Mathieu Nollet

In humans, decreases in rapid eye movement sleep (REMS) strongly predict Alzheimer’s disease (AD), alongside early degeneration of basal forebrain cholinergic neurons. We examined how β-amyloid pathology gradually erodes mouse cholinergic neurons. The familial AppNL-G-F allele was selectively expressed in medial septal (MS) cholinergic neurons of both sexes and compared with mice with global AppNL-G-F expression and selective genetic lesions of MS cholinergic cells. By 14 months, targeted AppNL-G-F allele expression had caused loss of 25% of MS cholinergic neurons and produced amyloid deposition in their terminal fields, particularly the hippocampus. REMS was reduced, together with cognitive and emotional alterations mirroring phenotypes in global mutants, which also showed selective MS cholinergic cell loss. Genetic lesioning of MS cholinergic cells recapitulated most phenotypes, identifying cholinergic loss, not amyloid deposition, as a probable cause of these phenotypes. Nevertheless, broadcasted amyloid from MS cholinergic neurons likely induced hippocampal astrocyte activation and epileptiform spikes.

Activating the adra2a receptors of the brain’s norepinephrine (NE) system produces NREM-like sleep and hypothermia. Dexmedetomidine (DEX), a selective α2 receptor ( adra2a ) agonist, is an important drug used in intensive care for arousable sedation. But for some patients, even slight decreases in body temperature during sedation could pose health risks such as increasing the likelihood of postoperative cognitive dysfunction. Where are the adra2a receptors at which DEX acts to induce hypothermia? A popular theory is that inhibitory adra2a receptors expressed on norepinephrinergic locus coeruleus (LC) neurons are DEX’s prime targets. To examine this, we genetically lesioned galanin ( gal )-expressing norepinephrinergic LC neurons in adult mice. In these ΔLC mice, baseline sleep–wake levels were unchanged, but surprisingly, core body temperatures were lower. Maintaining body temperature depended on NE/ gal projections from the LC to the medial preoptic (MPO) hypothalamus. Furthermore, without these LC neurons, DEX induced hypothermia more strongly. Knockdown with adra2a shRNA revealed that DEX induces hypothermia via adra2a receptors on MPO glutamate cells. When ΔLC mice were kept warm, DEX could induce the same amount of NREM-like sleep as well as it did for mice with an intact LC, and this sleep-like state in ΔLC mice had a higher delta frequency power than in control mice. Our results emphasize that inhibition of the LC by DEX is not required to induce robust sedation. By contrast, the LC likely has a fortuitous background action in protecting against drug-induced hypothermia and speeds recovery from hypothermia.

SUMMARY: In humans, decreases in rapid eye movement sleep (REMS) strongly predict Alzheimer’s disease (AD), alongside early degeneration of basal forebrain cholinergic neurons. We examined how β-amyloid pathology gradually erodes mouse cholinergic neurons. The familial App ^NL-G-F allele was selectively expressed in medial septal (MS) cholinergic neurons of both sexes and compared with mice with global App ^NL-G-F expression and selective genetic lesions of MS cholinergic cells. By 14 months, targeted App ^NL-G-F allele expression had caused loss of 25% of MS cholinergic neurons and produced amyloid deposition in their terminal fields, particularly the hippocampus. REMS was reduced, together with cognitive and emotional alterations mirroring phenotypes in global mutants, which also showed selective MS cholinergic cell loss. Genetic lesioning of MS cholinergic cells recapitulated most phenotypes, identifying cholinergic loss, not amyloid deposition, as a probable cause of these phenotypes. Nevertheless, broadcasted amyloid from MS cholinergic neurons likely induced hippocampal astrocyte activation and epileptiform spikes. Highlights: Amyloid in medial septum causes cholinergic neuron loss and Alzheimer’s symptoms Amyloid from medial septal axons may trigger pathology in distant brain regions Loss of acetylcholine, not amyloid spread, drives REM sleep and cognitive deficits Broadcasted septal amyloid induces hippocampal astrogliosis and epileptiform spikes GRAPHICAL

SUMMARY: REM sleep has been hypothesized to promote emotional resilience, but any neuronal circuits mediating this have not been identified. We find that in mice, somatostatin (Som) neurons in the entopeduncular nucleus (EP ^Som )/internal globus pallidus are predominantly active selectively during REM sleep. This unique REM activity is necessary and sufficient for maintaining normal REM sleep. Inhibiting or exciting EP ^Som neurons reduced or increased REM sleep duration, respectively. Activation of the sole downstream target of EP ^Som neurons, Vglut2 cells in the lateral habenula (LHb), increased sleep via the ventral tegmental area (VTA). A simple chemogenetic scheme to periodically inhibit the LHb over 4 days selectively removed a significant amount of cumulative REM sleep. Chronic REM reduction correlated with mice becoming anxious and more sensitive to aversive stimuli. Therefore, we suggest that REM sleep, in part generated by the EP→LHb→VTA circuit identified here, could contribute to stabilizing reactions to habitual aversive stimuli.

