazić, Katarina, "Uticaj opšte anestezije na spavanje u eksperimentalnom modelu holinergičke neuropatologije Parkinsonove bolesti - mogući rizici postoperativnog oporavka" in University of Belgrade, Faculty of Biology (2017):1-106,
https://hdl.handle.net/21.15107/rcub_nardus_9462 .

TY  - THES
AU  - Ćirić, Jelena
PY  - 2017
UR  - http://uvidok.rcub.bg.ac.rs/handle/123456789/1886
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2801
AB  - The aim of the present doctoral dissertation was to evaluate the impact
of aging during sleep in the rat models of Alzheimer’s and Parkinson’s disease
cholinergic neuropathology, and to determine the possible different and earlier
onset of age-related sleep disorder during healthy aging and aging with the
neurodegenerative diseases.
We used the bilateral nucleus basalis (NB) and nucleus pedunculopontinus
tegmentalis (PPT) lesioned rats as the in vivo models of functionally distinct
cholinergic neuropathology, and we followed the impact of aging on sleep
architecture, the electroencephalographic (EEG) microstructure and motor
control across sleep/wake states.
We evidenced the topographically distinct impact of healthy aging on
sleep architecture and motor control within the sensorimotor (SMCx) vs. motor
cortex (MCx). Whereas healthy aging consistently altered only the SMCx sleep
architecture, it increased the delta and beta cortical drives from both cortices
during Wake, but only through the MCx drive during rapid eye movement
sleep (REM).
Our results have shown for the first time that the earliest signs of aging
during distinct cholinergic neuropathology were expressed through a different
and topographically specific EEG microstructure during REM. EEG delta
amplitude attenuation within the SMCx was the earliest sign of aging in the NB
lesion, whereas EEG sigma amplitude augmentation within the MCx was the
earliest sign of aging in the PPT lesion during REM. In addition, aging was
differently expressed through the SMCx drive alterations, but it was commonly
expressed through the MCx drive alterations during all sleep/wake states.
This doctoral dissertation provided for the first time an evidence of
distinct REM sleep disorders and sleep state related cortical drives as the signs
of aging onset during functionally distinct cholinergic neuropathologies.
AB  - Cilj ove doktorske disertacije bio je da ispita uticaj starenja na spavanje u
eksperimentalnim modelima holinergičke neuropatologije Alchajmerove i
Parkinsonove bolesti, i da pronađe najranije znake poremećaja spavanja u
fiziološkom starenju i u starenju sa neurodegenerativnim bolestima.
Uticaj starenja na arhitekturu spavanja, elektroencefalografsku (EEG)
mikrostrukturu i motornu kontrolu, u toku svake faze spavanja, je praćen u
eksperimentalnim modelima bilateralnih oštećenja jedara nucleus basalis (NB) i
nucleus pedunculopontinus tegmentalis (PPT) u pacova, kao eksperimentalnim in
vivo modelima funkcionalno različitih holinergičkih neuropatologija.
Fiziološko starenje dovodi do topografski različitih promena arhitekture
spavanja i motorne kontrole iz senzomotorne kore (SMCx) u odnosu na
motornu koru (MCx). Pored promena arhitekture spavanja koje su se javile
samo u SMCx, fiziološko starenje dovodi i do povećanja propagacije delta i beta
oscilacija iz obe kore za vreme budnosti, ali samo iz MCx za vreme REM faze
spavanja.
Najraniji znaci starenja u eksperimentalnim modelima funkcionalno
različitih holinergičkih neuropatologija, dokazani po prvi put, predstavljaju
topografski specifične razlike u EEG mikrostrukturi za vreme REM faze
spavanja. Smanjenje delta EEG relativne amplitude u SMCx predstavlja najraniji
znak starenja kod NB lediranih pacova, dok povećanje sigma EEG relativne
amplitude u MCx predstavlja najraniji znak starenja kod PPT lediranih pacova,
za vreme REM faze spavanja. Pored toga, starenjem izazvane promene su
različito izražene kroz mišićnu kontrolu iz SMCx, a istovremeno i istovetno
izražene iz MCx u toku svih faza spavanja.
Ova doktorska disertacija je po prvi put dokazala različite poremećaje
REM faze spavanja i motorne kontrole u toku spavanja, kao najranije znake
početka starenja u funkcionalno različitim holinergičkim neuropatologijama.
PB  - University of Belgrade, Faculty of Biology
T2  - University of Belgrade, Faculty of Biology
T1  - Rani elektrofiziološki znaci poremećaja spavanja i motorne kontrole u starenju pacova sa neurodegeneracijom holinergičkih neurona
T1  - Early electrophysiological markers of the sleep and motor control disorders during aging in rats with neurodegeneration of the cholinergic neurons
SP  - 1
EP  - 147
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_2801
ER  - 

@phdthesis{
author = "Ćirić, Jelena",
year = "2017",
abstract = "The aim of the present doctoral dissertation was to evaluate the impact
of aging during sleep in the rat models of Alzheimer’s and Parkinson’s disease
cholinergic neuropathology, and to determine the possible different and earlier
onset of age-related sleep disorder during healthy aging and aging with the
neurodegenerative diseases.
We used the bilateral nucleus basalis (NB) and nucleus pedunculopontinus
tegmentalis (PPT) lesioned rats as the in vivo models of functionally distinct
cholinergic neuropathology, and we followed the impact of aging on sleep
architecture, the electroencephalographic (EEG) microstructure and motor
control across sleep/wake states.
We evidenced the topographically distinct impact of healthy aging on
sleep architecture and motor control within the sensorimotor (SMCx) vs. motor
cortex (MCx). Whereas healthy aging consistently altered only the SMCx sleep
architecture, it increased the delta and beta cortical drives from both cortices
during Wake, but only through the MCx drive during rapid eye movement
sleep (REM).
Our results have shown for the first time that the earliest signs of aging
during distinct cholinergic neuropathology were expressed through a different
and topographically specific EEG microstructure during REM. EEG delta
amplitude attenuation within the SMCx was the earliest sign of aging in the NB
lesion, whereas EEG sigma amplitude augmentation within the MCx was the
earliest sign of aging in the PPT lesion during REM. In addition, aging was
differently expressed through the SMCx drive alterations, but it was commonly
expressed through the MCx drive alterations during all sleep/wake states.
This doctoral dissertation provided for the first time an evidence of
distinct REM sleep disorders and sleep state related cortical drives as the signs
of aging onset during functionally distinct cholinergic neuropathologies., Cilj ove doktorske disertacije bio je da ispita uticaj starenja na spavanje u
eksperimentalnim modelima holinergičke neuropatologije Alchajmerove i
Parkinsonove bolesti, i da pronađe najranije znake poremećaja spavanja u
fiziološkom starenju i u starenju sa neurodegenerativnim bolestima.
Uticaj starenja na arhitekturu spavanja, elektroencefalografsku (EEG)
mikrostrukturu i motornu kontrolu, u toku svake faze spavanja, je praćen u
eksperimentalnim modelima bilateralnih oštećenja jedara nucleus basalis (NB) i
nucleus pedunculopontinus tegmentalis (PPT) u pacova, kao eksperimentalnim in
vivo modelima funkcionalno različitih holinergičkih neuropatologija.
Fiziološko starenje dovodi do topografski različitih promena arhitekture
spavanja i motorne kontrole iz senzomotorne kore (SMCx) u odnosu na
motornu koru (MCx). Pored promena arhitekture spavanja koje su se javile
samo u SMCx, fiziološko starenje dovodi i do povećanja propagacije delta i beta
oscilacija iz obe kore za vreme budnosti, ali samo iz MCx za vreme REM faze
spavanja.
Najraniji znaci starenja u eksperimentalnim modelima funkcionalno
različitih holinergičkih neuropatologija, dokazani po prvi put, predstavljaju
topografski specifične razlike u EEG mikrostrukturi za vreme REM faze
spavanja. Smanjenje delta EEG relativne amplitude u SMCx predstavlja najraniji
znak starenja kod NB lediranih pacova, dok povećanje sigma EEG relativne
amplitude u MCx predstavlja najraniji znak starenja kod PPT lediranih pacova,
za vreme REM faze spavanja. Pored toga, starenjem izazvane promene su
različito izražene kroz mišićnu kontrolu iz SMCx, a istovremeno i istovetno
izražene iz MCx u toku svih faza spavanja.
Ova doktorska disertacija je po prvi put dokazala različite poremećaje
REM faze spavanja i motorne kontrole u toku spavanja, kao najranije znake
početka starenja u funkcionalno različitim holinergičkim neuropatologijama.",
publisher = "University of Belgrade, Faculty of Biology",
journal = "University of Belgrade, Faculty of Biology",
title = "Rani elektrofiziološki znaci poremećaja spavanja i motorne kontrole u starenju pacova sa neurodegeneracijom holinergičkih neurona, Early electrophysiological markers of the sleep and motor control disorders during aging in rats with neurodegeneration of the cholinergic neurons",
pages = "1-147",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_2801"
}

Ćirić, J.. (2017). Rani elektrofiziološki znaci poremećaja spavanja i motorne kontrole u starenju pacova sa neurodegeneracijom holinergičkih neurona. in University of Belgrade, Faculty of Biology
University of Belgrade, Faculty of Biology., 1-147.
https://hdl.handle.net/21.15107/rcub_ibiss_2801

Ćirić J. Rani elektrofiziološki znaci poremećaja spavanja i motorne kontrole u starenju pacova sa neurodegeneracijom holinergičkih neurona. in University of Belgrade, Faculty of Biology. 2017;:1-147.
https://hdl.handle.net/21.15107/rcub_ibiss_2801 .

