scholarly journals Computational Evidence for a Competitive Thalamocortical Model of Spikes and Spindle Activity in Rolandic Epilepsy

2021 ◽  
Vol 15 ◽  
Author(s):  
Qiang Li ◽  
M. Brandon Westover ◽  
Rui Zhang ◽  
Catherine J. Chu
Keyword(s):  
Nrem Sleep ◽  
Mechanistic Explanation ◽  
Epileptic Encephalopathy ◽  
Thalamic Reticular Nucleus ◽  
School Age Children ◽  
Reticular Nucleus ◽  
Epilepsy Syndrome ◽  
Sleep Spindles ◽  
Rolandic Epilepsy ◽  
Nmda Current

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy syndrome, characterized by sleep-activated epileptiform spikes and seizures and cognitive deficits in school age children. Recent evidence suggests that this disease may be caused by disruptions to the Rolandic thalamocortical circuit, resulting in both an abundance of epileptiform spikes and a paucity of sleep spindles in the Rolandic cortex during non-rapid eye movement sleep (NREM); electrographic features linked to seizures and cognitive symptoms, respectively. The neuronal mechanisms that support the competitive shared thalamocortical circuitry between pathological epileptiform spikes and physiological sleep spindles are not well-understood. In this study we introduce a computational thalamocortical model for the sleep-activated epileptiform spikes observed in RE. The cellular and neuronal circuits of this model incorporate recent experimental observations in RE, and replicate the electrophysiological features of RE. Using this model, we demonstrate that: (1) epileptiform spikes can be triggered and promoted by either a reduced NMDA current or h-type current; and (2) changes in inhibitory transmission in the thalamic reticular nucleus mediates an antagonistic dynamic between epileptiform spikes and spindles. This work provides the first computational model that both recapitulates electrophysiological features and provides a mechanistic explanation for the thalamocortical switch between the pathological and physiological electrophysiological rhythms observed during NREM sleep in this common epileptic encephalopathy.

scholarly journals 0028 GABAA Receptors Of The Thalamic Reticular Nucleus Regulate Sleep Spindles: An In Vivo Investigation By CRISPR-cas9 Genetic Abscission

SLEEP ◽  
2018 ◽  
Vol 41 (suppl_1) ◽  
pp. A12-A12
Author(s):  
D S Uygun ◽  
C Yang ◽  
H Miwa ◽  
J T McKenna ◽  
J M McNally ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Sleep Spindles

scholarly journals Abnormal Sleep Spindles, Memory Consolidation, and Schizophrenia

2019 ◽  
Vol 15 (1) ◽  
pp. 451-479 ◽  
Author(s):  
Dara S. Manoach ◽  
Robert Stickgold
Keyword(s):  
Memory Consolidation ◽  
Sensory Information ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Future Research ◽  
Sleep Spindles ◽  
Treatment And Prevention ◽  
Overwhelming Evidence ◽  
Stage 2 Sleep ◽  
Impaired Sleep

There is overwhelming evidence that sleep is crucial for memory consolidation. Patients with schizophrenia and their unaffected relatives have a specific deficit in sleep spindles, a defining oscillation of non-rapid eye movement (NREM) Stage 2 sleep that, in coordination with other NREM oscillations, mediate memory consolidation. In schizophrenia, the spindle deficit correlates with impaired sleep-dependent memory consolidation, positive symptoms, and abnormal thalamocortical connectivity. These relations point to dysfunction of the thalamic reticular nucleus (TRN), which generates spindles, gates the relay of sensory information to the cortex, and modulates thalamocortical communication. Genetic studies are beginning to provide clues to possible neurodevelopmental origins of TRN-mediated thalamocortical circuit dysfunction and to identify novel targets for treating the related memory deficits and symptoms. By forging empirical links in causal chains from risk genes to thalamocortical circuit dysfunction, spindle deficits, memory impairment, symptoms, and diagnosis, future research can advance our mechanistic understanding, treatment, and prevention of schizophrenia.

scholarly journals 0071 Perineuronal Nets In The Thalamic Reticular Nucleus Regulate Neuronal Excitability And Gate Coupling Of Sleep Spindles To Cortical Slow Waves

