Derailment of Sleep Homeostatic Plasticity Affects the Most Plastic Brain Systems and Carries the Risk of Epilepsy.

Although a critical link between non-rapid eye movement (NREM) sleep and epilepsy has long been suspected, the interconnecting mechanisms have remained obscure. However, recent advances in sleep research have provided some clues. Sleep homeostatic plasticity is now recognized as an engine of the synaptic economy and a feature of the brain's ability to adapt to changing demands. This allows epilepsy to be understood as a cost of brain plasticity. On the one hand, plasticity is a force for development, but on the other it opens the possibility of epileptic derailment. Here, we provide a summary of the phenomena that link sleep and epilepsy. The concept of "system epilepsy", or epilepsy as a network disease, is introduced as a general approach to understanding the major epilepsy syndromes, i.e., epilepsies building upon functional brain networks. We discuss how epileptogenesis results in certain major epilepsies following the derailment of NREM sleep homeostatic plasticity. Post-traumatic epilepsy is presented as a general model for this kind of epileptogenesis.

Respiration organizes gamma synchrony in the prefronto-thalamic network.

Multiple cognitive operations are associated with the emergence of gamma oscillations in the medial prefrontal cortex (mPFC) although little is known about the mechanisms that control this rhythm. Using local field potential recordings from cats, we show that periodic bursts of gamma recur with 1 Hz regularity in the wake mPFC and are locked to the exhalation phase of the respiratory cycle. Respiration organizes long-range coherence in the gamma band between the mPFC and the nucleus reuniens the thalamus (Reu), linking the prefrontal cortex and the hippocampus. In vivo intracellular recordings of the mouse thalamus reveal that respiration timing is propagated by synaptic activity in Reu and likely underlies the emergence of gamma bursts in the prefrontal cortex. Our findings highlight breathing as an important substrate for long-range neuronal synchronization across the prefrontal circuit, a key network for cognitive operations.

Sleep, oscillations, and epilepsy.

Sleep and wake are defined through physiological and behavioral criteria and can be typically separated into non-rapid eye movement (NREM) sleep stages N1, N2, and N3, rapid eye movement (REM) sleep, and wake. Sleep and wake states are not homogenous in time. Their properties vary during the night and day cycle. Given that brain activity changes as a function of NREM, REM, and wake during the night and day cycle, are seizures more likely to occur during NREM, REM, or wake at a specific time? More generally, what is the relationship between sleep-wake cycles and epilepsy? We will review specific examples from clinical data and results from experimental models, focusing on the diversity and heterogeneity of these relationships. We will use a top-down approach, starting with the general architecture of sleep, followed by oscillatory activities, and ending with ionic correlates selected for illustrative purposes, with respect to seizures and interictal spikes. The picture that emerges is that of complexity; sleep disruption and pathological epileptic activities emerge from reorganized circuits. That different circuit alterations can occur across patients and models may explain why sleep alterations and the timing of seizures during the sleep-wake cycle are patient-specific.

Brain states in freely behaving marmosets.

STUDY OBJECTIVES: We evaluated common marmosets as a perspective animal model to study human sleep and wake states. METHODS: Using wireless neurologger recordings, we performed longitudinal multichannel local field potential (LFP) cortical, hippocampal, neck muscle, and video recordings in three freely behaving marmosets. The brain states were formally identified using self-organizing maps. RESULTS: Marmosets were generally awake during the day with occasional 1-2 naps, and they slept during the night. Major electrographic patterns fall in five clearly distinguished categories: wakefulness, drowsiness, light and deep NREM sleep, and REM. Marmosets typically had 14-16 sleep cycles per night, with either gradually increasing or relatively low, but stable delta power within the cycle. Overall, the delta power decreased throughout the night sleep. Marmosets demonstrated prominent high amplitude somatosensory mu-rhythm (10-15 Hz), accompanied with neocortical ripples, and alternated with occipital alpha rhythm (10-15 Hz). NREM sleep was characterized with the presence of high amplitude slow waves, sleep spindles and ripples in neocortex, and sharp-wave-ripple complexes in CA1. Light and deep stages differed in levels of delta and sigma power and muscle tone. REM sleep was defined with low muscle tone and activated LFP with predominant beta-activity and rare spindle-like or mu-like events. CONCLUSIONS: Multiple features of sleep-wake state distribution and electrographic patterns associated with behavioral states in marmosets closely match human states, although marmoset have shorter sleep cycles. This demonstrates that marmosets represent an excellent model to study origin of human electrographical rhythms and brain states.