Ćirić, Jelena, "Rani elektrofiziološki znaci poremećaja spavanja i motorne kontrole u starenju pacova sa neurodegeneracijom holinergičkih neurona" in University of Belgrade, Faculty of Biology (2017):1-147,
https://hdl.handle.net/21.15107/rcub_ibiss_2801 .

TY  - JOUR
AU  - Ćirić, Jelena
AU  - Lazić, Katarina
AU  - Petrović, Jelena
AU  - Kalauzi, A
AU  - Šaponjić, Jasna
PY  - 2017
UR  - http://www.oatext.com/sleep-spindles-as-an-early-biomarker-of-rem-sleep-disorder-in-a-rat-model-of-parkinsons-disease-cholinopathy.php
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3296
AB  - Rhythmic oscillations of neuronal populations, generated by different mechanisms, are present at several levels of the central nervous system and serve many important physiological or reflect pathological functions. Understanding the role of brain oscillations as possible biomarkers of brain function and plasticity is still a challenge, and despite extensive research, their role is still not well established. We recently demonstrated that the hallmarks of earlier aging onset during impaired thalamo-cortical cholinergic innervation (in a rat model of Parkinson’s disease cholinopathy) were consistently expressed, from 3 and one half to 5 and one half months of age, through increased electroencephalographic (EEG) sigma activity amplitude during rapid eye movement (REM) sleep, as a unique aging induced REM sleep phenomenon. In addition, there was altered motor cortical drive during non-rapid-eye-movement (NREM) and REM sleep. In order to explain this new aging-induced REM sleep phenomenon, we analyzed possible differences between control REM sleep spindle activity and REM sleep spindle activity at the onset of REM sleep “enriched“ with sigma activity (at 4 and one half months of age), following bilateral pedunculopontine tegmental nucleus (PPT) cholinergic neuronal loss in the rat. We analzyed differences in spindle density, duration, and frequency. We demonstrated in young adult Wistar rats with the severely impaired PPT cholinergic innervation the alterations in sleep spindle dynamics and pattern during REM sleep in the motor cortex as the earliest biomarkers for the onset of their altered aging processes.
T2  - Translational Brain Rhythmicity
T1  - Sleep spindles as an early biomarker of REM sleep disorder in a rat model of Parkinson’s disease cholinopathy
IS  - 1
VL  - 2
DO  - 10.15761/TBR.1000111
SP  - 1
EP  - 11
ER  - 

@article{
author = "Ćirić, Jelena and Lazić, Katarina and Petrović, Jelena and Kalauzi, A and Šaponjić, Jasna",
year = "2017",
abstract = "Rhythmic oscillations of neuronal populations, generated by different mechanisms, are present at several levels of the central nervous system and serve many important physiological or reflect pathological functions. Understanding the role of brain oscillations as possible biomarkers of brain function and plasticity is still a challenge, and despite extensive research, their role is still not well established. We recently demonstrated that the hallmarks of earlier aging onset during impaired thalamo-cortical cholinergic innervation (in a rat model of Parkinson’s disease cholinopathy) were consistently expressed, from 3 and one half to 5 and one half months of age, through increased electroencephalographic (EEG) sigma activity amplitude during rapid eye movement (REM) sleep, as a unique aging induced REM sleep phenomenon. In addition, there was altered motor cortical drive during non-rapid-eye-movement (NREM) and REM sleep. In order to explain this new aging-induced REM sleep phenomenon, we analyzed possible differences between control REM sleep spindle activity and REM sleep spindle activity at the onset of REM sleep “enriched“ with sigma activity (at 4 and one half months of age), following bilateral pedunculopontine tegmental nucleus (PPT) cholinergic neuronal loss in the rat. We analzyed differences in spindle density, duration, and frequency. We demonstrated in young adult Wistar rats with the severely impaired PPT cholinergic innervation the alterations in sleep spindle dynamics and pattern during REM sleep in the motor cortex as the earliest biomarkers for the onset of their altered aging processes.",
journal = "Translational Brain Rhythmicity",
title = "Sleep spindles as an early biomarker of REM sleep disorder in a rat model of Parkinson’s disease cholinopathy",
number = "1",
volume = "2",
doi = "10.15761/TBR.1000111",
pages = "1-11"
}

Ćirić, J., Lazić, K., Petrović, J., Kalauzi, A.,& Šaponjić, J.. (2017). Sleep spindles as an early biomarker of REM sleep disorder in a rat model of Parkinson’s disease cholinopathy. in Translational Brain Rhythmicity, 2(1), 1-11.
https://doi.org/10.15761/TBR.1000111

Ćirić J, Lazić K, Petrović J, Kalauzi A, Šaponjić J. Sleep spindles as an early biomarker of REM sleep disorder in a rat model of Parkinson’s disease cholinopathy. in Translational Brain Rhythmicity. 2017;2(1):1-11.
doi:10.15761/TBR.1000111 .

Ćirić, Jelena, Lazić, Katarina, Petrović, Jelena, Kalauzi, A, Šaponjić, Jasna, "Sleep spindles as an early biomarker of REM sleep disorder in a rat model of Parkinson’s disease cholinopathy" in Translational Brain Rhythmicity, 2, no. 1 (2017):1-11,
https://doi.org/10.15761/TBR.1000111 . .

TY  - JOUR
AU  - Lazić, Katarina
AU  - Petrović, Jelena
AU  - Ćirić, Jelena
AU  - Kalauzi, Aleksandar
AU  - Šaponjić, Jasna
PY  - 2017
UR  - http://linkinghub.elsevier.com/retrieve/pii/S0031938416306308
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3297
AB  - Postoperative sleep disorders, particularly the REM sleep disorder, may have a significant deleterious impact on postoperative outcomes and may contribute to the genesis of certain delayed postoperative complications. We have followed the effect of distinct anesthesia regimens (ketamine/diazepam vs. pentobarbital) over 6days following the induction of a stable anesthetized state in adult male Wistar rats, chronically instrumented for sleep recording. In order to compare the effect of both anesthetics in the physiological controls vs. the rats with impaired pedunculopontine tegmental nucleus (PPT) cholinergic innervation, during the operative procedure for the implantation of EEG and EMG electrodes, the bilateral PPT lesion was conducted using ibotenic acid (IBO). We have followed in particular post-anesthesia REM sleep. Our results show the distinct EEG microstructure of the motor cortex during the different stable anesthetized states, and their distinct impact on post-anesthesia REM sleep. In contrast to pentobarbital anesthesia, the ketamine/diazepam anesthesia potentiated the long-lasting post-anesthesia REM statewith higher muscle tone (REM1) vs. REM state with atonia (REM2). Whereas both anesthesias prolonged the post-anesthesia REM sleep duration, the long-term prolongation of the REM1 state was demonstrated only after the ketamine/diazepam anesthesia, first due to the increased number of REM1 episodes, and then due to the prolonged REM1 episodes duration. On the other hand, whereas both anesthetic regimens abolished the prolonged post-anesthesia REM/REM1 sleep and the EEG microstructure disorder during REM sleep, only the pentobarbital abolished the increased NREM/REM/NREM transitions, caused by the PPT lesion. In addition, in the PPT lesioned rats, the ketamine/diazepam anesthesia decreased the Wake/NREM/Wake transitions while the pentobarbital anesthesia decreased the Wake/REM/Wake transitions. Our present study suggests pentobarbital anesthesia as being highly beneficial for post-anesthesia REM sleep in the physiological condition as well as during PPT cholinergic neuropathology.
T2  - Physiology & Behavior
T1  - REM sleep disorder following general anesthesia in rats.
VL  - 168
DO  - 10.1016/j.physbeh.2016.10.013
SP  - 41
EP  - 54
ER  - 

@article{
author = "Lazić, Katarina and Petrović, Jelena and Ćirić, Jelena and Kalauzi, Aleksandar and Šaponjić, Jasna",
year = "2017",
abstract = "Postoperative sleep disorders, particularly the REM sleep disorder, may have a significant deleterious impact on postoperative outcomes and may contribute to the genesis of certain delayed postoperative complications. We have followed the effect of distinct anesthesia regimens (ketamine/diazepam vs. pentobarbital) over 6days following the induction of a stable anesthetized state in adult male Wistar rats, chronically instrumented for sleep recording. In order to compare the effect of both anesthetics in the physiological controls vs. the rats with impaired pedunculopontine tegmental nucleus (PPT) cholinergic innervation, during the operative procedure for the implantation of EEG and EMG electrodes, the bilateral PPT lesion was conducted using ibotenic acid (IBO). We have followed in particular post-anesthesia REM sleep. Our results show the distinct EEG microstructure of the motor cortex during the different stable anesthetized states, and their distinct impact on post-anesthesia REM sleep. In contrast to pentobarbital anesthesia, the ketamine/diazepam anesthesia potentiated the long-lasting post-anesthesia REM statewith higher muscle tone (REM1) vs. REM state with atonia (REM2). Whereas both anesthesias prolonged the post-anesthesia REM sleep duration, the long-term prolongation of the REM1 state was demonstrated only after the ketamine/diazepam anesthesia, first due to the increased number of REM1 episodes, and then due to the prolonged REM1 episodes duration. On the other hand, whereas both anesthetic regimens abolished the prolonged post-anesthesia REM/REM1 sleep and the EEG microstructure disorder during REM sleep, only the pentobarbital abolished the increased NREM/REM/NREM transitions, caused by the PPT lesion. In addition, in the PPT lesioned rats, the ketamine/diazepam anesthesia decreased the Wake/NREM/Wake transitions while the pentobarbital anesthesia decreased the Wake/REM/Wake transitions. Our present study suggests pentobarbital anesthesia as being highly beneficial for post-anesthesia REM sleep in the physiological condition as well as during PPT cholinergic neuropathology.",
journal = "Physiology & Behavior",
title = "REM sleep disorder following general anesthesia in rats.",
volume = "168",
doi = "10.1016/j.physbeh.2016.10.013",
pages = "41-54"
}

Lazić, K., Petrović, J., Ćirić, J., Kalauzi, A.,& Šaponjić, J.. (2017). REM sleep disorder following general anesthesia in rats.. in Physiology & Behavior, 168, 41-54.
https://doi.org/10.1016/j.physbeh.2016.10.013

Lazić K, Petrović J, Ćirić J, Kalauzi A, Šaponjić J. REM sleep disorder following general anesthesia in rats.. in Physiology & Behavior. 2017;168:41-54.
doi:10.1016/j.physbeh.2016.10.013 .

