Daily rhythms drive dynamism in sleep, oscillations and interneuron firing, while excitatory firing remains stable across 24 h.

The adaptation to the daily 24-h light-dark cycle is ubiquitous across animal species and is crucial for maintaining fitness. This free-running cycle occurs innately within multiple bodily systems, such as endogenous circadian rhythms in clock-gene expression and synaptic plasticity. These phenomena are well studied; however, it is unknown if and how the 24-h clock affects electrophysiologic network function in vivo.

Three-dimensional-printed headcap with embedded microdrive system for customizable multi-region brain recordings with neural probes.

Electrophysiological recordings from single neurons are crucial for understanding the complex functioning of the brain and for developing eventual therapeutic interventions. For electrophysiology, the accuracy and fidelity of invasive implantations of small devices remains unmatched. This study introduces an innovative, cost-efficient, 3D-printed headcap with embedded microdrive (THEM) system designed to streamline the manual labor-intensive electrode implantation process for efficient and precise multi-region brain neural probe implantations.

Quantifying social roles in multi-animal videos using subject-aware deep-learning.

Analyzing social behaviors is critical for many fields, including neuroscience, psychology, and ecology. While computational tools have been developed to analyze videos containing animals engaging in limited social interactions under specific experimental conditions, automated identification of the social roles of freely moving individuals in a multi-animal group remains unresolved. Here we describe a deep-learning-based system - named LabGym2 - for identifying and quantifying social roles in multi-animal groups.

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 (), 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.

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.

3D Printed Skull Cap and Benchtop Fabricated Microwire-Based Microelectrode Array for Custom Rat Brain Recordings.

Microwire microelectrode arrays (MEAs) have been a popular low-cost tool for chronic electrophysiological recordings and are an inexpensive means to record the electrical dynamics crucial to brain function. However, both the fabrication and implantation procedures for multi-MEAs on a single rodent are time-consuming and the accuracy and quality are highly manual skill-dependent. To address the fabrication and implantation challenges for microwire MEAs, (1) a computer-aided designed and 3D printed skull cap for the pre-determined implantation locations of each MEA and (2) a benchtop fabrication approach for low-cost custom microwire MEAs were developed.

Sleep Alterations in a Mouse Model of Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder showing progressive neuronal loss in several brain areas and a broad spectrum of motor and non-motor symptoms, including ataxia and altered sleep. While sleep disturbances are known to play pathophysiologic roles in other neurodegenerative disorders, their impact on SCA3 is unknown. Using spectrographic measurements, we sought to quantitatively characterize sleep electroencephalography (EEG) in SCA3 transgenic mice with confirmed disease phenotype.

Repeated Dosing of Ketamine in the Forced Swim Test: Are Multiple Shots Better Than One?

The anesthetic drug ketamine has been successfully repurposed as an antidepressant in human subjects. This represents a breakthrough for clinical psychopharmacology, because unlike monoaminergic antidepressants, ketamine has rapid onset, including in Major Depressive Disorder (MDD) that is resistant to conventional pharmacotherapy. This rapid therapeutic onset suggests a unique mechanism of action, which continues to be investigated in reverse translational studies in rodents.

Multiple cholinesterase inhibitors have antidepressant-like properties in the mouse forced swim test.

There is high clinical interest in improving the pharmacological treatment of individuals with Major Depressive Disorder (MDD). This neuropsychiatric disorder continues to cause significant morbidity and mortality worldwide, where existing pharmaceutical treatments such as selective serotonin reuptake inhibitors often have limited efficacy. In a recent publication, we demonstrated an antidepressant-like role for the acetylcholinesterase inhibitor (AChEI) donepezil in the C57BL/6J mouse forced swim test (FST).

Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model.

Objectives: Focal cortical dysplasia type II (FCDII) is one of the most common underlying pathologies in patients with drug-resistant epilepsy. However, mechanistic understanding of FCDII fails to keep pace with genetic discoveries, primarily due to the significant challenge in developing a clinically relevant animal model. Conceptually and clinically important questions, such as the unknown latent period of epileptogenesis and the controversial epileptogenic zone, remain unknown in all experimental FCDII animal models, making it even more challenging to investigate the underlying epileptogenic mechanisms.

Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities.

When stress becomes chronic it can trigger lasting brain and behavioral changes including Major Depressive Disorder (MDD). There is conflicting evidence regarding whether acetylcholinesterase inhibitors (AChEIs) may have antidepressant properties. In a recent publication, we demonstrated a strong dose-dependency of the effect of AChEIs on antidepressant-related behavior in the mouse forced swim test: whereas the AChEI donepezil indeed promotes depression-like behavior at a high dose, it has antidepressant-like properties at lower doses in the same experiment.

Sex- and stress-dependent effects of a single injection of ketamine on open field and forced swim behavior.

Ketamine has emerged as a novel treatment for common psychiatric conditions such as Major Depressive Disorder (MDD) and anxiety disorders, many of which can be initiated and exacerbated by psychological stress. Sex differences in the frequency of both anxiety and depressive disorders are well known and could be due to sex differences in neuroendocrine responses to stress. Ketamine is known to modulate the hormonal response to stress, specifically corticosterone.

The cholinesterase inhibitor donepezil has antidepressant-like properties in the mouse forced swim test.