SLEEP ◽  
2018 ◽  
Vol 41 (suppl_1) ◽  
pp. A29-A29
Author(s):  
J T McKenna ◽  
C Yang ◽  
F Katsuki ◽  
R E Strecker ◽  
R Basheer ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Slow Waves ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Sleep Spindles ◽  
Perineuronal Nets

scholarly journals Sleep-related thalamocortical spindles and delta oscillations are reduced during a ketamine-induced psychosis-relevant transition state

2019 ◽  
Author(s):  
A Mahdavi ◽  
Y Qin ◽  
A-S Aubry ◽  
D Cornec ◽  
S Kulikova ◽  
...  
Keyword(s):  
Transition State ◽  
Glutamate Receptors ◽  
Firing Pattern ◽  
Low Dose ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Sleep Spindles ◽  
Gamma Frequency ◽  
Underlying Mechanisms ◽  
Delta Oscillations

ABSTRACTBackgroundIn schizophrenia, sleep spindles are reduced, supporting the hypothesis that the thalamus and glutamate receptors play a crucial etio-pathophysiological role, whose underlying mechanisms remain unknown. We hypothesized that a reduced function of NMDA receptors is involved in the psychosis-related spindle deficit.MethodsAn electrophysiological multisite cell-to-network exploration was used to investigate, in sleeping rats, the effects of a ketamine-induced psychosis-relevant transition state in the sensorimotor and associative/cognitive thalamocortical (TC) systems.ResultsUnder the control condition, spontaneously-occurring spindles (intra-frequency: 10-16 waves/s) and delta-frequency (1-4Hz) oscillations were recorded in the EEG of the frontoparietal cortex, in thalamic extracellular recordings (n=16), in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons (n=8), and in intracellularly recorded TC neurons (n=8). The TRN cells rhythmically exhibited robust high-frequency bursts of action potentials (7 to 15 APs at 200-700 Hz). A single administration of low-dose ketamine fleetingly reduced TC spindles and delta oscillations, amplified ongoing gamma-(30-80Hz) and higher-frequency oscillations, and switched the firing pattern of both TC and TRN neurons from a burst mode to a single AP mode. Furthermore, ketamine strengthened the gamma-frequency band TRN-TC connectivity (n=11). The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta- and gamma-/higher-frequency TC oscillations (n=7).ConclusionThe present findings support the hypothesis that NMDA receptor hypofunction is involved in the psychosis-related reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion (from burst to single APs) of ongoing TC-TRN activities may have involved both the ascending reticular activating system and the corticothalamic pathway.LAY ABSTRACTSchizophrenia is a chronic debilitating disease. Sleep disturbances associated with a reduction in spindles are observed as warning signs prior to the first psychotic episode. Every spindle is a short-lasting (~0.5 s) set of bioelectric sinusoidal waves at the frequency of 10-16 Hz generated within the thalamus. Sleep spindles, easily identifiable in a scalp electroencephalogram, occur hundreds of times during sleep and are implicated in cognition like memory processes. For this reason, spindles are seen as an electro-biomarker of the quality of sleep and cognitive performance. In patients at high risk of psychotic transition, the density (number/time unit) of spindles is reduced. The underlying mechanisms of this change are unknown. Glutamate-mediated neurotransmission in the thalamus plays a key role in the generation of spindles and the etiology of schizophrenia. Therefore, we tested the hypothesis that a reduced function of glutamate receptors at the thalamic level is involved in the psychosis-related reduction in spindles. Using cell-to-network neurophysiological methods in sleeping rats, we demonstrate that systemic administration of the NMDA glutamate receptor antagonist, ketamine, significantly decreases spindle density. This effect is consistently prevented by the widely used antipsychotic drug, clozapine. These original findings support the hypothesis of the involvement of a reduced function of NMDA glutamate receptors in the sleep spindle deficit observed in psychosis-related disorders. The present findings lay the foundation for the development of innovative therapies aimed at preventing psychotic, bipolar, and depressive disorders.HIGHLIGHTSLow-dose ketamine has a fast onset arousal promoting effect.Ketamine fleetingly reduces, in the first-/higher-order thalamocortical systems, sleep spindles and slow-waves, and amplifies gamma- and higher-frequency oscillations.Ketamine switches the firing pattern from a burst mode to a single action potential mode in both the glutamatergic thalamocortical neurons and the GABAergic thalamic reticular nucleus neurons.Ketamine strengthens the gamma-frequency band connectivity between thalamocortical and thalamic reticular nucleus neurons.The reference antipsychotic clozapine consistently prevents the ketamine effects.