Lazić, Katarina, Petrović, Jelena, Ćirić, Jelena, Kalauzi, Aleksandar, Šaponjić, Jasna, "REM sleep disorder following general anesthesia in rats." in Physiology & Behavior, 168 (2017):41-54,
https://doi.org/10.1016/j.physbeh.2016.10.013 . .

TY  - CHAP
AU  - Šaponjić, Jasna
AU  - Petrović, Jelena
AU  - Ćirić, Jelena
AU  - Lazić, Katarina
PY  - 2016
UR  - http://dx.doi.org/10.5772/62949
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2474
UR  - http://www.intechopen.com/books/challenges-in-parkinson-s-disease/disorders-of-sleep-and-motor-control-during-the-impaired-cholinergic-innervation-in-rat-relevance-to
AB  - The medical profession has been generally very slow to acknowledge the importance of sleep medicine and sleep research. Disorders of sleep are related to anxiety, many mental and neurodegenerative diseases, cardiovascular and respiratory disorders, and obesity. Our knowledge of the neural substrates of sleep/wake states and sleep-related behavior disorders regulation in health and the diseases, over more than 50 years of sleep research, is based on the experiments in animal models, pharmacotherapy, and the neuropathological studies in humans. But, we still need further work in fundamental multidisciplinary and clinical research between sleep and neurodegenerative disease investigators to understand normal and abnormal sleep, and to provide new insights into preventive or disease-altering approaches for therapy. Our aim is to give an overview of our recent results related to the importance of thalamo-cortical cholinergic brain system in the disorders of sleep and motor control during sleep, with particular relevance to Parkinson’s disease.
PB  - Rijeka: InTech
T2  - Challenges in Parkinson’s Disease
T1  - Disorders of Sleep and Motor Control During the Impaired Cholinergic Innervation in Rat – Relevance to Parkinson’s Disease
DO  - 10.5772/62949
SP  - 136
EP  - 153
ER  - 

@inbook{
author = "Šaponjić, Jasna and Petrović, Jelena and Ćirić, Jelena and Lazić, Katarina",
year = "2016",
abstract = "The medical profession has been generally very slow to acknowledge the importance of sleep medicine and sleep research. Disorders of sleep are related to anxiety, many mental and neurodegenerative diseases, cardiovascular and respiratory disorders, and obesity. Our knowledge of the neural substrates of sleep/wake states and sleep-related behavior disorders regulation in health and the diseases, over more than 50 years of sleep research, is based on the experiments in animal models, pharmacotherapy, and the neuropathological studies in humans. But, we still need further work in fundamental multidisciplinary and clinical research between sleep and neurodegenerative disease investigators to understand normal and abnormal sleep, and to provide new insights into preventive or disease-altering approaches for therapy. Our aim is to give an overview of our recent results related to the importance of thalamo-cortical cholinergic brain system in the disorders of sleep and motor control during sleep, with particular relevance to Parkinson’s disease.",
publisher = "Rijeka: InTech",
journal = "Challenges in Parkinson’s Disease",
booktitle = "Disorders of Sleep and Motor Control During the Impaired Cholinergic Innervation in Rat – Relevance to Parkinson’s Disease",
doi = "10.5772/62949",
pages = "136-153"
}

Šaponjić, J., Petrović, J., Ćirić, J.,& Lazić, K.. (2016). Disorders of Sleep and Motor Control During the Impaired Cholinergic Innervation in Rat – Relevance to Parkinson’s Disease. in Challenges in Parkinson’s Disease
Rijeka: InTech., 136-153.
https://doi.org/10.5772/62949

Šaponjić J, Petrović J, Ćirić J, Lazić K. Disorders of Sleep and Motor Control During the Impaired Cholinergic Innervation in Rat – Relevance to Parkinson’s Disease. in Challenges in Parkinson’s Disease. 2016;:136-153.
doi:10.5772/62949 .

Šaponjić, Jasna, Petrović, Jelena, Ćirić, Jelena, Lazić, Katarina, "Disorders of Sleep and Motor Control During the Impaired Cholinergic Innervation in Rat – Relevance to Parkinson’s Disease" in Challenges in Parkinson’s Disease (2016):136-153,
https://doi.org/10.5772/62949 . .

