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Our sense of taste is critical for regulating food consumption. The fruit fly Drosophila represents a highly tractable model to investigate mechanisms of taste processing, but taste circuits beyond sensory neurons are largely unidentified. Here, we use a whole-brain connectome to investigate the organization of Drosophila taste circuits. We trace pathways from four populations of sensory neurons that detect different taste modalities and project to the subesophageal zone (SEZ), the primary taste region of the fly brain. We find that second-order taste neurons are primarily located within the SEZ and largely segregated by taste modality, whereas third-order neurons have more projections outside the SEZ and more overlap between modalities. Taste projections out of the SEZ innervate regions implicated in feeding, olfactory processing, and learning. We analyze interconnections within and between taste pathways, characterize modality-dependent differences in taste neuron properties, identify other types of inputs onto taste pathways, and use computational simulations to relate neuronal connectivity to predicted activity. These studies provide insight into the architecture of Drosophila taste circuits. [ABSTRACT FROM AUTHOR]

Recent technological advances in intracranial brain stimulation have enhanced the potential of neuromodulation for addressing neuropsychiatric disorders. We present a review of the methodology and the preliminary outcomes of the pioneering studies exploring intracranial biomarker detection and closed-loop neuromodulation to modulate high-symptom severity states in neuropsychiatric disorders. We searched PubMed, Scopus, Web of Science, Embase, and PsycINFO/PsycNet, followed by the reference and citation lists of retrieved articles. This search strategy yielded a total of 583 articles, of which 5 articles met the inclusion criteria, focusing on depression, obsessive-compulsive disorder, post-traumatic stress disorder, and binge eating disorder. We discuss the methodology of biomarker identification, the biomarkers identified, and the preliminary treatment outcomes for closed-loop neuromodulation. Successful biomarker identification hinges on investigating across various setting. Targeted neuromodulation, either directed at the biomarker or within its associated neural network, offers a promising treatment approach. Future research should seek to understand the mechanisms underlying the effects of neuromodulation as well as the long-term viability of these treatment effects across different neuropsychiatric conditions. [ABSTRACT FROM AUTHOR]

Cognitive impairment refers to abnormalities in learning, memory and cognitive judgment, mainly manifested as symptoms such as decreased memory, impaired orientation and reduced computational ability. As the fundamental unit of information processing in the brain, neural circuits have recently attracted great attention due to their functions in regulating pain, emotion and behavior. Furthermore, a growing number of studies have suggested that neural circuits play an important role in cognitive impairment. Neural circuits can affect perception, attention and decision-making, they can also regulate language skill, thinking and memory. Pathological conditions crucially affecting the integrity and preservation of neural circuits and their connectivity will heavily impact cognitive abilities. Nowadays, technological developments have led to many novel methods for studying neural circuits, such as brain imaging, optogenetic techniques, and chemical genetics approaches. Therefore, neural circuits show great promise as a potential target in mitigating cognitive impairment. In this review we discuss the pathogenesis of cognitive impairment and the regulation and detection of neural circuits, thus highlighting the role of neural circuits in cognitive impairment. Hence, therapeutic agents against cognitive impairment may be developed that target neural circuits important in cognition. [ABSTRACT FROM AUTHOR]

Neural electrical signals forced the muscle tissue to behave effective body gait. When neural activities are measured in a neural circuit, artificial electromechanical arm and leg can be controlled to mimic the movement and even vibration of limbs. In this paper, a simple neural circuit is used to drive an electromechanical arm (EMA) device by activating Ampere's force via the load circuit adhered to the moving beam, and the load circuit is coupled with the neural circuit for energy conversion. The circuit equations, field energy and moving equation of the beam are obtained for dynamical analysis. Furthermore, two EMAs are coupled via a spring for mimicking the cooperation between two arms or legs during synchronous movement, and then the same electrical signal is used to control the moving states of the coupled EMAs. This processing can describe the synchronous movements of two arms along horizontal linear motion under neural stimuli. Noisy disturbance is applied to detect and predict occurrence of stochastic resonance in the moving beams by calculating signal to noise ratio, and the average Hamilton energy vs. time is effective to predict the emergence of nonlinear stochastic and coherence resonance by approach the average power from physical aspect. The results provide helpful guidance to design complex electromechanical device for behaving complex gaits. That is, neural signals can be used to excite the electromechanical devices as muscles and then the body gaits are controlled effectively. [ABSTRACT FROM AUTHOR]

Background Objective Materials and methods Results Discussion and conclusion Although some studies have revealed the close relationship between leptin and premature ejaculation in clinical practice, whether and how leptin participates in the regulation of ejaculatory behaviors are still unknown.To explore the role of leptin on ejaculatory behaviors and its underlying mechanism.Copulation behavior tests were performed after acute and chronic leptin administration at peripheral and central levels. To compare changes in sympathetic nervous system activity, lumbar sympathetic nervous activity, serum noradrenaline levels, and the distribution of sympathetic fibers in vas deferens and seminal vesicles were analyzed. Construction of virus vector, immunohistochemistry, and optogenetics techniques were used to explore the neural circuit mechanism. The density of dendritic spines in parvocellular region of paraventricular nucleus was measured by Golgi staining.Acute administration of leptin had no effect on ejaculation behavior in male mice. However, both mount latency and ejaculation latency were significantly shortened, even if serum leptin decreased to normal level, after chronic administration of leptin at peripheral or central level. Additionally, sympathetic fibers in vas deferens and seminal vesicles obviously increased, in which arcuate nucleus‒paraventricular nucleus circuit and glutamatergic neurons in paraventricular nucleus played an important role. Dendritic spine density in parvocellular region increased after chronic leptin administration.The role of leptin in regulating ejaculation behavior was chronic, not acute, in which leptin chronically modulated sympathetic neuroplasticity via arcuate nucleus‒paraventricular nucleus circuit and glutamatergic neurons in paraventricular nucleus and promoted ejaculatory behaviors. Increased dendritic spine density in parvocellular region of paraventricular nucleus may be involved as well. [ABSTRACT FROM AUTHOR]

