Early-life sleep disruption impairs subtle social behaviours in prairie voles: a pose-estimation study.

Early-life sleep disruption (ELSD) has been shown to have long-lasting effects on social behaviour in adult prairie voles (Microtus ochrogaster), including impaired expression of pair bonding during partner preference testing. However, due to the limitations of manual behaviour tracking, the effects of ELSD across the time course of pair bonding have not yet been described, hindering our ability to trace mechanisms. Here, we used pose estimation to track prairie voles during opposite-sex cohabitation, the process leading to pair bonding. Male-female pairs were allowed to interact through a mesh divider in the home cage for 72 h, providing variables of body direction, distance-to-divider and locomotion speed. We found that control males displayed periodic patterns of body orientation towards females during cohabitation. In contrast, ELSD males showed reduced duration and ultradian periodicity of these body orientation behaviours towards females. Furthermore, in both sexes, ELSD altered spatial and temporal patterns of locomotion across the light/dark cycles of the 72 h recordings. This study allows a comprehensive behavioural assessment of the effects of ELSD on later life sociality and highlights subtle prairie vole behaviours. Our findings may shed light on neurodevelopmental disorders featuring sleep disruption and social deficits, such as autism spectrum disorders.

The temporal structure of REM sleep shows minute-scale fluctuations across brain and body in mice and humans.

Rapid eye movement sleep (REM) is believed to have a binary temporal structure with "phasic" and "tonic" microstates, characterized by motoric activity versus quiescence, respectively. However, we observed in mice that the frequency of theta activity (a marker of rodent REM) fluctuates in a nonbinary fashion, with the extremes of that fluctuation correlating with phasic-type and tonic-type facial motricity. Thus, phasic and tonic REM may instead represent ends of a continuum. These cycles of brain physiology and facial movement occurred at 0.01 to 0.06 Hz, or infraslow frequencies, and affected cross-frequency coupling and neuronal activity in the neocortex, suggesting network functional impact. We then analyzed human data and observed that humans also demonstrate nonbinary phasic/tonic microstates, with continuous 0.01 to 0.04-Hz respiratory rate cycles matching the incidence of eye movements. These fundamental properties of REM can yield insights into our understanding of sleep health.

Input Convergence, Synaptic Plasticity and Functional Coupling Across Hippocampal-Prefrontal-Thalamic Circuits.

Executive functions and working memory are long known to involve the prefrontal cortex (PFC), and two PFC-projecting areas: midline/paramidline thalamus (MLT) and cornus ammonis 1 (CA1)/subiculum of the hippocampal formation (HF). An increasing number of rodent electrophysiology studies are examining these substrates together, thus providing circuit-level perspectives on input convergence, synaptic plasticity and functional coupling, as well as insights into cognition mechanisms and brain disorders. Our review article puts this literature into a method-oriented narrative. As revisited throughout the text, limbic thalamic and hippocampal afferents to the PFC gate one another's inputs, which in turn are modulated by PFC interneurons and ascending monoaminergic projections. In addition, long-term synaptic plasticity, paired-pulse facilitation (PPF), and event-related potentials (ERP) dynamically vary across PFC-related circuits during learning paradigms and drug effects. Finally, thalamic-prefrontal loops, which have been shown to amplify both cognitive processes and limbic seizures, are also being implicated as relays in the prefrontal-hippocampal feedback, contributing to spatial navigation and decision making. Based on these issues, we conclude the review with a critical synthesis and some research directions.

Lithium modulates the muscarinic facilitation of synaptic plasticity and theta-gamma coupling in the hippocampal-prefrontal pathway.

Mood disorders are associated to functional unbalance in mesolimbic and frontal cortical circuits. As a commonly used mood stabilizer, lithium acts through multiple biochemical pathways, including those activated by muscarinic cholinergic receptors crucial for hippocampal-prefrontal communication. Therefore, here we investigated the effects of lithium on prefrontal cortex responses under cholinergic drive. Lithium-treated rats were anesthetized with urethane and implanted with a ventricular cannula for muscarinic activation, a recording electrode in the medial prefrontal cortex (mPFC), and a stimulating electrode in the intermediate hippocampal CA1. Either of two forms of synaptic plasticity, long-term potentiation (LTP) or depression (LTD), were induced during pilocarpine effects, which were monitored in real time through local field potentials. We found that lithium attenuates the muscarinic potentiation of cortical LTP (<20 min) but enhances the muscarinic potentiation of LTD maintenance (>80 min). Moreover, lithium treatment promoted significant cross-frequency coupling between CA1 theta (3-5 Hz) and mPFC low-gamma (30-55 Hz) oscillations. Interestingly, lithium by itself did not affect any of these measures. Thus, lithium pretreatment and muscarinic activation synergistically modulate the hippocampal-prefrontal connectivity. Because these alterations varied with time, oscillatory parameters, and type of synaptic plasticity, our study suggests that lithium influences prefrontal-related circuits through intricate dynamics, informing future experiments on mood disorders.