scholarly journals Selectively driving cholinergic fibers optically in the thalamic reticular nucleus promotes sleep

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Kun-Ming Ni ◽  
Xiao-Jun Hou ◽  
Ci-Hang Yang ◽  
Ping Dong ◽  
Yue Li ◽  
...  
Keyword(s):  
Eye Movement ◽  
Nicotinic Acetylcholine Receptors ◽  
Rem Sleep ◽  
Sleep Onset ◽  
Cholinergic Neurons ◽  
Nrem Sleep ◽  
Gabaergic Neurons ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Rapid Eye Movement

Cholinergic projections from the basal forebrain and brainstem are thought to play important roles in rapid eye movement (REM) sleep and arousal. Using transgenic mice in which channelrhdopsin-2 is selectively expressed in cholinergic neurons, we show that optical stimulation of cholinergic inputs to the thalamic reticular nucleus (TRN) activates local GABAergic neurons to promote sleep and protect non-rapid eye movement (NREM) sleep. It does not affect REM sleep. Instead, direct activation of cholinergic input to the TRN shortens the time to sleep onset and generates spindle oscillations that correlate with NREM sleep. It does so by evoking excitatory postsynaptic currents via α7-containing nicotinic acetylcholine receptors and inducing bursts of action potentials in local GABAergic neurons. These findings stand in sharp contrast to previous reports of cholinergic activity driving arousal. Our results provide new insight into the mechanisms controlling sleep.

scholarly journals Microglia modulate stable wakefulness via the thalamic reticular nucleus in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hanxiao Liu ◽  
Xinxing Wang ◽  
Lu Chen ◽  
Liang Chen ◽  
Stella E. Tsirka ◽  
...  
Keyword(s):  
Diurnal Variation ◽  
Eye Movement ◽  
Nrem Sleep ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Rapid Eye Movement ◽  
Metabolomic Analysis ◽  
The Brain ◽  
Ceramide Production ◽  
Brain Homeostasis

AbstractMicroglia are important for brain homeostasis and immunity, but their role in regulating vigilance remains unclear. We employed genetic, physiological, and metabolomic methods to examine microglial involvement in the regulation of wakefulness and sleep. Microglial depletion decreased stable nighttime wakefulness in mice by increasing transitions between wakefulness and non-rapid eye movement (NREM) sleep. Metabolomic analysis revealed that the sleep-wake behavior closely correlated with diurnal variation of the brain ceramide, which disappeared in microglia-depleted mice. Ceramide preferentially influenced microglia in the thalamic reticular nucleus (TRN), and local depletion of TRN microglia produced similar impaired wakefulness. Chemogenetic manipulations of anterior TRN neurons showed that they regulated transitions between wakefulness and NREM sleep. Their firing capacity was suppressed by both microglial depletion and added ceramide. In microglia-depleted mice, activating anterior TRN neurons or inhibiting ceramide production both restored stable wakefulness. These findings demonstrate that microglia can modulate stable wakefulness through anterior TRN neurons via ceramide signaling.

scholarly journals Deficient thalamo-cortical networks dynamics and sleep homeostatic processes in a redox dysregulation model relevant to schizophrenia.