With the development of neuroscience and oncology, the direct regulation effect of central nervous system circuits on tumors has been gradually revealed. Evidence indicates that the therapy targeting emotion-related encephalic regions may have great potential in blocking the promotion of breast cancer progression by depression. The underlying complex mechanisms involve the generation of depression and the regulation of tumors by central nervous system circuits. However, a systematic summary is lacking in this field. This article reviews the latest research progress of the central nervous system circuits and the generation of depression, the neural connection between the central nervous system and peripheral tumor, and the regulation of the tumor immune microenvironment by the sympathetic nervous system. It also systematically investigates the potential mechanism of the central nervous system circuit in the promotion of breast cancer progression by depression to establish new solutions for the comprehensive treatment of breast cancer. [ABSTRACT FROM AUTHOR]

The globus pallidus plays a pivotal role in the basal ganglia circuit. Parkinson’s disease is characterized by degeneration of dopamine-producing cells in the substantia nigra, which leads to dopamine deficiency in the brain that subsequently manifests as various motor and non-motor symptoms. This review aims to summarize the involvement of the globus pallidus in both motor and non-motor manifestations of Parkinson’s disease. The firing activities of parvalbumin neurons in the medial globus pallidus, including both the firing rate and pattern, exhibit strong correlations with the bradykinesia and rigidity associated with Parkinson’s disease. Increased beta oscillations, which are highly correlated with bradykinesia and rigidity, are regulated by the lateral globus pallidus. Furthermore, bradykinesia and rigidity are strongly linked to the loss of dopaminergic projections within the cortical-basal ganglia-thalamocortical loop. Resting tremors are attributed to the transmission of pathological signals from the basal ganglia through the motor cortex to the cerebellum-ventral intermediate nucleus circuit. The cortico–striato–pallidal loop is responsible for mediating pallidi-associated sleep disorders. Medication and deep brain stimulation are the primary therapeutic strategies addressing the globus pallidus in Parkinson’s disease. Medication is the primary treatment for motor symptoms in the early stages of Parkinson’s disease, while deep brain stimulation has been clinically proven to be effective in alleviating symptoms in patients with advanced Parkinson’s disease, particularly for the movement disorders caused by levodopa. Deep brain stimulation targeting the globus pallidus internus can improve motor function in patients with tremor-dominant and non-tremor-dominant Parkinson’s disease, while deep brain stimulation targeting the globus pallidus externus can alter the temporal pattern of neural activity throughout the basal ganglia–thalamus network. Therefore, the composition of the globus pallidus neurons, the neurotransmitters that act on them, their electrical activity, and the neural circuits they form can guide the search for new multi-target drugs to treat Parkinson’s disease in clinical practice. Examining the potential intra-nuclear and neural circuit mechanisms of deep brain stimulation associated with the globus pallidus can facilitate the management of both motor and non-motor symptoms while minimizing the side effects caused by deep brain stimulation.

Patients with congenital analgesia who lack the ability to sense temperature generally face low survival rates, highlighting a critical need to understand the underlying mechanisms of heat sensation. While previous research has focused on modeling neural responses to stimuli, the specific mechanisms by which heat-sensitive neurons respond to external temperature changes remain unclear. This gap in knowledge is particularly relevant, as identifying how these neurons react to diverse stimuli can provide insight into sensory deficits linked to congenital analgesia. In this study, we developed a model of heat-sensitive neurons based on the FitzHugh-Nagumo (FHN) neural circuit to investigate neuronal response patterns to external heat stimuli. Two distinct stimulus patterns, each combined with Gaussian white noise, were applied to the model to induce varied firing modes. By calculating the Hamilton energy for each firing mode, we quantified the impact of each external stimulus on neuronal activity. A correlation function was further defined to explore how different stimuli influence the selection of firing modes. Simulation results demonstrate that heat-sensitive neurons show a preferential response to stimuli that induce spike discharge over stimuli that induce r-clonic patterns, as seen in changes to the periodic attractor contours. When exposed to Chua's circuit stimulus, chaotic emission patterns reveal significant shifts in attractor contour, indicating a strong response to spike, r-clonic, and periodic stimuli. These findings suggest that external stimuli capable of inducing spike-and-wave or r-clonic patterns are sensitively detected by thermosensitive neurons, leading to heightened Hamilton energy release and increased regularity in neural activity. This study enhances our understanding of thermosensitive neuronal dynamics under complex stimuli, shedding light on potential response mechanisms relevant to sensory dysfunction in congenital analgesia and advancing the broader field of neural response modeling.

