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Mechanisms of decreased cholinergic arousal in focal seizures: In vivo whole-cell recordings from the pedunculopontine tegmental nucleus.

ABSTRACT: Focal limbic seizures often impair consciousness/awareness with major negative impact on quality of life. Recent work has shown that limbic seizures depress brainstem arousal systems, including reduced action potential firing in a key node: cholinergic neurons of the pedunculopontine tegmental nucleus (PPT). In vivo whole-cell recordings have not previously been achieved in PPT, but are used here with the goal of elucidating the mechanisms of reduced PPT cholinergic neuronal activity. An established model of focal limbic seizures was used in rats following brief hippocampal stimulation under light anesthesia. Whole-cell in vivo recordings were obtained from PPT neurons using custom-fabricated 9-10?mm tapered patch pipettes, and cholinergic neurons were identified histologically. Average membrane potential, input resistance, membrane potential fluctuations and variance were analyzed during seizures. A subset of PPT neurons exhibited reduced firing and hyperpolarization during seizures and stained positive for choline acetyltransferase. These PPT neurons showed a mean membrane potential hyperpolarization of -3.82?mV (±0.81 SEM, P?

SUBMITTER: Andrews JP

PROVIDER: S-EPMC6503533 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Mechanisms of decreased cholinergic arousal in focal seizures: In vivo whole-cell recordings from the pedunculopontine tegmental nucleus.

Andrews John P JP Yue Zongwei Z Ryu Jun Hwan JH Neske Garrett G McCormick David A DA Blumenfeld Hal H

Experimental neurology 20181210

Focal limbic seizures often impair consciousness/awareness with major negative impact on quality of life. Recent work has shown that limbic seizures depress brainstem arousal systems, including reduced action potential firing in a key node: cholinergic neurons of the pedunculopontine tegmental nucleus (PPT). In vivo whole-cell recordings have not previously been achieved in PPT, but are used here with the goal of elucidating the mechanisms of reduced PPT cholinergic neuronal activity. An establi ...[more]

PMID: 30543800

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Project description:BackgroundThe etiology of cervical dystonia is unknown. Cholinergic abnormalities have been identified in dystonia animal models and human imaging studies. Some animal models have cholinergic neuronal loss in the striatum and increased acetylcholinesterase activity in the pedunculopontine nucleus.ObjectivesThe objective of this study was to determine the presence of cholinergic abnormalities in the putamen and pedunculopontine nucleus in cervical dystonia human brain donors.MethodsFormalin-fixed brain tissues were obtained from 8 cervical dystonia and 7 age-matched control brains (controls). Pedunculopontine nucleus was available in only 6 cervical dystonia and 5 controls. Neurodegeneration was evaluated pathologically in the putamen, pedunculopontine nucleus, and other regions. Cholinergic neurons were detected using choline acetyltransferase immunohistochemistry in the putamen and pedunculopontine nucleus. Putaminal cholinergic neurons were quantified. A total of 6 cervical dystonia patients and 6 age-matched healthy controls underwent diffusion tensor imaging to determine if there were white matter microstructural abnormalities around the pedunculopontine nucleus.ResultsDecreased or absent choline acetyltransferase staining was identified in all 6 pedunculopontine nucleus samples in cervical dystonia. In contrast, strong choline acetyltransferase staining was present in 4 of 5 pedunculopontine nucleus controls. There were no differences in pedunculopontine nucleus diffusion tensor imaging between cervical dystonia and healthy controls. There was no difference in numbers of putaminal cholinergic neurons between cervical dystonia and controls.ConclusionsOur findings suggest that pedunculopontine nucleus choline acetyltransferase deficiency represents a functional cholinergic deficit in cervical dystonia. Structural lesions and confounding neurodegenerative processes were excluded by absence of neuronal loss, gliosis, diffusion tensor imaging abnormalities, and beta-amyloid, tau, and alpha-synuclein pathologies. © 2018 International Parkinson and Movement Disorder Society.

Project description:BackgroundIt is well established that nucleus basalis magnocellularis (NbM) lesions impair performance on tests of sustained attention. Previous work from this laboratory has also demonstrated that pedunculopontine tegmental nucleus (PPTg) lesioned rats make more omissions on a test of sustained attention, suggesting that it might also play a role in mediating this function. However, the results of the PPTg study were open to alternative interpretation. We aimed to resolve this by conducting a detailed analysis of the effects of damage to each brain region in the same sustained attention task used in our previous work. Rats were trained in the task before surgery and post-surgical testing examined performance in response to unpredictable light signals of 1500 ms and 4000 ms duration. Data for PPTg lesioned rats were compared to control rats, and rats with 192 IgG saporin infusions centred on the NbM. In addition to operant data, video data of rats' performance during the task were also analysed.ResultsBoth lesion groups omitted trials relative to controls but the effect was milder and transient in NbM rats. The number of omitted trials decreased in all groups when tested using the 4000 ms signal compared to the 1500 ms signal. This confirmed previous findings for PPTg lesioned rats. Detailed analysis revealed that the increase in omissions in PPTg rats was not a consequence of motor impairment. The video data (taken on selected days) showed reduced lever orientation in PPTg lesioned rats, coupled with an increase in unconditioned behaviours such as rearing and sniffing. In contrast NbM rats showed evidence of inadequate lever pressing.ConclusionThe question addressed here is whether the PPTg and NbM both have a role in sustained attention. Rats bearing lesions of either structure showed deficits in the test used. However, we conclude that the most parsimonious explanation for the deficit observed in PPTg rats is inadequate response organization, rather than impairment in sustained attention. Furthermore the impairment observed in NbM lesioned rats included lever pressing difficulties in addition to impaired sustained attention. Unfortunately we could not link these deficits directly to cholinergic neuronal loss.

Project description:The pedunculopontine nucleus (PPN) is a part of the reticular activating system which is composed of cholinergic, glutamatergic and GABAergic neurons. Early electrophysiological studies characterized and grouped PPN neurons based on certain functional properties (i.e., the presence or absence of the A-current, spike latency, and low threshold spikes). Although other electrophysiological characteristics of these neurons were also described (as high threshold membrane potential oscillations, great differences in spontaneous firing rate and the presence or absence of the M-current), systematic assessment of these properties and correlation of them with morphological markers are still missing. In this work, we conducted electrophysiological experiments on brain slices of genetically identified cholinergic neurons in the PPN. Electrophysiological properties were compared with rostrocaudal location of the neuronal soma and selected morphometric features obtained with post hoc reconstruction. We found that functional subgroups had different proportions in the rostral and caudal subregions of the nucleus. Neurons with A-current can be divided to early-firing and late-firing neurons, where the latter type was found exclusively in the caudal subregion. Similar to this, different parameters of high threshold membrane potential oscillations also showed characteristic rostrocaudal distribution. Furthermore, based on our data, we propose that high threshold oscillations rather emerge from neuronal somata and not from the proximal dendrites. In summary, we demonstrated the existence and spatial distribution of functional subgroups of genetically identified PPN cholinergic neurons, which are in accordance with differences found in projection and in vivo functional findings of the subregions. Being aware of functional differences of PPN subregions will help the design and analysis of experiments using genetically encoded opto- and chemogenetic markers for in vivo experiments.

Dataset Information

Mechanisms of decreased cholinergic arousal in focal seizures: In vivo whole-cell recordings from the pedunculopontine tegmental nucleus.

Publications

Mechanisms of decreased cholinergic arousal in focal seizures: In vivo whole-cell recordings from the pedunculopontine tegmental nucleus.

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