Compulsive Eating in a Rat Model of Binge Eating Disorder Under Conditioned Fear and Exploration of Neural Mechanisms With c-fos mRNA Expression.

Compulsive eating is the most obstinate feature of binge eating disorder. In this study, we observed the compulsive eating in our stress-induced binge-like eating rat model using a conflicting test, where sucrose and an aversively conditioned stimulus were presented at the same time. In this conflicting situation, the binge-like eating prone rats (BEPs), compared to the binge-like eating resistant rats (BERs), showed persistent high sucrose intake and inhibited fear response, respectively, indicating a deficit in palatability devaluation and stronger anxiolytic response to sucrose in the BEPs. We further analyzed the neuronal activation with c-fos mRNA in situ hybridization. Surprisingly, the sucrose access under conditioned fear did not inhibit the activity of amygdala; instead, it activated the central amygdala. In the BEPs, sucrose reduced the response of the paraventricular hypothalamic nucleus (PVN), while enhancing activities in the lateral hypothalamic area (LHA) to the CS. The resistance to devaluating the palatable food in the BEPs could be a result of persistent Acb response to sucrose intake and attenuated recruitment of the medial prefrontal cortex (mPFC). We interpret this finding as that the reward system of the BEPs overcame the homeostasis system and the stress-responding system.

Just a sound: A non-pharmacological treatment approach in epilepsy.

Benign epilepsy with centro-temporal spikes is typically not treated by antiepileptic drugs, but it leads to cognitive disfunctions. In this issue, Klinzing et al.1 demonstrate that closed-loop auditory stimulation delivered after paroxysmal spikes reduces the total number of paroxysmal spikes.

Neuronal activities during palatable food consumption in the reward system of binge-like eating female rats.

Binge eating disorder (BED), characterized by bingeing episodes and compulsivity, is the most prevalent eating disorder; however, little is known about its neurobiological underpinnings. In humans, BED is associated with desensitization of the reward system, specifically, the medial prefrontal cortex (mPFC), nucleus accumbens (Acb), and ventral tegmental area (VTA). Additionally, BED patients feel relieved during bingeing, suggesting that bingeing helps to decrease the negative emotions they were feeling prior to the binge episode. However, the mechanisms that underlie this feeling of relief in BED patients have not been well investigated. To investigate neuronal activity before and during palatable food consumption in BED, we performed in vivo electrophysiological recordings in a binge-like eating rat model (bingeing, n = 12 and non-bingeing, n = 14) and analyzed the firing rate of neurons in the mPFC, Acb, and VTA before and during access to sucrose solution. We also investigated changes in the firing rate of neurons in these regions during and between active bingeing, which may underlie the feeling of relief in BED patients. We found that neuronal firing rates of mPFC and VTA neurons in bingeing rats were lower than those in non-bingeing rats before and during sucrose consumption. Palatable food consumption increased neuronal firing rates during and between active bingeing in bingeing rats. Our results suggest a desynchronization in the activity of reward system regions, specifically in the mPFC, in bingeing rats, which may also contribute to BED. These results are consistent with those of functional magnetic resonance imaging (fMRI) studies that reported decreased activity in the reward system in BED patients. We propose that increased neuronal activity in the mPFC, Acb, or VTA produces an antidepressant effect in rats, which may underlie the sense of relief patients express during bingeing episodes.

A Wireless Electro-Optic Platform for Multimodal Electrophysiology and Optogenetics in Freely Moving Rodents.

This paper presents the design and the utilization of a wireless electro-optic platform to perform simultaneous multimodal electrophysiological recordings and optogenetic stimulation in freely moving rodents. The developed system can capture neural action potentials (AP), local field potentials (LFP) and electromyography (EMG) signals with up to 32 channels in parallel while providing four optical stimulation channels. The platform is using commercial off-the-shelf components (COTS) and a low-power digital field-programmable gate array (FPGA), to perform digital signal processing to digitally separate in real time the AP, LFP and EMG while performing signal detection and compression for mitigating wireless bandwidth and power consumption limitations. The different signal modalities collected on the 32 channels are time-multiplexed into a single data stream to decrease power consumption and optimize resource utilization. The data reduction strategy is based on signal processing and real-time data compression. Digital filtering, signal detection, and wavelet data compression are used inside the platform to separate the different electrophysiological signal modalities, namely the local field potentials (1-500 Hz), EMG (30-500 Hz), and the action potentials (300-5,000 Hz) and perform data reduction before transmitting the data. The platform achieves a measured data reduction ratio of 7.77 (for a firing rate of 50 AP/second) and weights 4.7 g with a 100-mAh battery, an on/off switch and a protective plastic enclosure. To validate the performance of the platform, we measured distinct electrophysiology signals and performed optogenetics stimulation in vivo in freely moving rondents. We recorded AP and LFP signals with the platform using a 16-microelectrode array implanted in the primary motor cortex of a Long Evans rat, both in anesthetized and freely moving conditions. EMG responses to optogenetic Channelrhodopsin-2 induced activation of motor cortex via optical fiber were also recorded in freely moving rodents.

