Axonal neurotransmitter release in the regulation of myelination.

Myelination of axons is a key determinant of fast action potential propagation, axonal health and circuit function. Previously considered a static structure, it is now clear that myelin is dynamically regulated in response to neuronal activity in the CNS. However, how activity-dependent signals are conveyed to oligodendrocytes remains unclear. Here we review the potential mechanisms by which neurons could communicate changing activity levels to myelin, with a focus on the accumulating body of evidence to support activity-dependent vesicular signalling directly onto myelin sheaths. We discuss recent in vivo findings of activity-dependent fusion of neurotransmitter vesicles from non-synaptic axonal sites, and how modulation of this vesicular fusion regulates the stability and growth of myelin sheaths. We also consider the potential mechanisms by which myelin could sense and respond to axon-derived signals to initiate remodelling, and the relevance of these adaptations for circuit function. We propose that axonal vesicular signalling represents an important and underappreciated mode of communication by which neurons can transmit activity-regulated signals to myelinating oligodendrocytes and, potentially, more broadly to other cell types in the CNS.

Molecular tools to capture active neural circuits.

To understand how neurons and neural circuits function during behaviors, it is essential to record neuronal activity in the brain in vivo. Among the various technologies developed for recording neuronal activity, molecular tools that induce gene expression in an activity-dependent manner have attracted particular attention for their ability to clarify the causal relationships between neuronal activity and behavior. In this review, we summarize recently developed activity-dependent gene expression tools and their potential contributions to the study of neural circuits.

Brain-wide mapping of c-Fos expression in nitroglycerin-induced models of migraine.

BACKGROUND: Migraine is a neurological disorder characterized by complex, widespread, and sudden attacks with an unclear pathogenesis, particularly in chronic migraine (CM). Specific brain regions, including the insula, amygdala, thalamus, and cingulate, medial prefrontal, and anterior cingulate cortex, are commonly activated by pain stimuli in patients with CM and animal models. This study employs fluorescence microscopy optical sectioning tomography (fMOST) technology and AAV-PHP.eB whole-brain expression to map activation patterns of brain regions in CM mice, thus enhancing the understanding of CM pathogenesis and suggesting potential treatment targets. METHODS: By repeatedly administering nitroglycerin (NTG) to induce migraine-like pain in mice, a chronic migraine model (CMM) was established. Olcegepant (OLC) was then used as treatment and its effects on mechanical pain hypersensitivity and brain region activation were observed. All mice underwent mechanical withdrawal threshold, light-aversive, and elevated plus maze tests. Viral injections were administered to the mice one month prior to modelling, and brain samples were collected 2 h after the final NTG/vehicle control injection for whole-brain imaging using fMOST. RESULTS: In the NTG-induced CMM, mechanical pain threshold decreased, photophobia, and anxiety-like behavior were observed, and OLC was found to improve these manifestations. fMOST whole-brain imaging results suggest that the isocortex-cerebral cortex plate region, including somatomotor areas (MO), somatosensory areas (SS), and main olfactory bulb (MOB), appears to be the most sensitive area of activation in CM (P < 0.05). Other brain regions such as the inferior colliculus (IC) and intermediate reticular nucleus (IRN) were also exhibited significant activation (P < 0.05). The improvement in migraine-like symptoms observed with OLC treatment may be related to its effects on these brain regions, particularly SS, MO, ansiform lobule (AN), IC, spinal nucleus of the trigeminal, caudal part (Sp5c), IRN, and parvicellular reticular nucleus (PARN) (P < 0.05). CONCLUSIONS: fMOST whole-brain imaging reveals c-Fos + cells in numerous brain regions. OLC improves migraine-like symptoms by modulating brain activity in some brain regions. This study demonstrates the activation of the specific brain areas in NTG-induced CMM and suggests some regions as a potential treatment mechanism according to OLC.

Anterior Cingulate Cortex Contributes to the Hyperlocomotion under Nitrogen Narcosis.

Nitrogen narcosis is a neurological syndrome that manifests when humans or animals encounter hyperbaric nitrogen, resulting in a range of motor, emotional, and cognitive abnormalities. The anterior cingulate cortex (ACC) is known for its significant involvement in regulating motivation, cognition, and action. However, its specific contribution to nitrogen narcosis-induced hyperlocomotion and the underlying mechanisms remain poorly understood. Here we report that exposure to hyperbaric nitrogen notably increased the locomotor activity of mice in a pressure-dependent manner. Concurrently, this exposure induced heightened activation among neurons in both the ACC and dorsal medial striatum (DMS). Notably, chemogenetic inhibition of ACC neurons effectively suppressed hyperlocomotion. Conversely, chemogenetic excitation lowered the hyperbaric pressure threshold required to induce hyperlocomotion. Moreover, both chemogenetic inhibition and genetic ablation of activity-dependent neurons within the ACC reduced the hyperlocomotion. Further investigation revealed that ACC neurons project to the DMS, and chemogenetic inhibition of ACC-DMS projections resulted in a reduction in hyperlocomotion. Finally, nitrogen narcosis led to an increase in local field potentials in the theta frequency band and a decrease in the alpha frequency band in both the ACC and DMS. These results collectively suggest that excitatory neurons within the ACC, along with their projections to the DMS, play a pivotal role in regulating the hyperlocomotion induced by exposure to hyperbaric nitrogen.