Sleep occupies a peculiar place in our lives and in science, being both eminently familiar and profoundly enigmatic. Historically, philosophers, scientists and artists questioned the meaning and purpose of sleep. If Shakespeare’s verses from MacBeth depicting “Sleep that soothes away all our worries” and “relieves the weary laborer and heals hurt minds” perfectly epitomize the alleviating benefits of sleep, it is only during the last two decades that the growing understanding of the sophisticated sleep regulatory mechanisms allows us to glimpse putative biological functions of sleep. Sleep control brings into play various brain-wide processes occurring at the molecular, cellular, circuit, and system levels, some of them overlapping with a number of disease-signaling pathways. Pathogenic processes, including mood disorders (e.g., major depression) and neurodegenerative illnesses such Huntington’s or Alzheimer’s diseases, can therefore affect sleep-modulating networks which disrupt the sleep-wake architecture, whereas sleep disturbances may also trigger various brain disorders. In this review, we describe the mechanisms underlying sleep regulation and the main hypotheses drawn about its functions. Comprehending sleep physiological orchestration and functions could ultimately help deliver better treatments for people living with neurodegenerative diseases.

In mice, social defeat stress (SDS), an ethological model for psychosocial stress, induces sleep. Such sleep could enable resilience, but how stress promotes sleep is unclear. Activity-dependent tagging revealed a subset of ventral tegmental area γ-aminobutyric acid (GABA)–somatostatin (VTA ^Vgat-Sst ) cells that sense stress and drive non–rapid eye movement (NREM) and REM sleep through the lateral hypothalamus and also inhibit corticotropin-releasing factor (CRF) release in the paraventricular hypothalamus. Transient stress enhances the activity of VTA ^Vgat-Sst cells for several hours, allowing them to exert their sleep effects persistently. Lesioning of VTA ^Vgat-Sst cells abolished SDS-induced sleep; without it, anxiety and corticosterone concentrations remained increased after stress. Thus, a specific circuit allows animals to restore mental and body functions by sleeping, potentially providing a refined route for treating anxiety disorders.

Major depression is a complex psychiatric disorder characterized by affective, cognitive, and physiological impairments that lead to maladaptive behavior. The high lifetime prevalence of this disabling condition, coupled with limitations of existing medications, make necessary the development of improved therapeutics. This requires animal models that allow investigation of key biological correlates of the disorder. Described in this article is the unpredictable chronic mild stress mouse model that can be used to screen for antidepressant drug candidates. Originally designed for rats, this model has been adapted for mice to capitalize on the advantages of this species as an experimental model, including inter‐strain variability, which permits an exploration of the contribution of genetic background; the ability to create transgenic animals; and lower cost. Thus, because it combines genetic features and socio‐environmental chronic stressful events, the unpredictable chronic mild stress model in mice is a relevant and valuable paradigm to gain insight into the etiological and developmental components of major depression, as well as to identify novel treatments for this condition. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.Basic Protocol 1: Unpredictable Chronic Mild Stress (UCMS) Test in MiceBasic Protocol 2: Assessment Of Self‐Directed Activity And Anhedonia in Mice

Every day, we sleep for a third of the day. Sleep is important for cognition, brain waste clearance, metabolism, and immune responses. The molecular mechanisms governing sleep are largely unknown. Here, we used a combination of single cell RNA sequencing and cell-type specific proteomics to interrogate the molecular underpinnings of sleep. Different cell types in three important brain regions for sleep (brainstem, cortex, and hypothalamus) exhibited diverse transcriptional responses to sleep need. Sleep restriction modulates astrocyte-neuron crosstalk and sleep need enhances expression of specific sets of transcription factors in different brain regions. In cortex, we also interrogated the proteome of two major cell types: astrocytes and neurons. Sleep deprivation differentially alters the expression of proteins in astrocytes and neurons. Similarly, phosphoproteomics revealed large shifts in cell-type specific protein phosphorylation. Our results indicate that sleep need regulates transcriptional, translational, and post-translational responses in a cell-specific manner.

Sleep is highly conserved across evolution, suggesting vital biological functions that are yet to be fully understood. Animals and humans experiencing partial sleep restriction usually exhibit detrimental physiological responses, while total and prolonged sleep loss could lead to death. The perturbation of sleep homeostasis is usually accompanied by an increase in hypothalamic–pituitary–adrenal (HPA) axis activity, leading to a rise in circulating levels of stress hormones (e.g. cortisol in humans, corticosterone in rodents). Such hormones follow a circadian release pattern under undisturbed conditions and participate in the regulation of sleep. The investigation of the consequences of sleep deprivation, from molecular changes to behavioural alterations, has been used to study the fundamental functions of sleep. However, the reciprocal relationship between sleep and the activity of the HPA axis is problematic when investigating sleep using traditional sleep-deprivation protocols that can induce stress per se. This is especially true in studies using rodents in which sleep deprivation is achieved by exogenous, and potentially stressful, sensory–motor stimulations that can undoubtedly confuse their conclusions. While more research is needed to explore the mechanisms underlying sleep loss and health, avoiding stress as a confounding factor in sleep-deprivation studies is therefore crucial. This review examines the evidence of the intricate links between sleep and stress in the context of experimental sleep deprivation, and proposes a more sophisticated research framework for sleep-deprivation procedures that could benefit from recent progress in biotechnological tools for precise neuromodulation, such as chemogenetics and optogenetics, as well as improved automated real-time sleep-scoring algorithms.