Peiling Zhou,1 Shiyu Peng,2 Sizhe Wen,1 Qinghui Lan,1 Yingyin Zhuang,1 Xuyan Li,1 Mengliang Shi,1,3 Changzheng Zhang1 1Guangdong Provincial Key Laboratory of Development and Education for Special Needs Children & School of Educational Sciences, Lingnan Normal University, Zhanjiang, 524048, People’s Republic of China; 2Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 3School of Education, South China Normal University, Guangzhou, 510631, People’s Republic of ChinaCorrespondence: Changzheng Zhang, School of Educational Sciences, Lingnan Normal University, 29 Cunjin Road, Zhanjiang, Guangdong Province, 524048, People’s Republic of China, Email neurozhang@163.com Mengliang Shi, School of Education, South China Normal University, 55 West Zhongshan Avenue, Shipai Street, Guangzhou, Guangdong Province, 510631, People’s Republic of China, Email 20240169@m.scnu.edu.cnAbstract: The cerebellum has long been implicated in the etiopathogenesis of autism spectrum disorder (ASD), and emerging evidence suggests a significant contribution by reciprocal neural circuits between the cerebellum and ventral tegmental area (VTA) in symptom expression. This review provides a concise overview of morphological and functional alterations in the cerebellum and VTA associated with ASD symptoms, primarily focusing on human studies while also integrating mechanistic insights from animal models. We propose that cerebello–VTA circuit dysfunctional is a major contributor to ASD symptoms and that these circuits are promising targets for drugs and therapeutic brain stimulation methods.Keywords: autism spectrum disorder, cerebellum, ventral tegmental area, neural circuit

Astrocytes play a crucial role in regulating sleep‐wake behavior. However, how astrocytes govern a specific sleep‐arousal circuit remains unknown. Here, the authors show that parafacial zone (PZ) astrocytes responded to sleep‐wake cycles with state‐differential Ca2+ activity, peaking during transitions from sleep to wakefulness. Using chemogenetic and optogenetic approaches, they find that activating PZ astrocytes elicited and sustained wakefulness by prolonging arousal episodes while impeding transitions from wakefulness to non‐rapid eye movement (NREM) sleep. Activation of PZ astrocytes specially induced the elevation of extracellular adenosine through the ATP hydrolysis pathway but not equilibrative nucleoside transporter (ENT) mediated transportation. Strikingly, the rise in adenosine levels induced arousal by activating A1 receptors, suggesting a distinct role for adenosine in the PZ beyond its conventional sleep homeostasis modulation observed in the basal forebrain (BF) and cortex. Moreover, at the circuit level, PZ astrocyte activation induced arousal by suppressing the GABA release from the PZGABA neurons, which promote NREM sleep and project to the parabrachial nucleus (PB). Thus, their study unveils a distinctive arousal‐promoting effect of astrocytes within the PZ through extracellular adenosine and elucidates the underlying mechanism at the neural circuit level. [ABSTRACT FROM AUTHOR]

Chronic visceral pain stems from internal organs and is frequently associated with functional gastrointestinal disorders, like irritable bowel syndrome (IBS). Since the underlying mechanisms of visceral pain remain largely unclear, clinical management is often limited and ineffective. Comprehensive research into the pathogenesis of visceral pain, along with the development of personalized therapeutic strategies, is crucial for advancing treatment options. Studies suggest that imbalances in purinergic receptors and neural circuit function are closely linked to the onset of visceral pain. In this review, we will explore the etiology and pathological mechanisms underlying visceral pain, with a focus on ion channels, epigenetic factors, and neural circuits, using functional gastrointestinal disorders as case studies. Finally, we will summarize and evaluate emerging treatments and potential initiatives aimed at managing visceral pain. [ABSTRACT FROM AUTHOR]

Anxiety disorders, common yet impactful emotional disturbances, significantly affect physical and mental health globally. Many neuron circuits are associated with anxiety regulation like septo-hippocampal loop, amygdala(AMYG), bed nucleus of the stria terminalis (BNST), ventral hippocampus (vHPC), and brain regions like medial prefrontal cortex (mPFC). However, the concrete mechanism of anxiety disorder in BNST is relatively unknown. Recent research showed BNST plays a critical role in modulating anxiety owing to its anatomical location and special circuit characteristics, which are considered to be a hub in the limbic system regulating anxiety. BNST consists with multiple subregions, which can project separately into different brain regions and exert projecting independently to various brain regions with distinct regulatory effects. Moreover, multiple signal pathways in BNST are reported to play significant roles in regulating anxiety and stress behavior. This review briefly describes anxiety disorders and subdivisions and functions of BNST, focusing on the main neural circuits that serve as fundamental pathways in both the genesis and potential treatment of anxiety disorders and the molecular mechanism of BNST on anxiety. The complexity of structures and mechanisms has facilitated the development of imaging techniques. Innovative multimodal imaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), have non-invasively illuminated BNST activities and their functional connections with other brain areas. These methodologies provide a deeper understanding of how BNST responds to anxiety-inducing stimuli, offering invaluable insights into its complex role in anxiety regulation. The continued exploration of BNST in anxiety research promises not only to elucidate fundamental neurobiological mechanisms but also to foster advancements in clinical treatments for anxiety disorders. [ABSTRACT FROM AUTHOR]