TY  - THES
AU  - Petrović, Jelena
PY  - 2015
UR  - http://eteze.bg.ac.rs/application/showtheses?thesesId=2924
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:11144/bdef:Content/download
UR  - http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=47560719
UR  - http://nardus.mpn.gov.rs/123456789/5447
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/2434
AB  - Alchajmerova bolest (AB) i Parkinsonova bolest (PB) su najčešće neurodegenerativne bolesti starenja. Neuropatologija AB i PB podrazumeva selektivan gubitak specifičnih populacija neurona, uključujući i holinergičke neurone bazalnog prednjeg mozga i moždanog stabla, kao i ushodni obrazac progresije neurodegeneracije od struktura u moždanom stablu uključenih u regulaciju REM („rapid eye movement”) spavanja ka prednjemoždanim regionima. Poremećaji ponašanja u toku REM spavanja („REM sleep behavior disorders” – RBD) veoma često ostaju neprimećeni kod AB i PB pacijenata i mogu se javiti godinama pa čak i decenijama pre motornih i kognitivnih poremećaja. Ovo ukazuje na značaj istraživanja poremećaja ponašanja u toku REM spavanja kao mogućeg ranog znaka pojave najčešćih neurodegenerativnih bolesti starenja.
Predmet istraživanja ove doktorske disertacije bio je da u eksperimentalnim modelima AB i PB holinergičke neuropatologije po prvi put ispita uticaj unilateralnih i bilateralnih lezija glavnog izvora kortikalne holinergičke inervacije (nucleus basalis, NB jedro) i glavnog izvora talamo-kortikalne holinergičke inervacije (nucleus pedunculopontinus tegmentalis, PPT jedro) velikog mozga pacova na spavanje i elektroencefalografske (EEG) ritmove. U ovim eksperimentalnim modelima holinergičke neuropatologije humanih bolesti (NB i PPT lezije) unilateralne lezije su predstavljale lakše oblike ili početne stadijume neurodegeneracija, dok su bilateralne lezije predstavljale teže oblike ili kasnije stadijume neurodegeneracija, a sama progresija bolesti je praćena ukupno 5 nedelja zavisno od eksperimentalne grupe. 
U skladu sa osnovnom hipotezom ove doktorske disertacije, da funkcionalno različiti centralni holinergički sistemi imaju različite regulatorne funkcije u toku spavanja, koje se mogu definisati na osnovu EEG aktivnosti, postavljen je i osnovni cilj istraživanja: da se kroz analizu arhitekture spavanja, strukture prelaznih stanja i EEG mikrostrukture osnovnih faza u toku spavanja (budnost, NREM – „non rapid eye movement”, REM) u eksperimentalnim modelima funkcionalno različite holinergičke neuropatologije pronađu potencijalni EEG markeri početka, težine i progresije neurodegeneracije, sa mogućnošću dalje primene ovako senzitivnih metoda (definisanih EEG markera) u eventualnoj prevenciji i promeni terapijskog pristupa u pacijenata sa rizikom razvoja AB i PB.
Mužjaci pacova Wistar soja su hronično implantirani za registrovanje spavanja. U toku operativne procedure za implantaciju elektroda za elektroencefalografiju (EEG) i elektromiografiju (EMG), korišćenjem tehnike stereotaksički navođene mikroinfuzije ibotenične kiseline (ekscitotoksina koji je generalni glutamatergički agonista), izvšene su selektivne unilateralne ili bilateralne NB ili PPT lezije. 
Eksperimentalni protokol registrovanja spavanja je počinjao dve nedelje nakon oporavka od operativne procedure implantacije hroničnih elektroda, sa ili bez unilateralnih ili bilateralnih NB ili PPT lezija. Registrovano je 6 sati spavanja, jednom nedeljno tokom četiri nedelje u eksperimentima NB lezija, odnosno jednom nedeljno tokom pet nedelja u eksperimentima PPT lezija, korišćenjem programa DataWave SciWorks Experimenter 8.0 (Datawave Technologies, Longmont, SAD). 
Nakon završetka eksperimentalnog protokola registrovanja spavanja, NB i PPT lezije su identifikovane NADPH – diaforaza histohemijskim bojenjem, a zatim i kvantifikovane u celokupnoj antero-posteriornoj dimenziji strukture korišćenjem ImageJ 1.46 programa (NIH, SAD). 
Analiza spavanja i EEG signala urađena je, kako u kontrolnih pacova tako i u pacova sa identifikovanim NB ili PPT lezijama, u MATLAB 6.5 programu, korišćenjem originalno razvijenog programskog paketa. Na usnimljene šestočasovne signale je najpre primenjena Furijeova transformacija, a zatim je svaka od 2160 Furijeovih epoha dužine 10 s  diferencirana kao budnost, NREM ili REM faza spavanja. Pored toga, za potrebe detaljnije analize poremećaja REM faze spavanja izazvanih bilateralnom PPT lezijom, grupisanje REM epoha je na osnovu snage EMG-a dodatno razdvojeno na dva podgrupisanja REM1 (REM epohe sa većom snagom EMG-a, patološki REM) i REM2 (REM epohe sa manjom snagom EMG-a, fiziološki REM). Potom je korišćenjem EEG signala senzomotorne i motorne kore urađena topografska analiza arhitekture spavanja, strukture prelaznih stanja u toku spavanja, EEG mikrostrukture svih osnovnih faza u toku spavanja, kao i analiza kortiko-muskularih koherencija između EEG-a senzomotorne ili motorne kore velikog mozga i EMG-a mišića dorzalne vratne muskulature. Za izračunavanje grupne raspodele gustine verovatnoće relativnih amplituda svih budnost/NREM/REM/REM1/REM2 konvencionalnih EEG frekventnih opsega u toku 6 h spavanja korišćena je PDE („Probability Density Estimate”) funkcija u MATLAB 6.5 programu. U daljoj funkcionalnoj analizi poremećaja REM faze spavanja, za svaki od konvencionalnih EEG frekventnih opsega su korišćenjem „cohere” funkcije u MATLAB 6.5 izračunate REM/REM1/REM2 kortiko-muskularne koherencije između EEG-a senzomotorne ili motorne kore i EMG-a mišića dorzalne vratne muskulature. Za statističku obradu svih podataka korišćena je neparametarska jednofaktorska Kruskal-Wallis ANOVA sa post-hoc Mann-Whitney U kontrastnim testom.
Bilateralna NB lezija je privremeno promenila arhitekturu spavanja 14 dana nakon lezije. Iako u slučaju fiziološke kontrole nije bilo razlika u trajanju budnosti, NREM i REM faze spavanja između senzomotorne i motorne kore, bilateralna NB lezija je u senzomotornoj kori smanjila trajanje budnosti i povećala trajanje NREM faze spavanja, dok je u motornoj kori smanjila trajanje budnosti i povećala trajanje REM faze spavanja. Istovremeno, u svim eksperimentalnim grupama, kako u fiziološkoj kontroli, tako i u unilateralnoj i bilateralnoj NB leziji, je EEG teta amplituda budnosti, NREM i REM faze spavanja bila niža u motornoj u odnosu na senzomotornu koru. Pored toga, bilateralna NB lezija je u senzomotornoj kori izazvala povećanje REM teta amplitude u trajanju od tri nedelje, dok su u motornoj kori i unilateralna i bilateralna NB lezija izazvale povećanje teta amplitude i u budnosti i u REM fazi spavanja.
PPT lezija nije promenila arhitekturu spavanja, ali je značajno izmenila strukturu prelaznih stanja, kao i EEG mikrostrukturu svih osnovnih faza spavanja. Obe lezije, i unilateralna i bilateralna PPT lezija, su dugotrajno povećale broj budnost/REM i REM/budnost prelaza tokom celokunog perioda od 5 nedelja. Ova promena u strukturi prelaznih stanja je od 28. dana bila praćena smanjenjem broja NREM/REM i REM/NREM prelaza, ali samo nakon bilateralne PPT lezije, kao težeg oblika holinergičke neurodegeneracije. Unilateralna PPT lezija je izazvala povećanje EEG teta amplitude budnosti i EEG beta amplitude REM faze spavanja, a od treće nedelje nakon lezije i pad EEG delta amplitude budnosti. Bilateralna PPT lezija je izazvala povećanje EEG beta amplitude tokom svih faza spavanja, kao i povećanje EEG gama amplitude REM faze spavanja i smanjenje EEG delta amplitude budnosti i NREM faze spavanja.
Poređenje efekata bilateralne NB i bilateralne PPT lezije (modeli težih, odnosno progresivnijih oblika holinergičke neurodegeneracije) na arhitekturu spavanja, strukturu prelaznih stanja i EEG mikrostrukturu svih osnovnih faza spavanja je pokazalo postojanje topografski specifičnih razlika u poremećajima nastalim kao posledica degeneracije funkcionalno različitih holinergičkih inervacija velikog mozga pacova. Za razliku od bilateralne NB lezije koja je privremeno izmenila trajanje budnosti i NREM faze spavanja u senzomotornoj kori, odnosno trajanje budnosti i REM faze spavanja u motornoj kori, bilateralna PPT lezija nije izmenila arhitekturu spavanja. Bilateralna PPT lezija je u obe kore dugotrajno (tokom 4 nedelje) povećala broj budnost/REM i REM/budnost prelaza i ovaj porast je bio praćen nekonzistentnim promenama u broju NREM/REM i REM/NREM prelaza u senzomotornoj kori, a u motornoj kori povećanjem broja ovih prelaza. Bilateralna NB lezija je u senzomotornoj kori smanjila broj NREM/REM i REM/NREM prelaza, dok je u motornoj kori povećala broj ovih prelaza tokom četiri nedelje. Promene u EEG mikrostrukturi nakon  bilateralne PPT lezije bile su i u senzomotornoj i u motornoj kori izražene kao dugotrajno (tokom 4 nedelje) povećanje beta i gama amplitude budnosti, NREM i REM faze spavanja, odnosno kao smanjenje delta amplitude budnosti, ali samo u senzomotornoj kori. Nasuprot tome, bilateralna NB lezija je izazvala samo povećanje REM teta amplitude u senzomotornoj kori koje je trajalo tri nedelje. 
Pored promena u strukturi prelaznih stanja u toku spavanja i EEG mikrostrukturi svih osnovnih faza spavanja, bilateralna PPT lezija je dodatno uslovila izdvajanje dva funkcionalno različita REM stanja u okviru REM faze spavanja, REM1 (PPT lezijom prouzrokovan patološki REM, REM bez atonije, REM sigma koherencije) i REM2 (fiziološki REM, REM sa atonijom, REM teta koherencije), naročito u motornoj kori. Iako nije promenila arhitekturu spavanja senzomotorne kore, bilateralna PPT lezija je u motornoj kori produžila trajanje patološkog REM1 stanja, a povećala broj budnost/REM1/budnost i NREM/REM2/NREM prelaza u obe kore. U osnovi izmenjene REM EEG mikrostrukture su bile povećana beta amplituda senzomotorne kore za vreme celokupnog REM stanja i povećana teta amplituda motorne kore samo za vreme REM1 stanja. Bilateralna PPT lezija je izazvala generalizovan pad REM/REM1/REM2 beta kortiko-muskularne koherencije i dovela do izmene kontrole mišića dorzalne vratne muskulature dominantno iz senzomotorne kore. 
Ova doktorska disertacija je, koristeći po prvi put nov eksperimentalni model holinergičke PB neuropatologije (PPT lezija), stereotaksički navođenu mikroinfuziju kao nov metodološki pristup za selektivne lezije moždanih jedara, nov histohemijski metod identifikacije deficita holinergičkih neurona, nov pristup u kvantifikaciji neuronskog deficita, kao i nov način analize EEG signala za vreme različitih faza spavanja, po prvi put dokazala topografski specifične razlike u arhitekturi spavanja, strukturi prelaznih stanja i EEG mikrostrukturi osnovnih faza spavanja (budnost, NREM, REM), koje su nastale usled poremećaja funkcionalno različitih holinergičkih inervacija velikog mozga pacova (NB lezija u odnosu na PPT leziju). U ovom novom eksperimentalnom modelu holinergičke PB neuropatologije po prvi put su dokazani dugotrajni i veoma ozbiljni poremećaji u spavanju izraženi kao: povećanje broja budnost/REM i REM/budnost prelaza, povećana kortikalna aktivacija tokom svih osnovnih faza spavanja, izdvajanje dva različita REM stanja (pojava patološkog REM stanja pored fiziološkog REM stanja), kao i dominantna izmena kontrole mišića dorzalne vratne muskulature iz senzomotorne kore, iskazana kao pad REM/REM1/REM2 beta koherencije.