Interaction between hippocampal-prefrontal plasticity and thalamic-prefrontal activity.

The prefrontal cortex integrates a variety of cognition-related inputs, either unidirectional, e.g., from the hippocampal formation, or bidirectional, e.g., with the limbic thalamus. While the former is usually implicated in synaptic plasticity, the latter is better known for regulating ongoing activity. Interactions between these processes via prefrontal neurons are possibly important for linking mnemonic and executive functions. Our work further elucidates such dynamics using in vivo electrophysiology in rats. First, we report that electrical pulses into CA1/subiculum trigger late-onset (>400 ms) firing responses in the medial prefrontal cortex, which are increased after induction of long-term potentiation. Then, we show these responses to be attenuated by optogenetic control of the paraventricular/mediodorsal thalamic area. This suggests that recruitment and plasticity of the hippocampal-prefrontal pathway is partially related to the thalamic-prefrontal loop. When dysfunctional, this interaction may contribute to cognitive deficits, psychotic symptoms, and seizure generalization, which should motivate future studies combining behavioural paradigms and long-range circuit assessment.

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research.

Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB1 and TRPV1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools.

Repeated Nicotine Strengthens Gamma Oscillations in the Prefrontal Cortex and Improves Visual Attention.

Nicotine has strong addictive as well as procognitive properties. While a large body of research on nicotine continues to inform us about mechanisms related to its reinforcing effects, less is known about clinically relevant mechanisms that subserve its cognitive-enhancing properties. Understanding the latter is critical for developing optimal strategies for treating cognitive deficits. The primary brain region implicated in cognitive functions improved by nicotine is the prefrontal cortex (PFC). Here we assessed the impact of nicotine on unit activity and local field potential oscillations in the PFC of behaving rats. An acute dose of nicotine produced a predominantly inhibitory influence on population activity, a small increase in gamma oscillations, and a decrease in theta and beta oscillations. After a daily dosing regimen, a shift to excitatory-inhibitory balance in single-unit activity and stronger gamma oscillations began to emerge. This pattern of plasticity was specific to the gamma band as lower frequency oscillations were suppressed consistently across daily nicotine treatments. Gamma oscillations are associated with enhanced attentional capacity. Consistent with this mechanism, the repeat dosing regimen in a separate cohort of subjects led to improved performance in an attention task. These data suggest that procognitive effects of nicotine may involve development of enhanced gamma oscillatory activity and a shift to excitatory-inhibitory balance in PFC neural activity. In the context of the clinical use of nicotine and related agonists for treating cognitive deficits, these data suggest that daily dosing may be critical to allow for development of robust gamma oscillations.

Acetazolamide potentiates the afferent drive to prefrontal cortex in vivo.

The knowledge on real-time neurophysiological effects of acetazolamide is still far behind the wide clinical use of this drug. Acetazolamide - a carbonic anhydrase inhibitor - has been shown to affect the neuromuscular transmission, implying a pH-mediated influence on the central synaptic transmission. To start filling such a gap, we chose a central substrate: hippocampal-prefrontal cortical projections; and a synaptic phenomenon: paired-pulse facilitation (a form of synaptic plasticity) to probe this drug's effects on interareal brain communication in chronically implanted rats. We observed that systemic acetazolamide potentiates the hippocampal-prefrontal paired-pulse facilitation. In addition to this field electrophysiology data, we found that acetazolamide exerts a net inhibitory effect on prefrontal cortical single-unit firing. We propose that systemic acetazolamide reduces the basal neuronal activity of the prefrontal cortex, whereas increasing the afferent drive it receives from the hippocampus. In addition to being relevant to the clinical and side effects of acetazolamide, these results suggest that exogenous pH regulation can have diverse impacts on afferent signaling across the neocortex.

Spread of Oropouche virus into the central nervous system in mouse.

Oropouche virus (OROV) is an important cause of arboviral illness in Brazil and other Latin American countries, with most cases clinically manifested as acute febrile illness referred to as Oropouche fever, including myalgia, headache, arthralgia and malaise. However, OROV can also affect the central nervous system (CNS) with clinical neurological implications. Little is known regarding OROV pathogenesis, especially how OROV gains access to the CNS. In the present study, neonatal BALB/c mice were inoculated with OROV by the subcutaneous route and the progression of OROV spread into the CNS was evaluated. Immunohistochemistry revealed that OROV infection advances from posterior parts of the brain, including the periaqueductal gray, toward the forebrain. In the early phases of the infection OROV gains access to neural routes, reaching the spinal cord and ascending to the brain through brainstem regions, with little inflammation. Later, as infection progresses, OROV crosses the blood-brain barrier, resulting in more intense spread into the brain parenchyma, with more severe manifestations of encephalitis.