Chronic Stress Induces Sex-Specific Functional and Morphological Alterations in Corticoaccumbal and Corticotegmental Pathways.

BACKGROUND: The medial prefrontal cortex (mPFC) is part of a complex circuit controlling stress responses by sending projections to different limbic structures including the nucleus accumbens (NAc) and ventral tegmental area (VTA). However, the impact of chronic stress on NAc- and VTA-projecting mPFC neurons is still unknown, and the distinct contribution of these pathways to stress responses in males and females is unclear. METHODS: Behavioral stress responses were induced by 21 days of chronic variable stress in male and female C57BL/6NCrl mice. An intersectional viral approach was used to label both pathways and assess the functional, morphological, and transcriptional adaptations in NAc- and VTA-projecting mPFC neurons in stressed males and females. Using chemogenetic approaches, we modified neuronal activity of NAc-projecting mPFC neurons to decipher their contribution to stress phenotypes. RESULTS: Chronic variable stress induced depressive-like behaviors in males and females. NAc- and VTA-projecting mPFC neurons exhibited sex-specific functional, morphological, and transcriptional alterations. The functional changes were more severe in females in NAc-projecting mPFC neurons, while males exhibited more drastic reductions in dendritic complexity in VTA-projecting mPFC neurons after chronic variable stress. Finally, chemogenetic overactivation of the corticoaccumbal pathway triggered anxiety and behavioral despair in both sexes, while its inhibition rescued the phenotype only in females. CONCLUSIONS: Our results suggest that stress responses in males and females result from pathway-specific changes in the activity of transcriptional programs controlling the morphological and synaptic properties of corticoaccumbal and corticotegmental pathways in a sex-specific fashion.

Differential Expression of DeltaFosB in Reward Processing Regions Between Binge Eating Prone and Resistant Female Rats.

Binge eating (BE) is characterized by the consumption of large amounts of palatable food in a discrete period and compulsivity. Even though BE is a common symptom in bulimia nervosa (BN), binge eating disorder (BED), and some cases of other specified feeding or eating disorders, little is known about its pathophysiology. We aimed to identify brain regions and neuron subtypes implicated in the development of binge-like eating in a female rat model. We separated rats into binge eating prone (BEP) and binge eating resistant (BER) phenotypes based on the amount of sucrose they consumed following foot-shock stress. We quantified deltaFosB (ΔFosB) expression, a stably expressed Fos family member, in different brain regions involved in reward, taste, or stress processing, to assess their involvement in the development of the phenotype. The number of ΔFosB-expressing neurons was: (1) higher in BEP than BER rats in reward processing areas [medial prefrontal cortex (mPFC), nucleus accumbens (Acb), and ventral tegmental area (VTA)]; (2) similar in taste processing areas [insular cortex, IC and parabrachial nucleus (PBN)]; and (3) higher in the paraventricular nucleus of BEP than BER rats, but not different in the locus coeruleus (LC), which are stress processing structures. To study subtypes of ΔFosB-expressing neurons in the reward system, we performed in situ hybridization for glutamate decarboxylase 65 and tyrosine hydroxylase (TH) mRNA after ΔFosB immunohistochemistry. In the mPFC and Acb, the proportions of γ-aminobutyric acidergic (GABAergic) and non-GABAergic ΔFosB-expressing neurons were similar in BER and BEP rats. In the VTA, while the proportion of dopaminergic ΔFosB-expressing neurons was similar in both phenotypes, the proportion of GABAergic ΔFosB-expressing neurons was higher in BER than BEP rats. Our results suggest that reward processing brain regions, particularly the VTA, are important for the development of binge-like eating.

Projections from the nucleus accumbens shell to the ventral pallidum are involved in the control of sucrose intake in adult female rats.