AB  - Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases of elderly. AD and PD neuropathology involves selective loss of specific neuronal population within the brain, including the basal forebrain and brainstem cholinergic neurons, with the ascending pattern of neurodegeneration progression from rapid eye movement (REM) sleep-related brainstem regulatory structures to the brain basal areas. REM sleep behavior disorders (RBD) very frequently go unnoticed in the AD and PD patients, and as a symptom, could precede the onset of motor and cognitive disturbances by years or even decades. This indicates the importance of RBD as a potential early marker of the neurodegenerative diseases of elderly.
Using the experimental models of AD and PD cholinergic neuropathology, this PhD thesis aimed to investigate for the first time the impact of unilateral and bilateral nucleus basalis (NB – the main source of cortical cholinergic innervation) and nucleus pedunculopontinus tegmentalis (PPT – the main source of thalamo-cortical cholinergic innervation) lesions on sleep and electroencephalographic (EEG) rhythms during sleep in rat. In these experimental models of cholinergic neuropathology (NB and PPT lesions) the unilateral lesions were used as the models of mild or early stage neurodegenerations, whereas the bilateral lesions were used as the models of severe or progressed neurodegenerations, and the follow up period was up to 5 weeks depending on the experimental group.
Based on the hypothesis that functionally distinct cholinergic systems have different regulatory functions during sleep, that could be defined by EEG activity, this study aimed to investigate the sleep/wake architecture, sleep/wake state-related transitions structure and EEG microstructure of three main brain states (Wake, NREM – non rapid eye movement, REM) in order to find the possible EEG markers for the onset, severity, and progression of the functionally distinct cholinergic innervations disorders. These EEG markers could be used as a sensitive and reliable methodology of early detection in the patients who are at risk to develop AD or PD, and for a potential prevention and modification of the therapeutic approach.
Male Wistar rats were chronically implanted for sleep recording. During operative procedure for the electroencephalographic (EEG) and electromyographic (EMG) electrodes implantation, the selective unilateral or bilateral NB or PPT lesions were performed by stereotaxically guided microinfusion of ibotenic acid (the general glutamate agonist).
Sleep recording sessions started after two weeks of recovery period. Sleep was recorded for 6 h, weekly, during 4 weeks in NB lesioned rats, and during 5 weeks in PPT lesioned rats, using DataWave SciWorks Experimenter 8.0 software (Datawave Technologies, Longmont, SAD).
At the end of recording sessions the NB and PPT lesions were identified by NADPH – diaphorase histochemistry, and quantified throughout the overall NB or PPT antero-posterior dimensions, using ImageJ 1.46 software (NIH, SAD).
Analysis of the signals recorded from the control rats and all rats with positively identified NB or PPT lesion was done in MATLAB 6.5 using originally developed software. Fourier analysis was applied on 6 h recordings, and each 10 s epoch was differentiated as Wake, NREM or REM state. Additionally, for detailed analysis of two distinct REM clusters, that emerged following bilateral PPT lesion, each REM epoch was further differentiated, based on the EMG power, as either REM without atonia (REM1, pathological REM), and REM with atonia (REM2, physiological REM). Further analysis included the topography of sleep/wake states architecture, sleep/wake state-related transitions structure, and EEG microstructure, as well as all REM related cortico-muscular coherences. To calculate the group probability density distribution of all conventional EEG frequency bands relative amplitudes/6 h for the Wake/NREM/REM/REM1/REM2 of each experimental group we used the Probability Density Estimate (PDE) routine within MATLAB 6.5. For the functional REM cluster differentiation the REM/REM1/REM2 cortico-muscular coherences (CMCs) were calculated separately, for each conventional EEG frequency band and each experimental group, between the EEG of sensorimotor or motor cortex and the EMG of the dorsal nuchal muscles using the MATLAB 6.5 cohere routine. All statistical analyses were done using Kruskal-Wallis ANOVA with post-hoc Mann-Whitney U two-tailed tests.
Bilateral NB lesion transiently altered sleep/wake states topography 14 days following lesion. While the control rats exhibited equivalent durations of Wake, NREM and REM, as determined by sensorimotor versus motor cortex EEG, the bilateral NB lesion decreased Wake duration in both cortices, with NREM duration increased within the sensorimotor cortex, and REM duration increased within the motor cortex. At the same time, Wake, NREM and REM theta relative amplitude was lower in motor versus sensorimotor cortex in all experimental groups. In sensorimotor cortex the bilateral NB lesion increased only REM theta amplitude for three weeks, whereas in motor cortex both Wake and REM theta amplitude were transiently increased 14 days following both the unilateral and bilateral NB lesion.
PPT lesion did not change the sleep/wake architecture but did change the sleep/wake state-related transitions structure and the Wake/NREM/REM EEG microstructures. Both the unilateral and bilateral PPT lesions sustainably increased Wake/REM and REM/Wake transitions during 5 weeks, followed by the decreased NREM/REM and REM/NREM transitions from 28 days only in the case of the bilateral PPT lesion, as a more severe cholinergic neurodegeneration. The unilateral PPT lesion augmented Wake theta and REM beta amplitude, and with a delay of one week it attenuated Wake delta amplitude. The bilateral PPT lesion augmented beta amplitude during all sleep states, and REM gamma amplitude, but simultaneously attenuated Wake and NREM delta amplitude.
Comparison of the bilateral NB versus bilateral PPT lesion (the models of severe or progressed cholinergic neurodegenerations) effects on the sleep/wake states architecture, sleep/wake state-related transitions structure and EEG microstructures indicated the topographically specific differentiation of functionally distinct cholinergic innervation disorders. Whereas the bilateral NB lesion transiently altered Wake/NREM duration within the sensorimotor cortex, and Wake/REM duration within the motor cortex, the bilateral PPT lesion did not change the sleep/wake states distributions. Bilateral PPT lesion sustainably (during 4 weeks) increased the Wake/REM and REM/Wake transitions within the both sensorimotor and motor cortex, followed by inconsistent dysregulation of the NREM/REM and REM/NREM transitions within the sensorimotor cortex, but oppositely by their increment within the motor cortex. Bilateral NB lesion sustainably (during 4 weeks) decreased the NREM/REM and REM/NREM transitions within the sensorimotor cortex, but oppositely increased them within the motor cortex. Sleep/wake state-related EEG microstructure following the bilateral PPT lesion was expressed as the sustained (during 4 weeks) Wake/NREM/REM beta and gamma amplitude augmentations within the both sensorimotor and motor cortex, and Wake delta amplitude attenuation, but only within the sensorimotor cortex. In contrast, the bilateral NB lesion augmented only REM theta amplitude within the sensorimotor cortex during three weeks.
Alongside the sleep/wake state-related transitions structure and Wake/NREM/REM EEG microstructure alteration, the bilateral PPT lesion in rats additionally potentiated the emergence of two distinct REM sleep states, REM1 (pathological REM, REM without atonia, sigma coherent REM) and REM2 (physiological REM, REM with atonia, theta coherent REM), specifically expressed within the motor cortex. Bilateral PPT lesion did not change the sleep/wake states architecture within the sensorimotor cortex, but pathologically increased the duration of REM1 within the motor cortex, alongside the increased Wake/REM1/Wake and NREM/REM2/NREM transitions within the both cortices. In addition, the augmented total REM beta amplitude within the sensorimotor cortex and REM1 theta amplitude within the motor cortex was the underlying EEG microstructure pathology. Finally, the bilateral PPT lesion dominantly induced sensorimotor cortex-dorsal nuchal muscle drive alteration, expressed throughout the REM/REM1/REM2 beta CMC decrease.
Introducing the novel experimental model of PD cholinergic neuropathology (PPT lesion), the stereotaxically guided microinfusion as a novel approach for the selective lesion of the brain nuclei, the novel histochemical method for the cholinergic neuronal loss identification, and the novel methodological approach for neuronal loss quantification, as well as the novel sleep-state related EEG signal analysis methodology, this PhD thesis evidenced for the first time the topographically different expression of the sleep/wake architecture, sleep/wake state-related transitions structure and Wake/NREM/REM EEG microstructure, induced by the functionally distinct cholinergic innervation disorders in rat (NB versus PPT lesion). This study demonstrated for the first time the PPT lesion (novel experimental model of PD cholinergic neuropathology) induced sustained and more severe sleep disturbances expressed as: the Wake/REM and REM/Wake transitions increase, augmented cortical activation across all sleep/wake states, potentiation of two distinct REM clusters, and dominant sensorimotor cortex-dorsal nuchal muscle drive alteration throughout the REM/REM1/REM2 beta CMC decrease.
PB  - Belgrade: University of Belgrade, Faculty of Biology
T2  - University of Belgrade, Faculty of Biology
T1  - Spavanje i elektroencefalografski ritmovi kao indikatori poremećaja funkcionalno različitih holinergičkih inervacija velikog mozga pacova
T1  - Sleep and electroencephalographic rhythms as an indicators of the functionally distinct cholinergic innervation disorders in rat brain
SP  - 1
EP  - 156
UR  - https://hdl.handle.net/21.15107/rcub_nardus_5447
ER  - 