O ciclo da vesícula sináptica, espinhos dendríticos e a transdução de sinal / Synaptic vesicle cycle, dendritic spines and signal transduction

No sistema nervoso, a sinapse é a estrutura que permite a um neurônio passar um sinal elétrico ou químico a outro neurônio ou outra célula (muscular ou glandular). A palavra sinapse vem de "synaptein", palavra que Sir Charles Scott Sherrington e seus colegas acunharam do grego "syn" (junto) e "haptein"(afivelar). As sinapses podem ser separadas entre elétricas e químicas, porém a maior parte da transmissão sináptica é realizada através das sinapses químicas. Apesar das sinapses químicas terem uma resposta mais lenta que as elétricas, elas possuem a vantagem da amplificação do sinal gerada através de uma cascata de segundos mensageiros. As sinapses químicas podem ser excitatórias ou inibitórias e são caracterizadas por um terminal pré-sináptico (onde estão presentes as vesículas que contêm os neurotransmissores) em contato com um terminal pós-sináptico (onde estão presentes os receptores ionotrópicos e metabotrópicos para esses neurotransmissores) separados pela fenda sináptica. As sinapses típicas acontecem sobre axônios (axo-axônicas), sobre dendritos (axo-dendríticas), sobre o soma de outro neurônio (axo-somáticas) e sobre os espinhos dendríticos...

In the nervous system, the synapse is the structure that allows a neuron pass an electrical or chemical signal to another neuron or another cell (muscle or glandular). The word synapse comes from "synaptein" that Sir Charles Scott Sherrington and his colleagues minted from the Greek "syn" (together) and "haptein"(buckling). Most part of the synaptic transmission is performed through chemical synapses. Chemical synapses have a slower response than the electric ones; they have the advantage of amplifying the signal generated through a cascade of second messengers. Chemical synapses can be excitatory or inhibitory and are characterized by a presynaptic terminal (where there are vesicles that contain the neurotransmitters) in contact with a postsynaptic terminal (where there are the ionotropic and metabotropic receptors) separated by the synaptic cleft. Synapses can occur on axons (axo-axonal), on dendrites (axodendritic), on soma (axo-somatic) and on dendritic spines...

Neurotransmissão glutamatérgica e plasticidade sináptica: aspectos moleculares, clínicos e filogenéticos / Glutamatergic neurotransmission and synaptic plasticity: molecular, clinical, and phylogenetic aspects

A comunicação entre neurônios é passível de constantes modificações, até mesmo no encéfalo adulto. Esta capacidade de circuitos neuronais fortalecerem ou enfraquecerem suas interações sinápticas específicas (fenômeno conhecido como plasticidade sináptica) pode ocorrer de acordo com as diferentes demandas ambientais, o que favorece a noção de que alterações dinâmicas na comunicação entre neurônios estão na base da flexibilidade comportamental (i.e., processos de aprendizagem e memória). Nas últimas décadas, o avanço das neurociências tem permitido uma melhor compreensão a respeito da plasticidade sináptica, especialmente a plasticidade de sinapses glutamatérgicas, cujos processos moleculares de modificação sináptica parecem estar entre os mais comuns de todo o sistema desse progresso na ciência básica tem contribuído para uma melhor compreensão acerca dos processos patológicos envolvendo as sinapses glutamatérgicas, como a doença de Alzheimer. Além disso, a crescente compreensão sobre o funcionamento da comunicação glutamatérgica tem ajudado a esclarecer como as sinapses, em geral, teriam se originado e evoluído na escala filogenética do reino animal (Metazoa)...

Communication between neurons is subject to constant changes, even in the adult brain. This ability of neural circuits to strengthen or weaken their specific synaptic interactions (a phenomenon known assynaptic plasticity) may occur according to different environmental demands, which favors the idea that dynamic changes in the communication between neurons underlie behavioral flexibility (i.e., learning and memory processes). In recent decades, advances in neuroscience has allowed a better understanding of synaptic plasticity, specially the plasticity of glutamatergic synapses, whose molecular processes of synaptic change appear to be among the most common throughout the central nervous system.Much of this progress in basic science has contributed to a better understanding of pathological processes involving the glutamatergic synapses, such as Alzheimer's disease. Furthermore, the growing understanding about the physiology of glutamatergic communication has helped explain how synapses, in general, would have originated and evolved in the phylogenetic scale of the Metazoa...