Netrin-3 Suppresses Diabetic Neuropathic Pain by Gating the Intra-epidermal Sprouting of Sensory

tDiabetic neuropathic pain(DNP)is the most common disabling complication of diabetes.Emerging evi-dence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area;however,the underlying molecular events remain poorly understood.Here we found that an axon guidance molecule,Netrin-3(Ntn-3),was expressed in the sensory neurons of mouse dorsal root ganglia(DRGs),and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model.Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice.In contrast,the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice.In con-clusion,our studies identified Ntn-3 as an important regula-tor of DNP pathogenesis by gating the aberrant sprouting of sensory axons,indicating that Ntn-3 is a potential druggable target for DNP treatment.

Quanti?cation of Tyrosine Hydroxylase and Erb B4 in the Locus Coeruleus of Mood Disorder Patients Using a Multispectral Method to Prevent Interference with Immunocytochemical Signals by Neuromelanin

The locus coeruleus(LC) has been studied in major depressive disorder(MDD) and bipolar disorder(BD). A major problem of immunocytochemical studies in the human LC is interference with the staining of the immunocytochemical end-product by the omnipresent natural brown pigment neuromelanin. Here, we used a multispectral method to untangle the two colors: blue immunocytochemical staining and brown neuromelanin.We found significantly increased tyrosine hydroxylase(TH) in the LC of MDD patients—thus validating the method—but not in BD patients, and we did not find significant changes in the receptor tyrosine-protein kinase ErbB4 in the LC in MDD or BD patients. We observed clear co-localization of ErbB4, TH, and neuromelanin in the LC neurons. The different stress-related molecular changes in the LC may contribute to the different clinical symptoms in MDD and BD.

Induction of Anxiety-Like Phenotypes by Knockdown of Cannabinoid Type-1 Receptors in the Amygdala of Marmosets

The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases,such as depression and anxiety.Meanwhile,the endocannabinoid system plays a crucial role in regulating emotions and mainly functions through the cannabinoid type-1 receptor(CB1R),which is strongly expressed in the amygdala of non-human primates(NHPs).However,it remains largely unknown how the CB1Rs in the amygdala of NHPs regulate mental diseases.Here,we investigated the role of CB1R by knocking down the cannabinoid receptor 1(CNR1)gene encoding CB1R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA.We found that CB1R knockdown in the amygdala induced anxiety-like behaviors,including disrupted night sleep,agitated psychomotor activity in new environments,and reduced social desire.Moreover,marmosets with CB1R-knockdown had up-regulated plasma cortisol levels.These results indicate that the knockdown of CB1Rs in the amygdala induces anxiety-like behaviors in marmosets,and this may be the mechanism underlying the regulation of anxiety by CB1Rs in the amygdala of NHPs.

A Standardized Protocol for the Induction of Specific Social Fear in Mice

Dear Editor,Social anxiety disorder(SAD)is one of the most common psychiatric disorders.It is characterized by intense and persistent fear of one or more social situations in which one is exposed to possible scrutiny by others[1].The lifetime prevalence of SAD ranges from 0.2%to 13%,with higher prevalence in high-income countries.Untreated SAD can last a lifetime and is often accompanied by impairments in social life,which severely compromises the quality of life.Furthermore,SAD is associated with a higher risk of other mental and physical disorders including depressive disor-ders,substance abuse disorders,general anxiety disorders,and cardiovascular diseases[2].

Anxiolytic Effect of Increased NREM Sleep after Acute Social Defeat Stress in Mice

Social defeat stress(SDS)plays a major role in the pathogenesis of psychiatric disorders like anxiety and depression.Sleep is generally considered to involve recovery of the brain from prior experience during wakefulness and is altered after acute SDS.However,the effect of acute SDS on sleep/wake behavior in mice varies between studies.In addition,whether sleep changes in response to stress contribute to anxiety is not well established.Here,we first investigated the effects of acute SDS on sleep/wake states in the active period in mice.Our results showed that total sleep time(time in rapid eyemovement[REM]and non-REM[NREM]sleep)increased in the active period after acute SDS.NREM sleep increased mainly during the first 3 h after SDS,while REM sleep increased at a later time.Then,we demonstrated that the increased NREM sleep had an anxiolytic benefit in acute SDS.Mice deprived of sleep for 1 h or 3 h after acute SDS remained in a highly anxious state,while in mice with ad libitum sleep the anxiety rapidly faded away.Altogether,our findings suggest an anxiolytic effect of NREM sleep,and indicate a potential therapeutic strategy for anxiety.

Neural circuit control of innate behaviors

All animals possess a plethora of innate behaviors that do not require extensive learning and are fundamental for their survival and propagation.With the advent of newly-developed techniques such as viral tracing and optogenetic and chemogenetic tools,recent studies are gradually unraveling neural circuits underlying different innate behaviors.Here,we summarize current development in our understanding of the neural circuits controlling predation,feeding,male-typical mating,and urination,highlighting the role of genetically defined neurons and their connections in sensory triggering,sensory to motor/motivation transformation,motor/motivation encoding during these different behaviors.Along the way,we discuss possible mechanisms underlying binge-eating disorder and the pro-social effects of the neuropeptide oxytocin,elucidating the clinical relevance of studying neural circuits underlying essential innate functions.Finally,we discuss some exciting brain structures recurrently appearing in the regulation of different behaviors,which suggests both divergence and convergence in the neural encoding of specific innate behaviors.Going forward,we emphasize the importance of multi-angle and cross-species dissections in delineating neural circuits that control innate behaviors.