In rodents, stimulation of the nucleus accumbens shell (AcbSh) directly or via its projection to the lateral hypothalamus (LH) attenuates food intake. The ventral pallidum (VP) receives dense projections from the AcbSh and is sensitive to the hedonic aspect of food and motivation for reward. However, the role of accumbal projections to the VP in the regulation of food intake was not well investigated. In the present study conducted on female rats, we examined the effects of stimulation of the AcbSh using optogenetics, or pharmacological inhibition of the rostral VP, or stimulation of projections from the AcbSh to the rostral VP using optogenetics on the consumption of 10% sucrose, lick microstructure and the expression of c-fos mRNA. Stimulation of the AcbSh, inhibition of the rostral VP with muscimol, or stimulation of axonal terminals from the AcbSh to the rostral VP resulted in a decrease in sucrose intake, meal duration, and total number of licks. The licking microstructure analysis showed that optogenetic stimulation of AcbSh or axonal terminals from the AcbSh to the rostral VP decreased the hedonic value of the sucrose. However, inhibition of the rostral VP decreased the motivation, whereas stimulation of the accumbal projections in the rostral VP increased the motivation to drink. This difference could be due to differential involvement of GABAergic and glutamatergic VP neurons. Stimulation of the AcbSh resulted in a decrease of c-fos mRNA expression in the LH and rostral VP, and stimulation of axonal terminals from the AcbSh to the rostral VP decreased c-fos mRNA expression only in the rostral VP. This study demonstrates that in adult female rats, in addition to the already known role of the AcbSh projections to the LH, AcbSh projections to the VP play a major role in the regulation of sucrose intake.

Slow Wave Sleep Is a Promising Intervention Target for Alzheimer's Disease.

Alzheimer's disease (AD) is the major cause of dementia, characterized by the presence of amyloid-beta plaques and neurofibrillary tau tangles. Plaques and tangles are associated with sleep-wake cycle disruptions, including the disruptions in non-rapid eye movement (NREM) slow wave sleep (SWS). Alzheimer's patients spend less time in NREM sleep and exhibit decreased slow wave activity (SWA). Consistent with the critical role of SWS in memory consolidation, reduced SWA is associated with impaired memory consolidation in AD patients. The aberrant SWA can be modeled in transgenic mouse models of amyloidosis and tauopathy. Animal models exhibited slow wave impairments early in the disease progression, prior to the deposition of amyloid-beta plaques, however, in the presence of abundant oligomeric amyloid-beta. Optogenetic rescue of SWA successfully halted the amyloid accumulation and restored intraneuronal calcium levels in mice. On the other hand, optogenetic acceleration of slow wave frequency exacerbated amyloid deposition and disrupted neuronal calcium homeostasis. In this review, we summarize the evidence and the mechanisms underlying the existence of a positive feedback loop between amyloid/tau pathology and SWA disruptions that lead to further accumulations of amyloid and tau in AD. Moreover, since SWA disruptions occur prior to the plaque deposition, SWA disruptions may provide an early biomarker for AD. Finally, we propose that therapeutic targeting of SWA in AD might lead to an effective treatment for Alzheimer's patients.

Spatio-temporal properties of sleep slow waves and implications for development.

Objective sleep quality can be measured by electroencephalography (EEG), a non-invasive technique to quantify electrical activity generated by the brain. With EEG, sleep depth is measured by appearance and an increase in slow wave activity (scalp-SWA). EEG slow waves (scalp-SW) are the manifestation of underlying synchronous membrane potential transitions between silent (DOWN) and active (UP) states. This bistable periodic rhythm is defined as slow oscillation (SO). During its "silent state" cortical neurons are hyperpolarized and appear inactive, while during its "active state" cortical neurons are depolarized, fire spikes and exhibit continuous synaptic activity, excitatory and inhibitory. In adults, data from high-density EEG revealed that scalp-SW propagate across the cortical mantle in complex patterns. However, scalp-SW propagation undergoes modifications across development. We present novel data from children, indicating that scalp-SW originate centro-parietally, and emerge more frontally by adolescence. Based on the concept that SO and SW could actively modify neuronal connectivity, we discuss whether they fulfill a key purpose in brain development by actively conveying modifications of the maturing brain.

Sleep-Wake Cycle in Young and Older Mice.