@phdthesis{
author = "Petrović, Jelena",
year = "2015",
abstract = "Alchajmerova bolest (AB) i Parkinsonova bolest (PB) su najčešće neurodegenerativne bolesti starenja. Neuropatologija AB i PB podrazumeva selektivan gubitak specifičnih populacija neurona, uključujući i holinergičke neurone bazalnog prednjeg mozga i moždanog stabla, kao i ushodni obrazac progresije neurodegeneracije od struktura u moždanom stablu uključenih u regulaciju REM („rapid eye movement”) spavanja ka prednjemoždanim regionima. Poremećaji ponašanja u toku REM spavanja („REM sleep behavior disorders” – RBD) veoma često ostaju neprimećeni kod AB i PB pacijenata i mogu se javiti godinama pa čak i decenijama pre motornih i kognitivnih poremećaja. Ovo ukazuje na značaj istraživanja poremećaja ponašanja u toku REM spavanja kao mogućeg ranog znaka pojave najčešćih neurodegenerativnih bolesti starenja.
Predmet istraživanja ove doktorske disertacije bio je da u eksperimentalnim modelima AB i PB holinergičke neuropatologije po prvi put ispita uticaj unilateralnih i bilateralnih lezija glavnog izvora kortikalne holinergičke inervacije (nucleus basalis, NB jedro) i glavnog izvora talamo-kortikalne holinergičke inervacije (nucleus pedunculopontinus tegmentalis, PPT jedro) velikog mozga pacova na spavanje i elektroencefalografske (EEG) ritmove. U ovim eksperimentalnim modelima holinergičke neuropatologije humanih bolesti (NB i PPT lezije) unilateralne lezije su predstavljale lakše oblike ili početne stadijume neurodegeneracija, dok su bilateralne lezije predstavljale teže oblike ili kasnije stadijume neurodegeneracija, a sama progresija bolesti je praćena ukupno 5 nedelja zavisno od eksperimentalne grupe. 
U skladu sa osnovnom hipotezom ove doktorske disertacije, da funkcionalno različiti centralni holinergički sistemi imaju različite regulatorne funkcije u toku spavanja, koje se mogu definisati na osnovu EEG aktivnosti, postavljen je i osnovni cilj istraživanja: da se kroz analizu arhitekture spavanja, strukture prelaznih stanja i EEG mikrostrukture osnovnih faza u toku spavanja (budnost, NREM – „non rapid eye movement”, REM) u eksperimentalnim modelima funkcionalno različite holinergičke neuropatologije pronađu potencijalni EEG markeri početka, težine i progresije neurodegeneracije, sa mogućnošću dalje primene ovako senzitivnih metoda (definisanih EEG markera) u eventualnoj prevenciji i promeni terapijskog pristupa u pacijenata sa rizikom razvoja AB i PB.
Mužjaci pacova Wistar soja su hronično implantirani za registrovanje spavanja. U toku operativne procedure za implantaciju elektroda za elektroencefalografiju (EEG) i elektromiografiju (EMG), korišćenjem tehnike stereotaksički navođene mikroinfuzije ibotenične kiseline (ekscitotoksina koji je generalni glutamatergički agonista), izvšene su selektivne unilateralne ili bilateralne NB ili PPT lezije. 
Eksperimentalni protokol registrovanja spavanja je počinjao dve nedelje nakon oporavka od operativne procedure implantacije hroničnih elektroda, sa ili bez unilateralnih ili bilateralnih NB ili PPT lezija. Registrovano je 6 sati spavanja, jednom nedeljno tokom četiri nedelje u eksperimentima NB lezija, odnosno jednom nedeljno tokom pet nedelja u eksperimentima PPT lezija, korišćenjem programa DataWave SciWorks Experimenter 8.0 (Datawave Technologies, Longmont, SAD). 
Nakon završetka eksperimentalnog protokola registrovanja spavanja, NB i PPT lezije su identifikovane NADPH – diaforaza histohemijskim bojenjem, a zatim i kvantifikovane u celokupnoj antero-posteriornoj dimenziji strukture korišćenjem ImageJ 1.46 programa (NIH, SAD). 
Analiza spavanja i EEG signala urađena je, kako u kontrolnih pacova tako i u pacova sa identifikovanim NB ili PPT lezijama, u MATLAB 6.5 programu, korišćenjem originalno razvijenog programskog paketa. Na usnimljene šestočasovne signale je najpre primenjena Furijeova transformacija, a zatim je svaka od 2160 Furijeovih epoha dužine 10 s  diferencirana kao budnost, NREM ili REM faza spavanja. Pored toga, za potrebe detaljnije analize poremećaja REM faze spavanja izazvanih bilateralnom PPT lezijom, grupisanje REM epoha je na osnovu snage EMG-a dodatno razdvojeno na dva podgrupisanja REM1 (REM epohe sa većom snagom EMG-a, patološki REM) i REM2 (REM epohe sa manjom snagom EMG-a, fiziološki REM). Potom je korišćenjem EEG signala senzomotorne i motorne kore urađena topografska analiza arhitekture spavanja, strukture prelaznih stanja u toku spavanja, EEG mikrostrukture svih osnovnih faza u toku spavanja, kao i analiza kortiko-muskularih koherencija između EEG-a senzomotorne ili motorne kore velikog mozga i EMG-a mišića dorzalne vratne muskulature. Za izračunavanje grupne raspodele gustine verovatnoće relativnih amplituda svih budnost/NREM/REM/REM1/REM2 konvencionalnih EEG frekventnih opsega u toku 6 h spavanja korišćena je PDE („Probability Density Estimate”) funkcija u MATLAB 6.5 programu. U daljoj funkcionalnoj analizi poremećaja REM faze spavanja, za svaki od konvencionalnih EEG frekventnih opsega su korišćenjem „cohere” funkcije u MATLAB 6.5 izračunate REM/REM1/REM2 kortiko-muskularne koherencije između EEG-a senzomotorne ili motorne kore i EMG-a mišića dorzalne vratne muskulature. Za statističku obradu svih podataka korišćena je neparametarska jednofaktorska Kruskal-Wallis ANOVA sa post-hoc Mann-Whitney U kontrastnim testom.
Bilateralna NB lezija je privremeno promenila arhitekturu spavanja 14 dana nakon lezije. Iako u slučaju fiziološke kontrole nije bilo razlika u trajanju budnosti, NREM i REM faze spavanja između senzomotorne i motorne kore, bilateralna NB lezija je u senzomotornoj kori smanjila trajanje budnosti i povećala trajanje NREM faze spavanja, dok je u motornoj kori smanjila trajanje budnosti i povećala trajanje REM faze spavanja. Istovremeno, u svim eksperimentalnim grupama, kako u fiziološkoj kontroli, tako i u unilateralnoj i bilateralnoj NB leziji, je EEG teta amplituda budnosti, NREM i REM faze spavanja bila niža u motornoj u odnosu na senzomotornu koru. Pored toga, bilateralna NB lezija je u senzomotornoj kori izazvala povećanje REM teta amplitude u trajanju od tri nedelje, dok su u motornoj kori i unilateralna i bilateralna NB lezija izazvale povećanje teta amplitude i u budnosti i u REM fazi spavanja.
PPT lezija nije promenila arhitekturu spavanja, ali je značajno izmenila strukturu prelaznih stanja, kao i EEG mikrostrukturu svih osnovnih faza spavanja. Obe lezije, i unilateralna i bilateralna PPT lezija, su dugotrajno povećale broj budnost/REM i REM/budnost prelaza tokom celokunog perioda od 5 nedelja. Ova promena u strukturi prelaznih stanja je od 28. dana bila praćena smanjenjem broja NREM/REM i REM/NREM prelaza, ali samo nakon bilateralne PPT lezije, kao težeg oblika holinergičke neurodegeneracije. Unilateralna PPT lezija je izazvala povećanje EEG teta amplitude budnosti i EEG beta amplitude REM faze spavanja, a od treće nedelje nakon lezije i pad EEG delta amplitude budnosti. Bilateralna PPT lezija je izazvala povećanje EEG beta amplitude tokom svih faza spavanja, kao i povećanje EEG gama amplitude REM faze spavanja i smanjenje EEG delta amplitude budnosti i NREM faze spavanja.
Poređenje efekata bilateralne NB i bilateralne PPT lezije (modeli težih, odnosno progresivnijih oblika holinergičke neurodegeneracije) na arhitekturu spavanja, strukturu prelaznih stanja i EEG mikrostrukturu svih osnovnih faza spavanja je pokazalo postojanje topografski specifičnih razlika u poremećajima nastalim kao posledica degeneracije funkcionalno različitih holinergičkih inervacija velikog mozga pacova. Za razliku od bilateralne NB lezije koja je privremeno izmenila trajanje budnosti i NREM faze spavanja u senzomotornoj kori, odnosno trajanje budnosti i REM faze spavanja u motornoj kori, bilateralna PPT lezija nije izmenila arhitekturu spavanja. Bilateralna PPT lezija je u obe kore dugotrajno (tokom 4 nedelje) povećala broj budnost/REM i REM/budnost prelaza i ovaj porast je bio praćen nekonzistentnim promenama u broju NREM/REM i REM/NREM prelaza u senzomotornoj kori, a u motornoj kori povećanjem broja ovih prelaza. Bilateralna NB lezija je u senzomotornoj kori smanjila broj NREM/REM i REM/NREM prelaza, dok je u motornoj kori povećala broj ovih prelaza tokom četiri nedelje. Promene u EEG mikrostrukturi nakon  bilateralne PPT lezije bile su i u senzomotornoj i u motornoj kori izražene kao dugotrajno (tokom 4 nedelje) povećanje beta i gama amplitude budnosti, NREM i REM faze spavanja, odnosno kao smanjenje delta amplitude budnosti, ali samo u senzomotornoj kori. Nasuprot tome, bilateralna NB lezija je izazvala samo povećanje REM teta amplitude u senzomotornoj kori koje je trajalo tri nedelje. 
Pored promena u strukturi prelaznih stanja u toku spavanja i EEG mikrostrukturi svih osnovnih faza spavanja, bilateralna PPT lezija je dodatno uslovila izdvajanje dva funkcionalno različita REM stanja u okviru REM faze spavanja, REM1 (PPT lezijom prouzrokovan patološki REM, REM bez atonije, REM sigma koherencije) i REM2 (fiziološki REM, REM sa atonijom, REM teta koherencije), naročito u motornoj kori. Iako nije promenila arhitekturu spavanja senzomotorne kore, bilateralna PPT lezija je u motornoj kori produžila trajanje patološkog REM1 stanja, a povećala broj budnost/REM1/budnost i NREM/REM2/NREM prelaza u obe kore. U osnovi izmenjene REM EEG mikrostrukture su bile povećana beta amplituda senzomotorne kore za vreme celokupnog REM stanja i povećana teta amplituda motorne kore samo za vreme REM1 stanja. Bilateralna PPT lezija je izazvala generalizovan pad REM/REM1/REM2 beta kortiko-muskularne koherencije i dovela do izmene kontrole mišića dorzalne vratne muskulature dominantno iz senzomotorne kore. 