Pathway Matters: Prefrontal Control of Negative Emotions via Distinct Downstream Regions

The infralimbic cortex(IL)is a major subregion of the medial prefrontal cortex(mPFC)that is essential for many advanced brain functions including emotions.Mounting studies have unraveled a critical role of the IL in the processing of negative emotions such as fear and anxiety.However,these studies also generate controversial data regarding the precise functions of the IL in the regulation of either fear or anxiety.On one hand,pharmacological inactivation of the IL attenuates anxiety-like behaviors and consistently,pharmacological activation of the IL produces anxiety-like behaviors[1].

Neural Circuitry Involving Substance P in Male Sexual Behavior

Male sexual behavior is an innate social behavior crucial for reproduction[1].Previous studies have identified several brain regions crucial for the control of both sexual and aggressive behaviors in males.Yet,molecularly specified neural circuits that specifically control male sexual behavior remain elusive.Consistent with the inherently rewarding nature of sexual behavior,previous research has implicated the role of the dopamine system in regulating sexual desire[2].However,the interaction between reward and copulation at the circuit level remains largely unexplored.Besides,it is unclear if the associated neural pathways are specific in modulating sexual reward.

Somatostatin-Positive Neurons in the Rostral Zona Incerta Modulate Innate Fear-Induced Defensive Response in Mice

Defensive behaviors induced by innate fear or Pavlovian fear conditioning are crucial for animals to avoid threats and ensure survival.The zona incerta(ZI)has been demonstrated to play important roles in fear learning and fear memory,as well as modulating auditory-induced innate defensive behavior.However,whether the neuronal subtypes in the ZI and specific circuits can mediate the innate fear response is largely unknown.Here,we found that somatostatin(SST)-positive neurons in the rostral ZI of mice were activated by a visual innate fear stimulus.Optogenetic inhibition of SST-positive neurons in the rostral ZI resulted in reduced flight responses to an overhead looming stimulus.Optogenetic activation of SST-positive neurons in the rostral ZI induced fear-like defensive behavior including increased immobility and bradycardia.In addition,we demonstrated that manipulation of the GABAergic projections from SST-positive neurons in the rostral ZI to the downstream nucleus reuniens(Re)mediated fear-like defensive behavior.Retrograde trans-synaptic tracing also revealed looming stimulus-activated neurons in the superior colliculus(SC)that projected to the Re-projecting SST-positive neurons in the rostral ZI(SC-ZIrSST-Re pathway).Together,our study elucidates the function of SST-positive neurons in the rostral ZI and the SC-ZIrSST-Re tri-synaptic circuit in mediating the innate fear response.

Path guided motion synthesis for Drosophila larvae

The deformability and high degree of freedom of mollusks bring challenges in mathematical modeling and synthesis of motions.Traditional analytical and statistical models are limited by either rigid skeleton assumptions or model capacity,and have difficulty in generating realistic and multi-pattern mollusk motions.In this work,we present a large-scale dynamic pose dataset of Drosophila larvae and propose a motion synthesis model named Path2Pose to generate a pose sequence given the initial poses and the subsequent guiding path.The Path2Pose model is further used to synthesize long pose sequences of various motion patterns through a recursive generation method.Evaluation analysis results demonstrate that our novel model synthesizes highly realistic mollusk motions and achieves state-of-the-art performance.Our work proves high performance of deep neural networks for mollusk motion synthesis and the feasibility of long pose sequence synthesis based on the customized body shape and guiding path.

Lighting up Oxytocin Neurons to Nurture the Brain

The sensory system develops earlier than the systems responsible for higher brain functions such as language and cognition[1].Moreover,sensory experiences in early life are critical for the development of the brain.However,how sensory experiences shape brain development is an important yet unresolved question in neuroscience.Previous work has demonstrated that deprivation of sensory inputs in the early developmental stage causes synaptic dysfunction in the sensory cortex.Interestingly,it has been reported that oxytocin can restore the deficits caused by somatosensory deprivation in neonatal mice,suggesting that oxytocin may play a key role in sensory-mediated synaptogenesis[2].Vision is one of the most important sensory inputs during early development in mammalians including humans[1],but the neural mechanism underlying vision-mediated brain development is still largely unknown.

Sense to Tune: Engaging Microglia with Dynamic Neuronal Activity

Microglia,the primary resident immune cells in the central nervous system(CNS),continuously survey the microenvironment via their ramified and motile processes to maintain brain homeostasis[1].As immune sentinels,microglia detect exogenous pathogens,elicit inflammation,promote tissue repair,and engage in the onset and progression of brain diseases[1].