2021 ◽  
Author(s):  
Christina Czekus ◽  
Pascal Steullet ◽  
Thomas Rusterholz ◽  
Ivan Bozic ◽  
Kim Do Cuenod ◽  
...  
Keyword(s):  
Recovery Period ◽  
Nrem Sleep ◽  
Sleep Architecture ◽  
Anterior Cingulate ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Glutathione Synthetase ◽  
Cortical Networks ◽  
Dorsal Thalamus ◽  
Sleep Homeostasis

A growing body of evidence implicates thalamo-cortical oscillations with the neuropathophysiology of schizophrenia (SZ) in both mice and humans. Yet, the precise mechanisms underlying sleep perturbations in SZ remain unclear. Here, we characterised the dynamics of thalamo-cortical networks across sleep-wake states in a mouse model carrying a mutation in the enzyme glutathione synthetase gene (Gclm-/-) associated with SZ in humans. We hypothesised that deficits in parvalbumin immunoreactive cells in the thalamic reticular nucleus (TRN) and the anterior cingulate cortex (ACC) -caused by oxidative stress - impact thalamocortical dynamics, thus affecting non-rapid eye movement (NREM) sleep and sleep homeostasis. Using polysomnographic recordings in mice, we showed that KO mice exhibited a fragmented sleep architecture, similar to SZ patients and altered sleep homeostasis responses revealed by an increase in NREM latency and slow wave activities during the recovery period (SR). Although NREM sleep spindle rate during spontaneous sleep was similar in Gclm-/- and Gcml +/+, KO mice lacked a proper homeostatic response during SR. Interestingly, using multisite electrophysiological recordings in freely-moving mice, we found that high order thalamic network dynamics showed increased synchronisation, that was exacerbated during the sleep recovery period subsequent to extended wakefulness (SD), possibly due to lower bursting activity in TRN-antero dorsal thalamus circuit in KO compared to WT littermates. Collectively, these findings provide a mechanism for SZ associated deficits of thalamo-cortical neuron dynamics and perturbations of sleep architecture.

scholarly journals 0129 LOCAL THALAMIC RETICULAR NUCLEUS INHIBITION OF T-TYPE CALCIUM CHANNELS REDUCES SLEEP SPINDLES IN MICE

SLEEP ◽  
2017 ◽  
Vol 40 (suppl_1) ◽  
pp. A48-A48
Author(s):  
JM McNally ◽  
C Shukla ◽  
S Thankachan ◽  
JT McKenna ◽  
C Yang ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Sleep Spindles

scholarly journals Thalamic Reticular Nucleus Parvalbumin Neurons Regulate Sleep Spindles and Electrophysiological Aspects of Schizophrenia in Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Stephen Thankachan ◽  
Fumi Katsuki ◽  
James T. McKenna ◽  
Chun Yang ◽  
Charu Shukla ◽  
...  
Keyword(s):  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Sleep Spindles ◽  
Parvalbumin Neurons

scholarly journals The Contribution of Thalamocortical Core and Matrix Pathways to Sleep Spindles

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Giovanni Piantoni ◽  
Eric Halgren ◽  
Sydney S. Cash
Keyword(s):  
Cortical Neurons ◽  
Computational Models ◽  
Spatial Scales ◽  
Fundamental Principle ◽  
Thalamic Reticular Nucleus ◽  
Reticular Nucleus ◽  
Sleep Spindles ◽  
Thalamocortical Projections ◽  
The Matrix ◽  
Intracranial Recordings

Sleep spindles arise from the interaction of thalamic and cortical neurons. Neurons in the thalamic reticular nucleus (TRN) inhibit thalamocortical neurons, which in turn excite the TRN and cortical neurons. A fundamental principle of anatomical organization of the thalamocortical projections is the presence of two pathways: the diffuse matrix pathway and the spatially selective core pathway. Cortical layers are differentially targeted by these two pathways with matrix projections synapsing in superficial layers and core projections impinging on middle layers. Based on this anatomical observation, we propose that spindles can be classified into two classes, those arising from the core pathway and those arising from the matrix pathway, although this does not exclude the fact that some spindles might combine both pathways at the same time. We find evidence for this hypothesis in EEG/MEG studies, intracranial recordings, and computational models that incorporate this difference. This distinction will prove useful in accounting for the multiple functions attributed to spindles, in that spindles of different types might act on local and widespread spatial scales. Because spindle mechanisms are often hijacked in epilepsy and schizophrenia, the classification proposed in this review might provide valuable information in defining which pathways have gone awry in these neurological disorders.

Sign in / Sign up

Export Citation Format

Share Document