Ova doktorska disertacija je, koristeći po prvi put nov eksperimentalni model holinergičke PB neuropatologije (PPT lezija), stereotaksički navođenu mikroinfuziju kao nov metodološki pristup za selektivne lezije moždanih jedara, nov histohemijski metod identifikacije deficita holinergičkih neurona, nov pristup u kvantifikaciji neuronskog deficita, kao i nov način analize EEG signala za vreme različitih faza spavanja, po prvi put dokazala topografski specifične razlike u arhitekturi spavanja, strukturi prelaznih stanja i EEG mikrostrukturi osnovnih faza spavanja (budnost, NREM, REM), koje su nastale usled poremećaja funkcionalno različitih holinergičkih inervacija velikog mozga pacova (NB lezija u odnosu na PPT leziju). U ovom novom eksperimentalnom modelu holinergičke PB neuropatologije po prvi put su dokazani dugotrajni i veoma ozbiljni poremećaji u spavanju izraženi kao: povećanje broja budnost/REM i REM/budnost prelaza, povećana kortikalna aktivacija tokom svih osnovnih faza spavanja, izdvajanje dva različita REM stanja (pojava patološkog REM stanja pored fiziološkog REM stanja), kao i dominantna izmena kontrole mišića dorzalne vratne muskulature iz senzomotorne kore, iskazana kao pad REM/REM1/REM2 beta koherencije., Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases of elderly. AD and PD neuropathology involves selective loss of specific neuronal population within the brain, including the basal forebrain and brainstem cholinergic neurons, with the ascending pattern of neurodegeneration progression from rapid eye movement (REM) sleep-related brainstem regulatory structures to the brain basal areas. REM sleep behavior disorders (RBD) very frequently go unnoticed in the AD and PD patients, and as a symptom, could precede the onset of motor and cognitive disturbances by years or even decades. This indicates the importance of RBD as a potential early marker of the neurodegenerative diseases of elderly.
Using the experimental models of AD and PD cholinergic neuropathology, this PhD thesis aimed to investigate for the first time the impact of unilateral and bilateral nucleus basalis (NB – the main source of cortical cholinergic innervation) and nucleus pedunculopontinus tegmentalis (PPT – the main source of thalamo-cortical cholinergic innervation) lesions on sleep and electroencephalographic (EEG) rhythms during sleep in rat. In these experimental models of cholinergic neuropathology (NB and PPT lesions) the unilateral lesions were used as the models of mild or early stage neurodegenerations, whereas the bilateral lesions were used as the models of severe or progressed neurodegenerations, and the follow up period was up to 5 weeks depending on the experimental group.
Based on the hypothesis that functionally distinct cholinergic systems have different regulatory functions during sleep, that could be defined by EEG activity, this study aimed to investigate the sleep/wake architecture, sleep/wake state-related transitions structure and EEG microstructure of three main brain states (Wake, NREM – non rapid eye movement, REM) in order to find the possible EEG markers for the onset, severity, and progression of the functionally distinct cholinergic innervations disorders. These EEG markers could be used as a sensitive and reliable methodology of early detection in the patients who are at risk to develop AD or PD, and for a potential prevention and modification of the therapeutic approach.
Male Wistar rats were chronically implanted for sleep recording. During operative procedure for the electroencephalographic (EEG) and electromyographic (EMG) electrodes implantation, the selective unilateral or bilateral NB or PPT lesions were performed by stereotaxically guided microinfusion of ibotenic acid (the general glutamate agonist).
Sleep recording sessions started after two weeks of recovery period. Sleep was recorded for 6 h, weekly, during 4 weeks in NB lesioned rats, and during 5 weeks in PPT lesioned rats, using DataWave SciWorks Experimenter 8.0 software (Datawave Technologies, Longmont, SAD).
At the end of recording sessions the NB and PPT lesions were identified by NADPH – diaphorase histochemistry, and quantified throughout the overall NB or PPT antero-posterior dimensions, using ImageJ 1.46 software (NIH, SAD).
Analysis of the signals recorded from the control rats and all rats with positively identified NB or PPT lesion was done in MATLAB 6.5 using originally developed software. Fourier analysis was applied on 6 h recordings, and each 10 s epoch was differentiated as Wake, NREM or REM state. Additionally, for detailed analysis of two distinct REM clusters, that emerged following bilateral PPT lesion, each REM epoch was further differentiated, based on the EMG power, as either REM without atonia (REM1, pathological REM), and REM with atonia (REM2, physiological REM). Further analysis included the topography of sleep/wake states architecture, sleep/wake state-related transitions structure, and EEG microstructure, as well as all REM related cortico-muscular coherences. To calculate the group probability density distribution of all conventional EEG frequency bands relative amplitudes/6 h for the Wake/NREM/REM/REM1/REM2 of each experimental group we used the Probability Density Estimate (PDE) routine within MATLAB 6.5. For the functional REM cluster differentiation the REM/REM1/REM2 cortico-muscular coherences (CMCs) were calculated separately, for each conventional EEG frequency band and each experimental group, between the EEG of sensorimotor or motor cortex and the EMG of the dorsal nuchal muscles using the MATLAB 6.5 cohere routine. All statistical analyses were done using Kruskal-Wallis ANOVA with post-hoc Mann-Whitney U two-tailed tests.
Bilateral NB lesion transiently altered sleep/wake states topography 14 days following lesion. While the control rats exhibited equivalent durations of Wake, NREM and REM, as determined by sensorimotor versus motor cortex EEG, the bilateral NB lesion decreased Wake duration in both cortices, with NREM duration increased within the sensorimotor cortex, and REM duration increased within the motor cortex. At the same time, Wake, NREM and REM theta relative amplitude was lower in motor versus sensorimotor cortex in all experimental groups. In sensorimotor cortex the bilateral NB lesion increased only REM theta amplitude for three weeks, whereas in motor cortex both Wake and REM theta amplitude were transiently increased 14 days following both the unilateral and bilateral NB lesion.
PPT lesion did not change the sleep/wake architecture but did change the sleep/wake state-related transitions structure and the Wake/NREM/REM EEG microstructures. Both the unilateral and bilateral PPT lesions sustainably increased Wake/REM and REM/Wake transitions during 5 weeks, followed by the decreased NREM/REM and REM/NREM transitions from 28 days only in the case of the bilateral PPT lesion, as a more severe cholinergic neurodegeneration. The unilateral PPT lesion augmented Wake theta and REM beta amplitude, and with a delay of one week it attenuated Wake delta amplitude. The bilateral PPT lesion augmented beta amplitude during all sleep states, and REM gamma amplitude, but simultaneously attenuated Wake and NREM delta amplitude.
Comparison of the bilateral NB versus bilateral PPT lesion (the models of severe or progressed cholinergic neurodegenerations) effects on the sleep/wake states architecture, sleep/wake state-related transitions structure and EEG microstructures indicated the topographically specific differentiation of functionally distinct cholinergic innervation disorders. Whereas the bilateral NB lesion transiently altered Wake/NREM duration within the sensorimotor cortex, and Wake/REM duration within the motor cortex, the bilateral PPT lesion did not change the sleep/wake states distributions. Bilateral PPT lesion sustainably (during 4 weeks) increased the Wake/REM and REM/Wake transitions within the both sensorimotor and motor cortex, followed by inconsistent dysregulation of the NREM/REM and REM/NREM transitions within the sensorimotor cortex, but oppositely by their increment within the motor cortex. Bilateral NB lesion sustainably (during 4 weeks) decreased the NREM/REM and REM/NREM transitions within the sensorimotor cortex, but oppositely increased them within the motor cortex. Sleep/wake state-related EEG microstructure following the bilateral PPT lesion was expressed as the sustained (during 4 weeks) Wake/NREM/REM beta and gamma amplitude augmentations within the both sensorimotor and motor cortex, and Wake delta amplitude attenuation, but only within the sensorimotor cortex. In contrast, the bilateral NB lesion augmented only REM theta amplitude within the sensorimotor cortex during three weeks.
Alongside the sleep/wake state-related transitions structure and Wake/NREM/REM EEG microstructure alteration, the bilateral PPT lesion in rats additionally potentiated the emergence of two distinct REM sleep states, REM1 (pathological REM, REM without atonia, sigma coherent REM) and REM2 (physiological REM, REM with atonia, theta coherent REM), specifically expressed within the motor cortex. Bilateral PPT lesion did not change the sleep/wake states architecture within the sensorimotor cortex, but pathologically increased the duration of REM1 within the motor cortex, alongside the increased Wake/REM1/Wake and NREM/REM2/NREM transitions within the both cortices. In addition, the augmented total REM beta amplitude within the sensorimotor cortex and REM1 theta amplitude within the motor cortex was the underlying EEG microstructure pathology. Finally, the bilateral PPT lesion dominantly induced sensorimotor cortex-dorsal nuchal muscle drive alteration, expressed throughout the REM/REM1/REM2 beta CMC decrease.
Introducing the novel experimental model of PD cholinergic neuropathology (PPT lesion), the stereotaxically guided microinfusion as a novel approach for the selective lesion of the brain nuclei, the novel histochemical method for the cholinergic neuronal loss identification, and the novel methodological approach for neuronal loss quantification, as well as the novel sleep-state related EEG signal analysis methodology, this PhD thesis evidenced for the first time the topographically different expression of the sleep/wake architecture, sleep/wake state-related transitions structure and Wake/NREM/REM EEG microstructure, induced by the functionally distinct cholinergic innervation disorders in rat (NB versus PPT lesion). This study demonstrated for the first time the PPT lesion (novel experimental model of PD cholinergic neuropathology) induced sustained and more severe sleep disturbances expressed as: the Wake/REM and REM/Wake transitions increase, augmented cortical activation across all sleep/wake states, potentiation of two distinct REM clusters, and dominant sensorimotor cortex-dorsal nuchal muscle drive alteration throughout the REM/REM1/REM2 beta CMC decrease.",
publisher = "Belgrade: University of Belgrade, Faculty of Biology",
journal = "University of Belgrade, Faculty of Biology",
title = "Spavanje i elektroencefalografski ritmovi kao indikatori poremećaja funkcionalno različitih holinergičkih inervacija velikog mozga pacova, Sleep and electroencephalographic rhythms as an indicators of the functionally distinct cholinergic innervation disorders in rat brain",
pages = "1-156",
url = "https://hdl.handle.net/21.15107/rcub_nardus_5447"
}