Rapid Eye Movement Sleep Consolidates Social Memory

Social memory is one of declarative memory which is essential for animals to exhibit appropriate social behaviors.Evidence suggests that the hippocampus,particularly the CA2 region,plays an important role in encoding and consolidating social memory[1].Rapid eye movement(REM)sleep has been suggested to contribute to social memory consolidation by up-regulating synaptic plasticity,local field potentials,and dendritic activity[2].

Serotonin:A Bridge for Infant-mother Bonding

Maternal affiliation behavior by infants is one of the most important social behaviors of mammalians.Attachment to its mother is optimal to ensure nutrition and protection,and therefore essential for an infant's survival.More importantly,maternal affiliation benefits animals'mental and physical health in adulthood[1].Despite the importance of maternal affiliation,its underlying molecular and circuit mechanisms are only partially understood.Ultrasonic vocalizations(USVs)emitted by mice and rats have been extensively studied in infant-mother behaviors since USVs reflected pups'emotional states and the eagerness to communicate with their mothers[2].

CMT2D neuropathy is influenced by vitamin D-mediated environmental pathway

Dear Editor,Peripheral neuropathy is a group of devastating diseases affecting periphe-ral nerves and may cause symptoms such as extreme numbness,muscle weakness,and paralysis.Currently,there are no effective therapies for these diseases.Great progress has been made in identifying genetic causes for peripheral neuropathy owing to the advances in genetic testing in the last decade.For example,>100 genes have been identified to be associated with Charcot–Marie–Tooth(CMT)neuropathy,a group of disorders among the most common forms of inherited peripheral neuropathy.

Microglia in depression:current perspectives

Major depressive disorder(MDD)is a prevalent psychiatric disease that involves malfunctions of different cell types in the brain.Accumulating studies started to reveal that microglia,the primary resident immune cells,play an important role in the development and progression of depression.Microglia respond to stress-triggered neuroinflammation,and through the release of proinflammatory cytokines and their metabolic products,microglia may modulate the function of neurons and astrocytes to regulate depression.In this review,we focused on the role of microglia in the etiology of depression.We discussed the dynamic states of microglia;the correlative and causal evidence of microglial abnormalities in depression;possible mechanisms of how microglia sense depression-related stress and modulate depression state;and how antidepressive therapies affect microglia.Understanding the role of microglia in depression may shed light on developing new treatment strategies to fight against this devastating mental illness.

Glutamatergic Neurons in the Caudal Zona Incerta Regulate Parkinsonian Motor Symptoms in Mice

Parkinson’s disease(PD)is the second most common and fastest-growing neurodegenerative disorder.In recent years,it has been recognized that neurotransmitters other than dopamine and neuronal systems outside the basal ganglia are also related to PD pathogenesis.However,little is known about whether and how the caudal zona incerta(ZIc)regulates parkinsonian motor symptoms.Here,we showed that specific glutamatergic but not GABAergic ZIc^(VgluT2) neurons regulated these symptoms.ZIc^(VgluT2) neuronal activation induced time-locked parkinsonian motor symptoms.In mouse models of PD,the ZIc^(VgluT2) neurons were hyperactive and inhibition of their activity ameliorated the motor deficits.ZIc^(VgluT2) neurons monosynaptically projected to the substantia nigra pars reticulata.Incerta-nigral circuit activation induced parkinsonian motor symptoms.Together,our findings provide a direct link between the ZIc,its glutamatergic neurons,and parkinsonian motor symptoms for the first time,help to better understand the mechanisms of PD,and supply a new important potential therapeutic target for PD.

Lighting Up Neural Circuits by Viral Tracing

Neurons are highly interwoven to form intricate neural circuits that underlie the diverse functions of the brain.Dissecting the anatomical organization of neural circuits is key to deciphering how the brain processes information,produces thoughts,and instructs behaviors.Over the past decades,recombinant viral vectors have become the most commonly used tracing tools to define circuit architecture.In this review,we introduce the current categories of viral tools and their proper application in circuit tracing.We further discuss some advances in viral tracing strategy and prospective innovations of viral tools for future study.

Progress in Human Brain Banking in China

Human brain banks collect,preserve,and distribute postmortem and biopsied brain samples for histological,pathological,and molecular research.Different from the western countries,human brain banking in China has remained preliminary over decades.However,joint efforts during the past few years have substantially promoted this key frontier of neuroscience in China.This special topic brings together review and perspective articles on the ethical,administrative,and practical issues of brain banking.Several original studies report molecular and pathological characterizations based on banked human brain samples.

Brain Macrophages:Close or Distant Relatives?

The concept of a mononuclear phagocyte system in which tissue-resident macrophages arise from the circulating monocytes has been dogma in immunology for more than half a century[1].While monocytes do give rise to macrophages under certain conditions,recent studies clearly dem on strate that monocytes do not primarily contribute to most adult tissue-resident macrophage pools under the steady state[2].Instead,the majority of adult tissue-resident macrophages are derived from erythromyeloid progenitors(EMPs)in the yolk sac that seed tissue before birth[2].