Integrated neural tracing and in-situ barcoded sequencing reveals the logic of SCN efferent circuits in regulating circadian behaviors

The circadian clock coordinates rhythms in numerous physiological processes to maintain organismal homeostasis. Since the suprachiasmatic nucleus(SCN) is widely accepted as the circadian pacemaker, it is critical to understand the neural mechanisms by which rhythmic information is transferred from the SCN to peripheral clocks. Here, we present the first comprehensive map of SCN efferent connections and suggest a molecular logic underlying these projections. The SCN projects broadly to most major regions of the brain, rather than solely to the hypothalamus and thalamus. The efferent projections from different subtypes of SCN neurons vary in distance and intensity, and blocking synaptic transmission of these circuits affects circadian rhythms in locomotion and feeding to different extents. We also developed a barcoding system to integrate retrograde tracing with in-situ sequencing, allowing us to link circuit anatomy and spatial patterns of gene expression. Analyses using this system revealed that brain regions functioning downstream of the SCN receive input from multiple neuropeptidergic cell types within the SCN, and that individual SCN neurons generally project to a single downstream brain region.This map of SCN efferent connections provides a critical foundation for future investigations into the neural circuits underlying SCNmediated rhythms in physiology. Further, our new barcoded tracing method provides a tool for revealing the molecular logic of neuronal circuits within heterogeneous brain regions.

Neurocircuitry of Predatory Hunting

Predatory hunting is an important type of innate behavior evolutionarily conserved across the animal king-dom.It is typically composed of a set of sequential actions,including prey search,pursuit,attack,and consumption.This behavior is subject to control by the nervous system.Early studies used toads as a model to probe the neuroethology of hunting,which led to the proposal of a sensory-triggered release mechanism for hunting actions.More recent stud-ies have used genetically-trackable zebrafish and rodents and have made breakthrough discoveries in the neuroethol-ogy and neurocircuits underlying this behavior.Here,we review the sophisticated neurocircuitry involved in hunting and summarize the detailed mechanism for the circuitry to encode various aspects of hunting neuroethology,including sensory processing,sensorimotor transformation,motivation,and sequential encoding of hunting actions.We also discuss the overlapping brain circuits for hunting and feeding and point out the limitations of current studies.We propose that hunting is an ideal behavioral paradigm in which to study the neuroethology of motivated behaviors,which may shed new light on epidemic disorders,including bingeeating,obesity,and obsessive-compulsive disorders.

Brain Mechanisms Underlying Panic Attack and Panic Disorder

Panic disorder is a psychiatric disorder characterized by recurrent panic attacks,with a prevalence of~4%in the general population,causing heavy personal and socioeconomic burdens.The similarities of animal defense responses to clinical panic attack symptoms in humans make it possible to translate neuroanatomical pathways identified in animal studies to panic disorder in humans.Therefore,in this review we first present a basic overview of panic disorder in humans including the main subtypes,models commonly used to trigger panic attacks,related hypotheses,the neurotransmitter systems that may be involved,and the current clinical treatments to give the reader a comprehensive understanding of panic disorder.The animal section introduces the models that trigger panic-like behavior in animals and the brain regions that may be involved,providing insights for future elucidation of the neural circuit mechanisms behind panic attacks.

Correction to:Brain Mechanisms Underlying Panic Attack and Panic Disorder

Correction to:Neurosci.Bull.https://doi.org/10.1007/s12264-023-01088-9 The original version of this article unfortunately contained some mistakes,and the corrections are as follows,Some sentences contain incorrect references.The corrected content is provided below.

DEMETHYLATION REGULATOR 1 regulates DNA demethylation of the nuclear and mitochondrial genomes

Active DNA demethylation effectively modulates gene expression during plant development and in response to stress.However,little is known about the upstream regulatory factors that regulate DNA demethylation.We determined that the demethylation regulator 1(demr1)mutant exhibits a distinct DNA methylation profile at selected loci queried by methylation-sensitive polymerase chain reaction and globally based on whole-genome bisulfite sequencing.Notably,the transcript levels of the DNA demethylase gene REPRESSOR OF SILENCING 1(ROS1)were lower in the demr1 mutant.We established that DEMR1 directly binds to the ROS1 promoter in vivo and in vitro,and the methylation level in the DNA methylation monitoring sequence of ROS1 promoter decreased by 60%in the demr1 mutant.About 40%of the hyper-differentially methylated regions(DMRs)in the demr1 mutant were shared with the ros1-4 mutant.Genetic analysis indicated that DEMR1 acts upstream of ROS1 to positively regulate abscisic acid(ABA)signaling during seed germination and seedling establishment stages.Surprisingly,the loss of DEMR1 function also caused a rise in methylation levels of the mitochondrial genome,impaired mitochondrial structure and an early flowering phenotype.Together,our results show that DEMR1 is a novel regulator of DNA demethylation of both the nuclear and mitochondrial genomes in response to ABA and plant development in Arabidopsis.