Sleep plays a key role in multiple cognitive functions and sleep pattern changes with aging. Human studies revealed that aging decreases sleep efficiency and reduces the total sleep time, the time spent in slow-wave sleep (SWS), and the delta power (1-4 Hz) during sleep; however, some studies of sleep and aging in mice reported opposing results. The aim of our work is to estimate how features of sleep-wake state in mice during aging could correspond to age-dependent changes observed in human. In this study, we investigated the sleep/wake cycle in young (3 months old) and older (12 months old) C57BL/6 mice using local-field potentials (LFPs). We found that older adult mice sleep more than young ones but only during the dark phase of sleep-wake cycle. Sleep fragmentation and sleep during the active phase (dark phase of cycle), homologous to naps, were higher in older mice. Older mice show a higher delta power in frontal cortex, which was accompanied with similar trend for age differences in slow wave density. We also investigated regional specificity of sleep-wake electrographic activities and found that globally posterior regions of the cortex show more rapid eye movement (REM) sleep whereas somatosensory cortex displays more often SWS patterns. Our results indicate that the effects of aging on the sleep-wake activities in mice occur mainly during the dark phase and the electrode location strongly influence the state detection. Despite some differences in sleep-wake cycle during aging between human and mice, some features of mice sleep share similarity with human sleep during aging.

Ionic and synaptic mechanisms of seizure generation and epileptogenesis.

The biophysical mechanisms underlying epileptogenesis and the generation of seizures remain to be better understood. Among many factors triggering epileptogenesis are traumatic brain injury breaking normal synaptic homeostasis and genetic mutations disrupting ionic concentration homeostasis. Impairments in these mechanisms, as seen in various brain diseases, may push the brain network to a pathological state characterized by increased susceptibility to unprovoked seizures. Here, we review recent computational studies exploring the roles of ionic concentration dynamics in the generation, maintenance, and termination of seizures. We further discuss how ionic and synaptic homeostatic mechanisms may give rise to conditions which prime brain networks to exhibit recurrent spontaneous seizures and epilepsy.

Slow wave detection in sleeping mice: Comparison of traditional and machine learning methods.

BACKGROUND: During slow-wave sleep the electroencephalographic (EEG) and local field potential (LFP) recordings reveal the presence of large amplitude slow waves. Systematic extraction of individual slow waves is not trivial. NEW METHOD: In this study, we used the neural network pattern recognition to detect individual slow waves in LFP recorded from mice as well as other commonly used methods that are based on fast frequencies modulation, amplitude, or duration. RESULTS: The number and quality of events detected as slow waves depended on the chosen method of detection, level of thresholds, or on combination of methods. Each individual method yields some false-positive and false-negative detections. Typically, the fast frequency-method has a higher false discovery rate, but almost no missing waves; amplitude-based method has relatively high false-positive and false-negative rates; duration-based method has low false-negative rates; neural network pattern recognition approach has the lowest false-positive rate among individual methods, often rejecting waves that were falsely detected by other approaches. Combining all 4 detection methods practically eliminated false-positive errors, but a large number of slow waves remained undetected. CONCLUSIONS: The use of a particular method of slow wave detection needs to be adjusted to the objectives of a given study: to detect all slow waves, but also numerous false positives can be achieved using the fast frequency approach. Neural network pattern recognition method alone can detect slow waves with the lowest false-positive rate, that can be further minimized with the use of combination of other methods.

Sleep, Anesthesia, and Plasticity.

Two theories continuously clash: does sleep downscale or potentiate synapses? A study in Neuron by González-Rueda et al. (2018) demonstrates overall synaptic depression during anesthesia-induced slow-wave activity. Because anesthesia is typically associated with amnesia, the question of whether slow-wave sleep potentiates or depresses cortical synapses remains open.

New class of reduced computationally efficient neuronal models for large-scale simulations of brain dynamics.

During slow-wave sleep, brain electrical activity is dominated by the slow (< 1 Hz) electroencephalogram (EEG) oscillations characterized by the periodic transitions between active (or Up) and silent (or Down) states in the membrane voltage of the cortical and thalamic neurons. Sleep slow oscillation is believed to play critical role in consolidation of recent memories. Past computational studies, based on the Hodgkin-Huxley type neuronal models, revealed possible intracellular and network mechanisms of the neuronal activity during sleep, however, they failed to explore the large-scale cortical network dynamics depending on collective behavior in the large populations of neurons. In this new study, we developed a novel class of reduced discrete time spiking neuron models for large-scale network simulations of wake and sleep dynamics. In addition to the spiking mechanism, the new model implemented nonlinearities capturing effects of the leak current, the Ca2+ dependent K+ current and the persistent Na+ current that were found to be critical for transitions between Up and Down states of the slow oscillation. We applied the new model to study large-scale two-dimensional cortical network activity during slow-wave sleep. Our study explained traveling wave dynamics and characteristic synchronization properties of transitions between Up and Down states of the slow oscillation as observed in vivo in recordings from cats. We further predict a critical role of synaptic noise and slow adaptive currents for spike sequence replay as found during sleep related memory consolidation.