Sex-specific expression of distinct serotonin receptors mediates stress vulnerability of adult hippocampal neural stem cells in mice.

Women are more vulnerable to stress and have a higher likelihood of developing mood disorders. The serotonin (5HT) system has been highly implicated in stress response and mood regulation. However, sex-dependent mechanisms underlying serotonergic regulation of stress vulnerability remain poorly understood.

Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain.

Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain.

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer's disease proteopathology for precision medication.

Current amyloid beta-targeting approaches for Alzheimer's disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD.

Ventral pallidal glutamatergic neurons regulate wakefulness and emotion through separated projections.

Insomnia is often comorbid with depression, but the underlying neuronal circuit mechanism remains elusive. Recently, we reported that GABAergic ventral pallidum (VP) neurons control wakefulness associated with motivation. However, whether and how other subtypes of VP neurons regulate arousal and emotion are largely unknown.

Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer's mouse model.

Background: Alzheimer's disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined.

Activation of hypothalamic-enhanced adult-born neurons restores cognitive and affective function in Alzheimer's disease.

Patients with Alzheimer's disease (AD) exhibit progressive memory loss, depression, and anxiety, accompanied by impaired adult hippocampal neurogenesis (AHN). Whether AHN can be enhanced in impaired AD brain to restore cognitive and affective function remains elusive. Here, we report that patterned optogenetic stimulation of the hypothalamic supramammillary nucleus (SuM) enhances AHN in two distinct AD mouse models, 5×FAD and 3×Tg-AD.

Optimizing memory performance and emotional states: multi-level enhancement of adult hippocampal neurogenesis.

Adult hippocampal neurogenesis (AHN) plays a key role in modulating memory and emotion processing. A fundamental question remains on how to effectively modulate AHN to improve hippocampal function. Here, we review recent work on how distinct aspects of hippocampal neurogenesis, including the number, maturation state, and activity of adult-born neurons (ABNs), contribute to overall hippocampal function.

Hypothalamic modulation of adult hippocampal neurogenesis in mice confers activity-dependent regulation of memory and anxiety-like behavior.

Adult hippocampal neurogenesis plays a critical role in memory and emotion processing, and this process is dynamically regulated by neural circuit activity. However, it remains unknown whether manipulation of neural circuit activity can achieve sufficient neurogenic effects to modulate behavior. Here we report that chronic patterned optogenetic stimulation of supramammillary nucleus (SuM) neurons in the mouse hypothalamus robustly promotes neurogenesis at multiple stages, leading to increased production of neural stem cells and behaviorally relevant adult-born neurons (ABNs) with enhanced maturity.

Ventral pallidal GABAergic neurons control wakefulness associated with motivation through the ventral tegmental pathway.

The ventral pallidum (VP) regulates motivation, drug addiction, and several behaviors that rely on heightened arousal. However, the role and underlying neural circuits of the VP in the control of wakefulness remain poorly understood. In the present study, we sought to elucidate the specific role of VP GABAergic neurons in controlling sleep-wake behaviors in mice.

Neuropeptides Modulate Local Astrocytes to Regulate Adult Hippocampal Neural Stem Cells.

Neural stem cells (NSCs) in the dentate gyrus (DG) reside in a specialized local niche that supports their neurogenic proliferation to produce adult-born neurons throughout life. How local niche cells interact at the circuit level to ensure continuous neurogenesis from NSCs remains unknown. Here we report the role of endogenous neuropeptide cholecystokinin (CCK), released from dentate CCK interneurons, in regulating neurogenic niche cells and NSCs.

Supramammillary nucleus synchronizes with dentate gyrus to regulate spatial memory retrieval through glutamate release.

The supramammillary nucleus (SuM) provides substantial innervation to the dentate gyrus (DG). It remains unknown how the SuM and DG coordinate their activities at the circuit level to regulate spatial memory. Additionally, SuM co-releases GABA and glutamate to the DG, but the relative role of GABA versus glutamate in regulating spatial memory remains unknown.

Loss of Microglia and Impaired Brain-Neurotrophic Factor Signaling Pathway in a Comorbid Model of Chronic Pain and Depression.

Major depressive disorder (MDD) and chronic pain are two complex disorders that often coexist. The underlying basis for this comorbidity is unknown. In the current investigation, microglia and the brain-derived neurotrophic factor (BDNF)-cAMP response element-binding protein (CREB) pathway were investigated.

Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D receptors.