External electric and mechanical stimuli can induce shape deformation in excitable media because of its intrinsic flexible property. When the signals propagation in the media is described by a neural network, creation of heterogeneity or defect is considered as the effect of shape deformation due to accumulation or release of energy in the media. In this paper, a temperature-light sensitive neuron model is developed from a nonlinear circuit composed of a phototube and a thermistor, and the physical energy is kept in capacitive and inductive terms. Furthermore, the Hamilton energy for this function neuron is obtained in theoretical way. A regular neural network is built on a square array by activating electric synapse between adjacent neurons, and a few of neurons in local area is excited by noisy disturbance, which induces local energy diversity, and continuous coupling enables energy propagation and diffusion. Initially, the Hamilton energy function for a temperature-light sensitive neuron can be obtained. Then, the finite neurons are applied noise to obtain energy diversity to explore the energy spread between neurons in the network. For keeping local energy balance, one intrinsic parameter is regulated adaptively until energy diversity in this local area is decreased greatly. Regular pattern formation indicates that local energy balance creates heterogeneity or defects and a few of neurons show continuous parameter shift for keeping energy balance in a local area, which supports gradient energy distribution for propagating waves in the network. [ABSTRACT FROM AUTHOR]

Persistent pain frequently precipitates the development of anxiety disorders, yet the underlying mechanisms are not fully understood. In this study, we employed a mouse model that simulates trigeminal neuralgia and observed a marked reduction in the activity of GABAergic neurons in the lateral habenula (LHb), a critical region for modulating pain and anxiety. We utilized precise optogenetic and chemogenetic techniques to modulate these neurons, which significantly alleviated behaviors associated with pain and anxiety. Our investigations revealed an inhibitory pathway from the LHb GABAergic neurons to the posterior paraventricular thalamus. Activation of this pathway primarily mitigated pain-related behaviors, with minimal effects on anxiety. Conversely, interactions between GABAergic and glutamatergic neurons within the LHb were essential in alleviating both pain and anxiety following trigeminal nerve damage. Additionally, we identified that β-sitosterol interacts directly with LHb GABAergic neurons via the estrogen receptor α, providing dual therapeutic effects for both pain and anxiety. These findings highlight the critical role of reduced GABAergic neuronal activity in the LHb in the intersection of pain and anxiety, pointing to promising therapeutic possibilities. [ABSTRACT FROM AUTHOR]

As for human language learning and birdsong acquisition, fruit flies adjust their auditory perception based on past sound experiences. This phenomenon is known as song preference learning in flies. Recent advancements in omics databases, such as the single-cell transcriptome and brain connectomes, have been integrated into traditional molecular genetics, making the fruit fly an outstanding model for studying the neural basis of "Nature and Nurture" in auditory perception and behaviors. This minireview aims to provide an overview of song preference in flies, including the nature of the phenomenon and its underlying neural mechanisms. Specifically, we focus on the neural circuitry involved in song preference learning, with which auditory experiences shape the song preference of flies. This shaping process depends on an integration hub that processes external sensory stimuli and internal states to enable flexible control of behavior. We also briefly review recent findings on the signals that feed into this integration hub, modulating song preference of flies in an experience-dependent manner. [ABSTRACT FROM AUTHOR]

The activation of autonomic and hypothalamo-pituitary-adrenal (HPA) systems occurs interdependently with behavioral adjustments under varying environmental demands. Nevertheless, laboratory rodent studies examining the neural bases of stress responses have generally attributed increments in these systems to be monolithic, regardless of whether an active or passive coping strategy is employed. Using the shock probe defensive burying test (SPDB) to measure stress-coping features naturalistically in male and female rats, we identify a neural pathway whereby activity changes may promote distinctive response patterns of hemodynamic and HPA indices typifying active and passive coping phenotypes. Optogenetic excitation of the rostral medial prefrontal cortex (mPFC) input to the ventrolateral periaqueductal gray (vlPAG) decreased passive behavior (immobility), attenuated the glucocorticoid hormone response, but did not prevent arterial pressure and heart rate increases associated with rats' active behavioral (defensive burying) engagement during the SPDB. In contrast, inhibition of the same pathway increased behavioral immobility and attenuated hemodynamic output but did not affect glucocorticoid increases. Further analyses confirmed that hemodynamic increments occurred preferentially during active behaviors and decrements during immobility epochs, whereas pathway manipulations, regardless of the directionality of effect, weakened these correlational relationships. Finally, neuroanatomical evidence indicated that the influence of the rostral mPFC→vlPAG pathway on coping response patterns is mediated predominantly through GABAergic neurons within vlPAG. These data highlight the importance of this prefrontal→midbrain connection in organizing stress-coping responses and in coordinating bodily systems with behavioral output for adaptation to aversive experiences. [ABSTRACT FROM AUTHOR]

Patients with congenital analgesia who lack the ability to sense temperature generally face low survival rates, highlighting a critical need to understand the underlying mechanisms of heat sensation. While previous research has focused on modeling neural responses to stimuli, the specific mechanisms by which heat-sensitive neurons respond to external temperature changes remain unclear. This gap in knowledge is particularly relevant, as identifying how these neurons react to diverse stimuli can provide insight into sensory deficits linked to congenital analgesia. In this study, we developed a model of heat-sensitive neurons based on the FitzHugh-Nagumo (FHN) neural circuit to investigate neuronal response patterns to external heat stimuli. Two distinct stimulus patterns, each combined with Gaussian white noise, were applied to the model to induce varied firing modes. By calculating the Hamilton energy for each firing mode, we quantified the impact of each external stimulus on neuronal activity. A correlation function was further defined to explore how different stimuli influence the selection of firing modes. Simulation results demonstrate that heat-sensitive neurons show a preferential response to stimuli that induce spike discharge over stimuli that induce r-clonic patterns, as seen in changes to the periodic attractor contours. When exposed to Chua's circuit stimulus, chaotic emission patterns reveal significant shifts in attractor contour, indicating a strong response to spike, r-clonic, and periodic stimuli. These findings suggest that external stimuli capable of inducing spike-and-wave or r-clonic patterns are sensitively detected by thermosensitive neurons, leading to heightened Hamilton energy release and increased regularity in neural activity. This study enhances our understanding of thermosensitive neuronal dynamics under complex stimuli, shedding light on potential response mechanisms relevant to sensory dysfunction in congenital analgesia and advancing the broader field of neural response modeling. [ABSTRACT FROM AUTHOR]