Finding new antidepressant agents is of high clinical priority given that many cases of major depressive disorder (MDD) do not respond to conventional monoaminergic antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Recent findings of effective fast-acting antidepressants indicate that there are biological substrates to be taken advantage of for fast relief of depression and that we may find further treatments in this category. In this vein, the cholinergic system may be a relatively overlooked target for antidepressant medications, given its major role in motivation and attention.

Patterned activation of action potential patterns during offline states in the neocortex: replay and non-replay.

Action potential generation (spiking) in the neocortex is organized into repeating non-random patterns during both awake experiential states and non-engaged states ranging from inattention to sleep to anaesthesia-and even occur in slice preparations. Repeating patterns in a given population of neurons between states may imply a common means by which cortical networks can be engaged despite brain state changes, but super-imposed on this common firing is a variability that is both specific to ongoing inputs and can be re-shaped by experience. This similarity with specifically induced variance may allow for a range of processes including perception, memory consolidation and network homeostasis.

Author Correction: Neuronal firing rates diverge during REM and homogenize during non-REM.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Rodent ketamine depression-related research: Finding patterns in a literature of variability.

Discovering that the anesthetic drug ketamine has rapidly acting antidepressant effects in many individuals with major depression is one of the most important findings in clinical psychopharmacology in recent decades. The initial report of these effects in human subjects was based on a foundation of rodent preclinical studies carried out in the 1990s, and subsequent investigation has included both further studies in individuals with depression, as well as reverse translational experiments in animal models, especially rodents. While there is general agreement in the rodent literature that ketamine has rapidly-acting, and generally sustained, antidepressant-like properties, there are also points of contention across studies, including the precise mechanism of action of this drug.

In vivo electrophysiological recordings of the effects of antidepressant drugs.

Antidepressant drugs are a standard biological treatment for various neuropsychiatric disorders, yet relatively little is known about their electrophysiologic and synaptic effects on mood systems that set moment-to-moment emotional tone. In vivo electrical recording of local field potentials (LFPs) and single neuron spiking has been crucial for elucidating important details of neural processing and control in many other systems, and yet electrical approaches have not been broadly applied to the actions of antidepressants on mood-related circuits. Here we review the literature encompassing electrophysiologic effects of antidepressants in animals, including studies that examine older drugs, and extending to more recently synthesized novel compounds, as well as rapidly acting antidepressants.

Stress-sensitive antidepressant-like effects of ketamine in the mouse forced swim test.

Major depression is a stress-linked disease with significant morbidity and the anesthetic drug ketamine is of growing interest in the treatment of depression, since in responsive individuals a single dose has rapid (within hours) antidepressant effects that can be sustained for over a week in some instances. This combination of fast action and a therapeutic effect that lasts far beyond the drug's half-life points to a unique mechanism of action. In this reverse translational study, we investigate the degree to which ketamine counteracts stress-related depression-like behavioral responses by determining whether it affects unstressed animals similarly to stressed mice.

Neuronal firing rates diverge during REM and homogenize during non-REM.

Neurons fire at highly variable intrinsic rates and recent evidence suggests that low- and high-firing rate neurons display different plasticity and dynamics. Furthermore, recent publications imply possibly differing rate-dependent effects in hippocampus versus neocortex, but those analyses were carried out separately and with potentially important differences. To more effectively synthesize these questions, we analyzed the firing rate dynamics of populations of neurons in both hippocampal CA1 and frontal cortex under one framework that avoids the pitfalls of previous analyses and accounts for regression to the mean (RTM).

Cognitive and Physiologic Impacts of the Infraslow Oscillation.

Brain states are traditionally recognized via sleep-wake cycles, but modern neuroscience is beginning to identify many sub-states within these larger arousal types. Multiple lines of converging evidence now point to the infraslow oscillation (ISO) as a mediator of brain sub-states, with impacts ranging from the creation of resting state networks (RSNs) in awake subjects to interruptions in neural activity during sleep. This review will explore first the basic characteristics of the ISO in human subjects before reviewing findings in sleep and in animals.

Gamma oscillations as a biomarker for major depression: an emerging topic.

Identifying biomarkers for major depression is of high importance for improving diagnosis and treatment of this common and debilitating neuropsychiatric disorder, as the field seeks to move toward both personalized and more effective treatments. Here we focus on electroencephalography (EEG) or direct scalp voltage recordings as such a biomarker, with an emphasis on gamma and high gamma oscillations (or "rhythms"). In the last several decades, alpha and theta band rhythms have been found to provide information on depressive state as well as recovery, but the gamma band is less well characterized with respect to depression.

Temporal coupling of field potentials and action potentials in the neocortex.

The local field potential (LFP) is an aggregate measure of group neuronal activity and is often correlated with the action potentials of single neurons. In recent years, investigators have found that action potential firing rates increase during elevations in power high-frequency band oscillations (50-200 Hz range). However, action potentials also contribute to the LFP signal itself, making the spike-LFP relationship complex.

Sleep regulation of the distribution of cortical firing rates.

Sleep is thought to mediate both mnemonic and homeostatic functions. However, the mechanism by which this brain state can simultaneously implement the 'selective' plasticity needed to consolidate novel memory traces and the 'general' plasticity necessary to maintain a well-functioning neuronal system is unclear. Recent findings show that both of these functions differentially affect neurons based on their intrinsic firing rate, a ubiquitous neuronal heterogeneity.