A neuropsin-based optogenetic tool for precise control of Gq signaling

G_(q)-coupled receptors regulate numerous physiological processes by activating enzymes and inducing intracellular Ca^(2+)signals.There is a strong need for an optogenetic tool that enables powerful experimental control over G_(q) signaling.Here,we present chicken opsin 5(cOpn5)as the long sought-after,single-component optogenetic tool that mediates ultra-sensitive optical control of intracellular G_(q) signaling with high temporal and spatial resolution.Expressing cOpn5 in HEK 293T cells and primary mouse astrocytes enables blue light-triggered,G_(q)-dependent Ca^(2+) release from intracellular stores and protein kinase C activation.Strong Ca^(2+) transients were evoked by brief light pulses of merely 10 ms duration and at 3 orders lower light intensity of that for common optogenetic tools.Photostimulation of cOpn5-expressing cells at the subcellular and single-cell levels generated fast intracellular Ca^(2+)transition,thus demonstrating the high spatial precision of cOpn5 optogenetics.The cOpn5-mediated optogenetics could also be applied to activate neurons and control animal behavior in a circuit-dependent manner.cOpn5 optogenetics may find broad applications in studying the mechanisms and functional relevance of G_(q) signaling in both non-excitable cells and excitable cells in all major organ systems.

New advances in molecular and neural mechanisms of sleep regulation

Sleep exists ubiquitously among invertebrate and vertebrate animals.While sleep survives millions of years of evolution,it is unclear exactly what essential functions that sleep provides to animals.Sleep and wakefulness are mainly regulated by circadian and homeostatic mechanisms[1,2].

Discovery of dipeptidyl peptidase Ⅳ(DPP4) inhibitors based on a novel indole scaffold

Dipeptidyl peptidase Ⅳ（DPP4） inhibitors are proven in the treatment of type 2 diabetes.We designed and synthesized a series of novel indole compounds that selectively inhibit the activity of DPP4 over dipeptidyl peptidase 9（DPP9）（〉200 fold）.We further co-crystallized DPP4 with indole sulfonamide（compound 1） to confirm a proposed binding mode.Good metabolic stability of the indole compounds represents another positive attribute for further development.

An optical brain-to-brain interface supports rapid information transmission for precise locomotion control

Brain-to-brain interfaces(BtBIs) hold exciting potentials for direct communication between individual brains. However,technical challenges often limit their performance in rapid information transfer. Here, we demonstrate an optical brain-to-brain interface that transmits information regarding locomotor speed from one mouse to another and allows precise, real-time control of locomotion across animals with high information transfer rate. We found that the activity of the genetically identified neuromedin B(NMB) neurons within the nucleus incertus(NI) precisely predicts and critically controls locomotor speed. By optically recording Ca2+ signals from the NI of a "Master" mouse and converting them to patterned optogenetic stimulations of the NI of an "Avatar" mouse, the Bt BI directed the Avatar mice to closely mimic the locomotion of their Masters with information transfer rate about two orders of magnitude higher than previous Bt BIs. These results thus provide proof-of-concept that optical Bt BIs can rapidly transmit neural information and control dynamic behaviors across individuals.

A Deep Mesencephalic Nucleus Circuit Regulates Licking Behavior

Licking behavior is important for water intake.The deep mesencephalic nucleus(DpMe)has been implicated in instinctive behaviors.However,whether the DpMe is involved in licking behavior and the precise neural circuit behind this behavior remains unknown.Here,we found that the activity of the DpMe decreased during water intake.Inhibition of vesicular glutamate transporter 2-positive(VGLUT2+)neurons in the DpMe resulted in increased water intake.Somatostatin-expressing(SST+),but not protein kinase C-expressing(PKC-8+),GABAergic neurons in the central amygdala(CeA)preferentially innervated DpMe VGLUT2+neurons.The SST+neurons in the CeA projecting to the DpMe were activated at the onset of licking behavior.Activation of these CeA SST+GABAergic neurons,but not PKC-8+GABAergic neurons,projecting to the DpMe was sufficient to induce licking behavior and promote water intake.These findings redefine the roles of the DpMe and reveal a novel CeAssT_DpMevcLUT?cireuit that regulaes icking behavior and promotes water intake.