Neural communication requires both fast-acting neurotransmitters and neuromodulators that function on slower timescales to communicate. Endogenous bioactive peptides, often called "neuropeptides," comprise the largest and most diverse class of neuromodulators that mediate crosstalk between the brain and peripheral tissues to regulate physiology and behaviors conserved across the animal kingdom. Neuropeptide signaling can be terminated through receptor binding and internalization or degradation by extracellular enzymes called neuropeptidases. Inactivation by neuropeptidases can shape the dynamics of signaling in vivo by specifying both the duration of signaling and the anatomic path neuropeptides can travel before they are degraded. For most neuropeptides, the identity of the relevant inactivating peptidase(s) is unknown. Here, we established a screening platform in C. elegans utilizing mass spectrometry-based peptidomics to discover neuropeptidases and simultaneously profile the in vivo specificity of these enzymes against each of more than 250 endogenous peptides. We identified NEP-2, a worm ortholog of the mammalian peptidase neprilysin-2, and demonstrated that it regulates specific neuropeptides, including those in the egg-laying circuit. We found that NEP-2 is required in muscle cells to regulate signals from neurons to modulate both behavior and health in the reproductive system. Taken together, our results demonstrate that peptidases, which are an important node of regulation in neuropeptide signaling, affect the dynamics of signaling to impact behavior, physiology, and aging. [Display omitted] • Neuropeptidomic screen identified a neuropeptidase, NEP-2, and its targets • NEP-2 regulates NLP-3 neuropeptides to modulate egg-laying behavior • Expression of nep-2 in muscle, and not neurons, is required for proper egg laying • Targeting NEP-2 in animals with compromised egg-laying (matricide) improves health Neuropeptidases are an important and understudied node of regulation in peptidergic circuits. Lo et al. use neuropeptidomics to identify NEP-2 as a neuropeptidase in C. elegans and simultaneously link it to endogenous peptide targets. They demonstrate how NEP-2 regulates the dynamics of peptidergic signaling to impact behavior and aging. [ABSTRACT FROM AUTHOR]

Neurons typically release both a neurotransmitter and one or more neuropeptides, but how these signals are integrated within neural circuits to generate and tune behaviors remains poorly understood. We studied how the two hermaphrodite-specific neurons (HSNs) activate the egg-laying circuit of Caenorhabditis elegans by releasing both the neurotransmitter serotonin and NLP-3 neuropeptides. Egg laying occurs in a temporal pattern with approximately 2-min active phases, during which eggs are laid, separated by approximately 20-min inactive phases, during which no eggs are laid. To understand how serotonin and NLP-3 neuropeptides together help produce this behavior pattern, we identified the G-protein-coupled receptor neuropeptide receptor 36 (NPR-36) as an NLP-3 neuropeptide receptor using genetic and molecular experiments. We found that NPR-36 is expressed in, and promotes egg laying within, the egg-laying muscle cells, the same cells where two serotonin receptors also promote egg laying. During the active phase, when HSN activity is high, we found that serotonin and NLP-3 neuropeptides each have a different effect on the timing of egg laying. During the inactive phase, HSN activity is low, which may result in release of only serotonin, yet mutants lacking either serotonin or nlp-3 signaling have longer inactive phases. This suggests that NLP-3 peptide signaling may persist through the inactive phase to help serotonin signaling terminate the inactive phase. We propose a model for neural circuit function in which multiple signals with short- and long-lasting effects compete to generate and terminate persistent internal states, thus patterning a behavior over tens of minutes. • C. elegans HSNs release NLP-3 peptides and serotonin to activate egg laying • These signals act via different receptors on the same muscles to pattern behavior • The two signals together initiate egg laying after ∼20-min inactive phases • Each signal then causes egg-laying events at different frequencies over ∼2 min Individual neurons typically release both a neurotransmitter and neuropeptides, but how these signals function together remains largely unclear. Butt et al. determine how serotonin and neuropeptides released by a pair of C. elegans neurons combine their effects on the same target cells to generate a complex temporal pattern of egg-laying behavior. [ABSTRACT FROM AUTHOR]

