Lateral habenula neurocircuits mediate the maternal disruptive effect of maternal stress: A hypothesis

Up to 20%of women experience stress-related disorders during the postpartum period;however,little is known about the specific neural circuitry by which maternal stress exerts its negative impacts on mental health and maternal caregiving behavior.Theoretically,such a circuitry should serve as an interface between the stress response system and maternal neural network,transmitting stress signals to the neural circuitry that mediates maternal behavior.In this paper,I propose that the lateral habenula(LHb)serves this interface function.Evidence shows that the LHb plays a key role in encoding stress-induced effects and in the pathophysiology of major depression and stressrelated anxiety,and thus may play a role in maternal behavior as part of the maternal brain network.I hypothesize that maternal stress acts upon the LHb and two of its major downstream targets,i.e.,ventral tegmental area(VTA)and dorsal raphe nucleus(DRN),compromising the maternal care and contributing to postpartum mental disorders.This hypothesis makes three predictions:(1)maternal stress enhances LHb neuronal activity;(2)activation of DRN-and VTA-projecting neurons in the LHb mimics the detrimental effects of maternal stress on maternal behavior;and(3)suppression of DRN-and VTA-projecting neurons in the LHb attenuates the detrimental effects of maternal stress on maternal care in stressed mothers.Confirmation of this hypothesis is expected to enhance our understanding of the neurocircuit mechanisms mediating stress effects on maternal behavior.

Potentiation of the lateral habenula-ventral tegmental area pathway underlines the susceptibility to depression in mice with chronic pain

Chronic pain often develops severe mood changes such as depression.However,how chronic pain leads to depression remains elusive and the mechanisms determining individuals’responses to depression are largely unexplored.Here we found that depression-like behaviors could only be observed in 67.9%of mice with chronic neuropathic pain,leaving 32.1%of mice with depression resilience.We determined that the spike discharges of the ventral tegmental area(VTA)-projecting lateral habenula(LHb)glutamatergic(Glu)neurons were sequentially increased in sham,resilient and susceptible mice,which consequently inhibited VTA dopaminergic(DA)neurons through a LHbGlu-VTAGABA-VTADA circuit.Furthermore,the LHbGlu-VTADA excitatory inputs were dampened via GABAB receptors in a pre-synaptic manner.Regulation of LHb-VTA pathway largely affected the development of depressive symptoms caused by chronic pain.Our study thus identifies a pivotal role of the LHb-VTA pathway in coupling chronic pain with depression and highlights the activity-dependent contribution of LHbGlu-to-VTADA inhibition in depressive behavioral regulation.

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Modulate the Anesthetic Potency of Isoflurane in Mice

The lateral hypothalamic area(LHA)plays a pivotal role in regulating consciousness transition,in which orexinergic neurons,GABAergic neurons,and melanin-concentrating hormone neurons are involved.Glutamatergic neurons have a large population in the LHA,but their anesthesia-related effect has not been explored.Here,we found that genetic ablation of LHA glutamatergic neurons shortened the induction time and prolonged the recovery time of isoflurane anesthesia in mice.In contrast,chemogenetic activation of LHA glutamatergic neurons increased the time to anesthesia and decreased the time to recovery.Optogenetic activation of LHA glutamatergic neurons during the maintenance of anesthesia reduced the burst suppression pattern of the electroencephalogram(EEG)and shifted EEG features to an arousal pattern.Photostimulation of LHA glutamatergic projections to the lateral habenula(LHb)also facilitated the emergence from anesthesia and the transition of anesthesia depth to a lighter level.Collectively,LHA glutamatergic neurons and their projections to the LHb regulate anesthetic potency and EEG features.

Sexual Dimorphism of Inputs to the Lateral Habenula in Mice

The lateral habenula(LHb),which is a critical neuroanatomical hub and a regulator of midbrain monoaminergic centers,is activated by events resulting in negative valence and contributes to the expression of both appetitive and aversive behaviors.However,whole-brain cell-type-specific monosynaptic inputs to the LHb in both sexes remain incompletely elucidated.In this study,we used viral tracing combined with in situ hybridization targeting vesicular glutamate transporter 2(vGlut2)and glutamic acid decarboxylase 2(Gad2)to generate a comprehensive whole-brain atlas of inputs to glutamatergic andγ-aminobutyric acid(GABA)ergic neurons in the LHb.We found>30 ipsilateral and contralateral brain regions that projected to the LHb.Of these,there were significantly more monosynaptic LHb-projecting neurons from the lateral septum,anterior hypothalamus,dorsomedial hypothalamus,and ventromedial hypothalamus in females than in males.More interestingly,we found a stronger GABAergic projection from the medial septum to the LHb in males than in females.Our results reveal a comprehensive connectivity atlas of glutamatergic and GABAergic inputs to the LHb in both sexes,which may facilitate a better understanding of sexual dimorphism in physiological and pathological brain functions.

Lycium barbarum polysaccharide-glycoprotein preventative treatment ameliorates aversive stimuli-induced depression

Previous studies have shown that Lycium barbarum polysaccharide,the main active component of Lycium barbarum,exhibits antiinflammatory and antioxidant effects in treating neurological diseases.However,the therapeutic action of Lycium barbarum polysaccharide on depression has not been studied.In this investigation,we established mouse models of depression using aversive stimuli including exposure to fox urine,air puff and foot shock and physical restraint.Concurrently,we administered 5 mg/kg per day Lycium barbarum polysaccharide-glycoprotein to each mouse intragastrically for the 28 days.Our results showed that long-term exposure to aversive stimuli significantly enhanced depressive-like behavior evaluated by the sucrose preference test and the forced swimming test and increased anxietylike behaviors evaluated using the open field test.In addition,aversive stimuli-induced depressed mice exhibited aberrant neuronal activity in the lateral habenula.Importantly,concurrent Lycium barbarum polysaccharide-glycoprotein treatment significantly reduced these changes.These findings suggest that Lycium barbarum polysaccharide-glycoprotein is a potential preventative intervention for depression and may act by preventing aberrant neuronal activity and microglial activation in the lateral habenula.The study was approved by the Jinan University Institutional Animal Care and Use Committee(approval No.20170301003)on March 1,2017.

光干预降低可卡因记忆消退后复吸行为的神经环路机制

毒品成瘾已经成为一个严峻挑战,特别是因滥用造成的可卡因高复吸率给社会带来严重负担。尽管我们在神经生物学层面对成瘾的理解取得了显著进展,但仍缺乏有效降低复吸的戒断手段.在这项研究中,我们发现在可卡因戒断期实施亮光干预(BLT)并结合消退训练可防止可卡因驱动的复吸行为,该效应是通过丘脑-外侧核通路所介导。实验证实,在可卡因戒断进程中,外侧核(LHb)被激活,而通过BLT抑制LHb可减少可卡因驱动的复吸行为:本文阐明了BLT的作用是通过激活投射至LHb的腹外侧膝状体和膝状体间小叶(VLGN/IGL)神经元或抑制该通路中突触后LHb神经元实现。此外,BLT可以改善药物戒断引起的负性情绪。本研究结果表明在可卡因戒断期间施加BLT可能成为一种实现药物戒除的有效手段.