Petrović, J.. (2015). Spavanje i elektroencefalografski ritmovi kao indikatori poremećaja funkcionalno različitih holinergičkih inervacija velikog mozga pacova. in University of Belgrade, Faculty of Biology
Belgrade: University of Belgrade, Faculty of Biology., 1-156.
https://hdl.handle.net/21.15107/rcub_nardus_5447

Petrović J. Spavanje i elektroencefalografski ritmovi kao indikatori poremećaja funkcionalno različitih holinergičkih inervacija velikog mozga pacova. in University of Belgrade, Faculty of Biology. 2015;:1-156.
https://hdl.handle.net/21.15107/rcub_nardus_5447 .

Petrović, Jelena, "Spavanje i elektroencefalografski ritmovi kao indikatori poremećaja funkcionalno različitih holinergičkih inervacija velikog mozga pacova" in University of Belgrade, Faculty of Biology (2015):1-156,
https://hdl.handle.net/21.15107/rcub_nardus_5447 .

TY  - JOUR
AU  - Petrović, Jelena
AU  - Ćirić, Jelena
AU  - Lazić, Katarina
AU  - Kalauzi, Aleksandar
AU  - Šaponjić, Jasna
PY  - 2013
UR  - http://www.scopus.com/inward/record.url?eid=2-s2.0-84881370170&partnerID=tZOtx3y1
UR  - http://www.sciencedirect.com/science/article/pii/S0014488613000605
UR  - http://www.ncbi.nlm.nih.gov/pubmed/23481548
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3298
AB  - The pedunculopontine tegmental nucleus (PPT) represents a major aggregation of cholinergic neurons in the mammalian brainstem, which is important in the generation and maintenance of REM sleep. We investigated the effects of unilateral and bilateral PPT lesions on sleep and all the conventional sleep-state related EEG frequency bands amplitudes, in an attempt to find the EEG markers for the onset and progression of PPT cholinergic neuronal degeneration. The experiments were performed on 35 adult male Wistar rats, chronically implanted for sleep recording. During the surgical procedure for EEG and EMG electrodes implantation, the unilateral or bilateral PPT lesion was produced under ketamine/diazepam anesthesia, by the stereotaxically guided microinfusion of 100 nl 0.1M ibotenic acid (IBO) into PPT. We applied Fourier analysis to signals acquired throughout 6h of recordings, and each 10s epoch was differentiated as a Wake, NREM or REM state. We also calculated the group probability density estimates (PDE) of all Wake, NREM and REM conventional EEG frequency amplitudes, and the number of all the transition states using MATLAB 6.5. Our results show that the unilateral or bilateral PPT lesions did not change the sleep/wake architecture, but did change the sleep/wake state transitions structure and the sleep/state related "EEG microstructure". Unilateral or bilateral PPT lesions sustainably increased Wake/REM and REM/Wake transitions from 14 to 35 days after lesions. This was followed by decreased NREM/REM and REM/NREM transitions from 28 days only in the case of the bilateral PPT lesion. The unilateral PPT lesion augmented both Wake theta and REM beta while it also attenuated the relative amplitude of the Wake delta frequency, with a delay of one week. Following a bilateral PPT lesion there was augmentation of the relative amplitude of the Wake, NREM, and REM beta and REM gamma frequency which occurred simultaneously to NREM and Wake delta attenuation. We have shown that the PPT cholinergic neuronal loss sustainably increased the number of the Wake/REM and REM/Wake transitions and augmented sleep-states related cortical activation that was simultaneously expressed by the high frequency amplitude augmentation, as well as Wake and NREM delta frequency attenuation.
T2  - Experimental Neurology
T1  - Lesion of the pedunculopontine tegmental nucleus in rat augments cortical activation and disturbs sleep/wake state transitions structure.
VL  - 247
DO  - 10.1016/j.expneurol.2013.02.007
SP  - 562
EP  - 71
ER  - 

@article{
author = "Petrović, Jelena and Ćirić, Jelena and Lazić, Katarina and Kalauzi, Aleksandar and Šaponjić, Jasna",
year = "2013",
abstract = "The pedunculopontine tegmental nucleus (PPT) represents a major aggregation of cholinergic neurons in the mammalian brainstem, which is important in the generation and maintenance of REM sleep. We investigated the effects of unilateral and bilateral PPT lesions on sleep and all the conventional sleep-state related EEG frequency bands amplitudes, in an attempt to find the EEG markers for the onset and progression of PPT cholinergic neuronal degeneration. The experiments were performed on 35 adult male Wistar rats, chronically implanted for sleep recording. During the surgical procedure for EEG and EMG electrodes implantation, the unilateral or bilateral PPT lesion was produced under ketamine/diazepam anesthesia, by the stereotaxically guided microinfusion of 100 nl 0.1M ibotenic acid (IBO) into PPT. We applied Fourier analysis to signals acquired throughout 6h of recordings, and each 10s epoch was differentiated as a Wake, NREM or REM state. We also calculated the group probability density estimates (PDE) of all Wake, NREM and REM conventional EEG frequency amplitudes, and the number of all the transition states using MATLAB 6.5. Our results show that the unilateral or bilateral PPT lesions did not change the sleep/wake architecture, but did change the sleep/wake state transitions structure and the sleep/state related "EEG microstructure". Unilateral or bilateral PPT lesions sustainably increased Wake/REM and REM/Wake transitions from 14 to 35 days after lesions. This was followed by decreased NREM/REM and REM/NREM transitions from 28 days only in the case of the bilateral PPT lesion. The unilateral PPT lesion augmented both Wake theta and REM beta while it also attenuated the relative amplitude of the Wake delta frequency, with a delay of one week. Following a bilateral PPT lesion there was augmentation of the relative amplitude of the Wake, NREM, and REM beta and REM gamma frequency which occurred simultaneously to NREM and Wake delta attenuation. We have shown that the PPT cholinergic neuronal loss sustainably increased the number of the Wake/REM and REM/Wake transitions and augmented sleep-states related cortical activation that was simultaneously expressed by the high frequency amplitude augmentation, as well as Wake and NREM delta frequency attenuation.",
journal = "Experimental Neurology",
title = "Lesion of the pedunculopontine tegmental nucleus in rat augments cortical activation and disturbs sleep/wake state transitions structure.",
volume = "247",
doi = "10.1016/j.expneurol.2013.02.007",
pages = "562-71"
}

Petrović, J., Ćirić, J., Lazić, K., Kalauzi, A.,& Šaponjić, J.. (2013). Lesion of the pedunculopontine tegmental nucleus in rat augments cortical activation and disturbs sleep/wake state transitions structure.. in Experimental Neurology, 247, 562-71.
https://doi.org/10.1016/j.expneurol.2013.02.007

Petrović J, Ćirić J, Lazić K, Kalauzi A, Šaponjić J. Lesion of the pedunculopontine tegmental nucleus in rat augments cortical activation and disturbs sleep/wake state transitions structure.. in Experimental Neurology. 2013;247:562-71.
doi:10.1016/j.expneurol.2013.02.007 .

Petrović, Jelena, Ćirić, Jelena, Lazić, Katarina, Kalauzi, Aleksandar, Šaponjić, Jasna, "Lesion of the pedunculopontine tegmental nucleus in rat augments cortical activation and disturbs sleep/wake state transitions structure." in Experimental Neurology, 247 (2013):562-71,
https://doi.org/10.1016/j.expneurol.2013.02.007 . .