Stereotyped brain asymmetry, also known as laterality, is widespread and multiscale, encompassing asymmetrical molecular function, left–right (LR) asymmetrical neurons or circuits, structural differences, and lateralized behaviors. Brain laterality can modulate a wide variety of behaviors and cognitive functions, including sleep, memory, food preference, fear, and anxiety. Long-term memory is among the most evolutionary conserved cognitive traits influenced by brain lateralization. The mechanisms and molecular pathways governing brain laterality vary widely among model organisms. The current limited understanding of the diversity of asymmetries hinders the definition of common principles and conserved symmetry-breaking mechanisms. The concordance between body and brain LR asymmetry can be strong, partial, or completely absent, raising questions about the emergence and coordination of asymmetry between the brain and body. Chirality is a fundamental trait of living organisms, encompassing the homochirality of biological molecules and the left–right (LR) asymmetry of visceral organs and the brain. The nervous system in bilaterian organisms displays a lateralized organization characterized by the presence of asymmetrical neuronal circuits and brain functions that are predominantly localized within one hemisphere. Although body asymmetry is relatively well understood, and exhibits robust phenotypic expression and regulation via conserved molecular mechanisms across phyla, current findings indicate that the asymmetry of the nervous system displays greater phenotypic, genetic, and evolutionary variability. In this review we explore the use of nematode, zebrafish, and Drosophila genetic models to investigate neuronal circuit asymmetry. We discuss recent discoveries in the context of body–brain concordance and highlight the distinct characteristics of nervous system asymmetry and its cognitive correlates. [ABSTRACT FROM AUTHOR]

Human-derived monoclonal antibodies (HD-mAbs) can be used to study neural proteotypes, cell populations defined by their proteome rather than their transcriptome. The human antibody repertoire is a nearly inexhaustible source of unique HD-mAbs that can be used to manipulate select proteotypes. Because autoantibodies can cause neuropsychiatric symptoms, some HD-mAbs may help map neural proteotypes to behavioral phenomena. HD-mAbs can traverse the placenta and are easily ported across model systems. Antibody engineering can be used to tune the functional properties of HD-mAbs, thereby increasing their versatility. A major aim of neuroscience is to identify and model the functional properties of neural cells whose dysfunction underlie neuropsychiatric illness. In this article, we propose that human-derived monoclonal autoantibodies (HD-mAbs) are well positioned to selectively target and manipulate neural subpopulations as defined by their protein expression; that is, cellular proteotypes. Recent technical advances allow for efficient cloning of autoantibodies from neuropsychiatric patients. These HD-mAbs can be introduced into animal models to gain biological and pathobiological insights about neural proteotypes of interest. Protein engineering can be used to modify, enhance, silence, or confer new functional properties to native HD-mAbs, thereby enhancing their versatility. Finally, we discuss the challenges and limitations confronting HD-mAbs as experimental research tools for neuroscience. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a common comorbidity of chronic pain, significantly disrupting patients' quality of life. Despite this comorbidity being clinically recognized, the underlying neuropathological mechanisms remain unclear. Recent preclinical studies have focused on the fundamental mechanisms underlying the coexistence of chronic pain and cognitive decline. Pain chronification is accompanied by structural and functional changes in the neural substrate of cognition. Based on the developments in electrophysiology and optogenetics/chemogenetics, we summarized the relevant neural circuits involved in pain-induced cognitive impairment, as well as changes in connectivity and function in brain regions. We then present the cellular and molecular alternations related to pain-induced cognitive impairment in preclinical studies, mainly including modifications in neuronal excitability and structure, synaptic plasticity, glial cells and cytokines, neurotransmitters and other neurochemicals, and the gut-brain axis. Finally, we also discussed the potential treatment strategies and future research directions. [ABSTRACT FROM AUTHOR]

Abstract Interactions between the microbiota and host have been proven to be critical regulators of homeostasis, and pain perception is no exception. Emerging evidence has identified the mechanisms by which microbiota dysbiosis contributes to hyperalgesia and revealed the potential value of microbiota‐associated therapies in pain management. Herein, the authors introduce the basic knowledge of pain and microbiota for readers who are not simultaneously majoring in these two fields. The clarified mechanisms underlying the regulation of pain by the microbiota are outlined in terms of three ways. This review summarizes the current advancements in pain management and microbiology research for clinicians who wish to focus on this area. Probiotics, fecal microbiota transplantation, and other methods of microbiota modulation for pain management have entered clinical translation. The authors further propose the present limitations and prospects for high‐quality development of preclinical and clinical investigations. Importantly, despite the large amount of attention given to gut bacteria, this review also puts forward great expectations on the role of nongut and nonbacterial microbiota in pain sensation. Efforts to decipher the mechanisms of microbiota functions will help to promote achievements in pain management from bench to bedside.

Recent technological advances in intracranial brain stimulation have enhanced the potential of neuromodulation for addressing neuropsychiatric disorders. We present a review of the methodology and the preliminary outcomes of the pioneering studies exploring intracranial biomarker detection and closed-loop neuromodulation to modulate high-symptom severity states in neuropsychiatric disorders. We searched PubMed, Scopus, Web of Science, Embase, and PsycINFO/PsycNet, followed by the reference and citation lists of retrieved articles. This search strategy yielded a total of 583 articles, of which 5 articles met the inclusion criteria, focusing on depression, obsessive-compulsive disorder, post-traumatic stress disorder, and binge eating disorder. We discuss the methodology of biomarker identification, the biomarkers identified, and the preliminary treatment outcomes for closed-loop neuromodulation. Successful biomarker identification hinges on investigating across various setting. Targeted neuromodulation, either directed at the biomarker or within its associated neural network, offers a promising treatment approach. Future research should seek to understand the mechanisms underlying the effects of neuromodulation as well as the long-term viability of these treatment effects across different neuropsychiatric conditions.