Nucleus accumbens (NAc) is involved in behaviors that depend on heightened wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D receptor (DR)-expressing neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc DR neurons.

The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA).

Thermoregulation-Independent Regulation of Sleep by Serotonin Revealed in Mice Defective in Serotonin Synthesis.

A role for 5-hydroxytryptamine (5-HT) or serotonin in sleep has been known for decades but was challenged by recent papers that concluded that the apparent sleep phenotype was secondary to defective thermoregulation. Those studies used mice lacking serotonergic neurons resulting from the loss of function mutations in the gene encoding the LIM homeobox transcription factor 1 (). Here we show that, while mutants failed to keep the physiologic body temperature, they exhibited more activities at the room and elevated temperatures.

Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice.

Sleep control is ascribed to a two-process model, a widely accepted concept that posits homoeostatic drive and a circadian process as the major sleep-regulating factors. Cognitive and emotional factors also influence sleep-wake behaviour; however, the precise circuit mechanisms underlying their effects on sleep control are unknown. Previous studies suggest that adenosine has a role affecting behavioural arousal in the nucleus accumbens (NAc), a brain area critical for reinforcement and reward.

Ethanol inhibits histaminergic neurons in mouse tuberomammillary nucleus slices via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites.

Aim: Ethanol, one of the most frequently used and abused substances in our society, has a profound impact on sedation. However, the neuronal mechanisms underlying its sedative effect remain unclear. In this study, we investigated the effects of ethanol on histaminergic neurons in the tuberomammillary nucleus (TMN), a brain region thought to be critical for wakefulness.

Signaling mechanism underlying the histamine-modulated action of hypoglossal motoneurons.

Histamine, an important modulator of the arousal states of the central nervous system, has been reported to contribute an excitatory drive at the hypoglossal motor nucleus to the genioglossus (GG) muscle, which is involved in the pathogenesis of obstructive sleep apnea. However, the effect of histamine on hypoglossal motoneurons (HMNs) and the underlying signaling mechanisms have remained elusive. Here, whole-cell patch-clamp recordings were conducted using neonatal rat brain sections, which showed that histamine excited HMNs with an inward current under voltage-clamp and a depolarization membrane potential under current-clamp via histamine H1 receptors (H1Rs).

Basal Forebrain Cholinergic Neurons Primarily Contribute to Inhibition of Electroencephalogram Delta Activity, Rather Than Inducing Behavioral Wakefulness in Mice.

The basal forebrain (BF) cholinergic neurons have long been thought to be involved in behavioral wakefulness and cortical activation. However, owing to the heterogeneity of BF neurons and poor selectivity of traditional methods, the precise role of BF cholinergic neurons in regulating the sleep-wake cycle remains unclear. We investigated the effects of cell-selective manipulation of BF cholinergic neurons on the sleep-wake behavior and electroencephalogram (EEG) power spectrum using the pharmacogenetic technique, the 'designer receptors exclusively activated by designer drugs (DREADD)' approach, and ChAT-IRES-Cre mice.

Paeoniflorin Promotes Non-rapid Eye Movement Sleep via Adenosine A1 Receptors.

Paeoniflorin (PF, C23H28O11), one of the principal active ingredients of Paeonia Radix, exerts depressant effects on the central nervous system. We determined whether PF could modulate sleep behaviors and the mechanisms involved. Electroencephalogram and electromyogram recordings in mice showed that intraperitoneal PF administered at a dose of 25 or 50 mg/kg significantly shortened the sleep latency and increased the amount of non-rapid eye movement (NREM).

Gelsemine alleviates both neuropathic pain and sleep disturbance in partial sciatic nerve ligation mice.

Aim: Gelsemine, an alkaloid from the Chinese herb Gelsemium elegans (Gardn & Champ) Benth., is effective in mitigating chronic pain in rats. In the present study we investigated whether the alkaloid improved sleep disturbance, the most common comorbid symptoms of chronic pain, in a mouse model of neuropathic pain.

Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, induces sleep via the benzodiazepine site of GABA(A) receptor in mice.

Magnolol (6,6',7,12-tetramethoxy-2,2'-dimethyl-1-beta-berbaman, C(18)H(18)O(2)), an active ingredient of the bark of Magnolia officinalis, has been reported to exert potent anti-epileptic effects via the GABA(A) receptor. The receptor also mediates sleep in humans and animals. The aim of this study was to determine whether magnolol could modulate sleep behaviors by recording EEG and electromyogram in mice.