The serotonergic neurons in the raphe nucleus are implicated in various cognitive functions such as learning and emotion. In vertebrates, the raphe nucleus is divided into the dorsal raphe and the median raphe. In contrast to the abundance of knowledge on the functions of the dorsal raphe, the roles of the serotonergic neurons in the median raphe are relatively unknown. The studies using zebrafish revealed that the median raphe serotonergic neurons receive input from the two distinct pathways from the habenula and the IPN. The use of zebrafish may reveal the function of the Hb-IPN-median raphe pathway. To clarify the functions of the median raphe serotonergic neurons, it is necessary to distinguish them from those in the dorsal raphe. Most median raphe serotonergic neurons originate from rhombomere 2 in mice, and we generated the transgenic zebrafish which can label the serotonergic neurons derived from rhombomere 2. In this study, we found the serotonergic neurons derived from rhombomere 2 are localized in the median raphe and project axons to the rostral dorsal pallium in zebrafish. This study suggests that this transgenic system has the potential to specifically reveal the function and information processing of the Hb-IPN-raphe-telencephalon circuit in learning.

Involvement of memristive term and additive physical variables including magnetic flux and charge can enhance the physical description of the biophysical neurons. Neural circuits coupled with memristors can be built and tamed to mimic the intrinsic biophysical characteristics and dynamical properties of biological neurons, and these memristive oscillator models are effective in predicting the mode transition in neural activities and self-organization in collective electric behaviors of neural networks. Any proposal of memristive map neurons requires reliable physical description. For example, the energy definition and self-adaptive working mechanism are crucial to verify the reliability of memristive maps. A capacitive variable is useful to describe the membrane potential, while the complexity of ion channels requires careful evaluation and description by using inductive variables relative to the electromagnetic field. In this work, a charge-controlled memristor is connected to an inductor in series for building a hybrid ion channel, and then a capacitor and a nonlinear resistor are combined to couple the ion channel. As a result, a simple memristive neural circuit is designed to discern the inner effect of electric field and magnetic field synchronously. The energy function is defined and verified with theoretical proof. Furthermore, a linear transformation is applied to convert this memristive neuron into a memristive map with an exact energy description, in which its dynamics and mode transition will be controlled by an adaptive law when its energy is beyond the threshold. Additive noise is imposed to induce coherence resonance, which can be detected by using the statistical analysis and average value for Hamilton energy function during changes in noise intensity. This scheme provides guidance for energy definition in memristive maps and the intrinsic energy regulation mechanism in neural activities is explained from physical and dynamical aspects. [ABSTRACT FROM AUTHOR]

For most quadrupeds, locomotion involves alternating movements of the fore- and hindlimbs. In birds, however, while walking generally involves alternating movements of the legs, to generate lift and thrust, the wings are moved synchronously with each other. Neural circuits in the spinal cord, referred to as central pattern generators (CPGs), are the source of the basic locomotor rhythms and patterns. Given the differences in the patterns of movement of the wings and legs, it is likely that the neuronal components and connectivity of the CPG that coordinates wing movements differ from those that coordinate leg movements. In this study, we used in vitro preparations of embryonic chicken spinal cords (E11–E14) to compare the neural responses of spinal CPGs that control and coordinate wing flapping with those that control alternating leg movements. We found that in response to N-methyl-d-aspartate (NMDA) or a combination of NMDA and serotonin (5-HT), the intact chicken spinal cord produced rhythmic outputs that were synchronous both bilaterally and between the wing and leg segments. Despite this, we found that this rhythmic output was disrupted by an antagonist of glycine receptors in the lumbosacral (legs), but not the brachial (wing) segments. Thus, our results provide evidence of differences between CPGs that control the wings and legs in the spinal cord of birds. [ABSTRACT FROM AUTHOR]

Behavioral studies play a crucial role in unraveling the mechanisms underlying brain function. Recent advances in optogenetics, neuronal typing and labeling, and circuit tracing have facilitated the dissection of the neural circuitry involved in various important behaviors. The identification of monosynaptic connections, both upstream and downstream of specific neurons, serves as the foundation for understanding complex neural circuits and studying behavioral mechanisms. However, the practical implementation and mechanistic understanding of monosynaptic connection tracing techniques and functional identification remain challenging, particularly for inexperienced researchers. Improper application of these methods and misinterpretation of results can impede experimental progress and lead to erroneous conclusions. In this paper, we present a comprehensive description of the principles, specific operational details, and key steps involved in tracing anterograde and retrograde monosynaptic connections. We outline the process of functionally identifying monosynaptic connections through the integration of optogenetics and electrophysiological techniques, providing practical guidance for researchers. [ABSTRACT FROM AUTHOR]

Information patterns in a neuron model describe the possible modes in which information is processed and transmitted within neurons and neural networks. An improved Rulkov neuron with the aim of revealing its unexplored dynamics is introduced and investigated, with possible application to information coding carried out in this work. After introducing the neuron model, its stability around the single equilibrium point is examined, and it is discovered that the system is able to exhibit both stable and unstable dynamics. Using two-parameter charts, the system's global stability dynamics are obtained, and windows of the hidden and self-excited dynamics involving both chaotic and periodic states are clearly separated. For the validation of the result of the mathematical model, an electronic circuit was developed in Pspice simulation environment, and both results were in good accord. Finally, a network of 500 improved Rulkov neurons under the chain configuration is used to explore the phenomenon of the information patterns. From that investigation, it was found that the improved Rulkov neural lattice under modulational instability presents repetitive, regular stripes of bright and dark bands that are almost periodic and localized in space and time related to synchronization. These results could provide guidance in discerning information processing patterns in the nervous system. [ABSTRACT FROM AUTHOR]

Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PLmediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders. [ABSTRACT FROM AUTHOR]

Anxiety disorders, common yet impactful emotional disturbances, significantly affect physical and mental health globally. Many neuron circuits are associated with anxiety regulation like septo-hippocampal loop, amygdala(AMYG), bed nucleus of the stria terminalis (BNST), ventral hippocampus (vHPC), and brain regions like medial prefrontal cortex (mPFC). However, the concrete mechanism of anxiety disorder in BNST is relatively unknown. Recent research showed BNST plays a critical role in modulating anxiety owing to its anatomical location and special circuit characteristics, which are considered to be a hub in the limbic system regulating anxiety. BNST consists with multiple subregions, which can project separately into different brain regions and exert projecting independently to various brain regions with distinct regulatory effects. Moreover, multiple signal pathways in BNST are reported to play significant roles in regulating anxiety and stress behavior. This review briefly describes anxiety disorders and subdivisions and functions of BNST, focusing on the main neural circuits that serve as fundamental pathways in both the genesis and potential treatment of anxiety disorders and the molecular mechanism of BNST on anxiety. The complexity of structures and mechanisms has facilitated the development of imaging techniques. Innovative multimodal imaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), have non-invasively illuminated BNST activities and their functional connections with other brain areas. These methodologies provide a deeper understanding of how BNST responds to anxiety-inducing stimuli, offering invaluable insights into its complex role in anxiety regulation. The continued exploration of BNST in anxiety research promises not only to elucidate fundamental neurobiological mechanisms but also to foster advancements in clinical treatments for anxiety disorders.

Interactions between excitatory and inhibitory neurons are critical to computations in cortical circuits but their organization is difficult to assess with standard electrophysiological approaches. Within the medial entorhinal cortex, representation of location by grid and other spatial cells involves circuits in layer 2 in which excitatory stellate cells interact with each other via inhibitory parvalbumin expressing interneurons. Whether this connectivity is structured to support local circuit computations is unclear. Here, we introduce strategies to address the functional organization of excitatory-inhibitory interactions using crossed Cre- and Flp-driver mouse lines to direct targeted presynaptic optogenetic activation and postsynaptic cell identification. We then use simultaneous patch-clamp recordings from postsynaptic neurons to assess their shared input from optically activated presynaptic populations. We find that extensive axonal projections support spatially organized connectivity between stellate cells and parvalbumin interneurons, such that direct connections are often, but not always, shared by nearby neurons, whereas multisynaptic interactions coordinate inputs to neurons with greater spatial separation. We suggest that direct excitatory-inhibitory synaptic interactions may operate at the scale of grid cell clusters, with local modules defined by excitatory-inhibitory connectivity, while indirect interactions may coordinate activity at the scale of grid cell modules.

As for human language learning and birdsong acquisition, fruit flies adjust their auditory perception based on past sound experiences. This phenomenon is known as song preference learning in flies. Recent advancements in omics databases, such as the single-cell transcriptome and brain connectomes, have been integrated into traditional molecular genetics, making the fruit fly an outstanding model for studying the neural basis of “Nature and Nurture” in auditory perception and behaviors. This minireview aims to provide an overview of song preference in flies, including the nature of the phenomenon and its underlying neural mechanisms. Specifically, we focus on the neural circuitry involved in song preference learning, with which auditory experiences shape the song preference of flies. This shaping process depends on an integration hub that processes external sensory stimuli and internal states to enable flexible control of behavior. We also briefly review recent findings on the signals that feed into this integration hub, modulating song preference of flies in an experience-dependent manner.

Chronic predator stress (CPS) is an important and ecologically relevant tool for inducing anhedonia in animals, but the neural circuits underlying the associated neurobiological changes remain to be identified. Using cell-type-specific manipulations, we found that corticotropin-releasing hormone (CRH) neurons in the medial subthalamic nucleus (mSTN) enhance struggle behaviors in inescapable situations and lead to anhedonia, predominately through projections to the external globus pallidus (GPe). Recordings of in vivo neuronal activity revealed that CPS distorted mSTN-CRH neuronal responsivity to negative and positive stimuli, which may underlie CPS-induced behavioral despair and anhedonia. Furthermore, we discovered presynaptic inputs from the bed nucleus of the stria terminalis (BNST) to mSTN-CRH neurons projecting to the GPe that were enhanced following CPS, and these inputs may mediate such behaviors. This study identifies a neurocircuitry that co-regulates escape response and anhedonia in response to predator stress. This new understanding of the neural basis of defensive behavior in response to predator stress will likely benefit our understanding of neuropsychiatric diseases.

Gamma band synchronization can facilitate local and long-range neural communication. In the primary visual cortex, visual stimulus properties within a specific location determine local synchronization strength, while the match of stimulus properties between distant locations controls long-range synchronization. The neural basis for the differential control of local and global gamma band synchronization is unknown. Combining electrophysiology, optogenetics, and computational modeling, we found that VIP disinhibitory interneurons in mouse cortex linearly scale gamma power locally without changing its stimulus tuning. Conversely, they suppress long-range synchronization when two regions process non-matched stimuli, tuning gamma coherence globally. Modeling shows that like-to-like connectivity across space and specific VIP→SST inhibition capture these opposing effects. VIP neurons thus differentially impact local and global properties of gamma rhythms depending on visual stimulus statistics. They may thereby construct gamma-band filters for spatially extended but continuous image features, such as contours, facilitating the downstream generation of coherent visual percepts.