The nucleus accumbens shell: a neural hub at the interface of homeostatic and hedonic feeding.

Feeding behavior is a complex physiological process regulated by the interplay between homeostatic and hedonic feeding circuits. Among the neural structures involved, the nucleus accumbens (NAc) has emerged as a pivotal region at the interface of these two circuits. The NAc comprises distinct subregions and in this review, we focus mainly on the NAc shell (NAcSh). Homeostatic feeding circuits, primarily found in the hypothalamus, ensure the organism's balance in energy and nutrient requirements. These circuits monitor peripheral signals, such as insulin, leptin, and ghrelin, and modulate satiety and hunger states. The NAcSh receives input from these homeostatic circuits, integrating information regarding the organism's metabolic needs. Conversely, so-called hedonic feeding circuits involve all other non-hunger and -satiety processes, i.e., the sensory information, associative learning, reward, motivation and pleasure associated with food consumption. The NAcSh is interconnected with hedonics-related structures like the ventral tegmental area and prefrontal cortex and plays a key role in encoding hedonic information related to palatable food seeking or consumption. In sum, the NAcSh acts as a crucial hub in feeding behavior, integrating signals from both homeostatic and hedonic circuits, to facilitate behavioral output via its downstream projections. Moreover, the NAcSh's involvement extends beyond simple integration, as it directly impacts actions related to food consumption. In this review, we first focus on delineating the inputs targeting the NAcSh; we then present NAcSh output projections to downstream structures. Finally we discuss how the NAcSh regulates feeding behavior and can be seen as a neural hub integrating homeostatic and hedonic feeding signals, via a functionally diverse set of projection neuron subpopulations.

Behavioral Animal Models and Neural-Circuit Framework of Depressive Disorder.

Depressive disorder is a chronic, recurring, and potentially life-endangering neuropsychiatric disease. According to a report by the World Health Organization, the global population suffering from depression is experiencing a significant annual increase. Despite its prevalence and considerable impact on people, little is known about its pathogenesis. One major reason is the scarcity of reliable animal models due to the absence of consensus on the pathology and etiology of depression. Furthermore, the neural circuit mechanism of depression induced by various factors is particularly complex. Considering the variability in depressive behavior patterns and neurobiological mechanisms among different animal models of depression, a comparison between the neural circuits of depression induced by various factors is essential for its treatment. In this review, we mainly summarize the most widely used behavioral animal models and neural circuits under different triggers of depression, aiming to provide a theoretical basis for depression prevention.

Translating Molecular Approaches to Oligodendrocyte-Mediated Neurological Circuit Modulation.

The central nervous system (CNS) exhibits remarkable adaptability throughout life, enabled by intricate interactions between neurons and glial cells, in particular, oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs). This adaptability is pivotal for learning and memory, with OLs and OPCs playing a crucial role in neural circuit development, synaptic modulation, and myelination dynamics. Myelination by OLs not only supports axonal conduction but also undergoes adaptive modifications in response to neuronal activity, which is vital for cognitive processing and memory functions. This review discusses how these cellular interactions and myelin dynamics are implicated in various neurocircuit diseases and disorders such as epilepsy, gliomas, and psychiatric conditions, focusing on how maladaptive changes contribute to disease pathology and influence clinical outcomes. It also covers the potential for new diagnostics and therapeutic approaches, including pharmacological strategies and emerging biomarkers in oligodendrocyte functions and myelination processes. The evidence supports a fundamental role for myelin plasticity and oligodendrocyte functionality in synchronizing neural activity and high-level cognitive functions, offering promising avenues for targeted interventions in CNS disorders.

Synaptic cell adhesion molecules contribute to the pathogenesis and progression of fragile X syndrome.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a monogenic cause of autism spectrum disorders. Deficiencies in the fragile X messenger ribonucleoprotein, encoded by the FMR1 gene, lead to various anatomical and pathophysiological abnormalities and behavioral deficits, such as spine dysmorphogenesis and learning and memory impairments. Synaptic cell adhesion molecules (CAMs) play crucial roles in synapse formation and neural signal transmission by promoting the formation of new synaptic contacts, accurately organizing presynaptic and postsynaptic protein complexes, and ensuring the accuracy of signal transmission. Recent studies have implicated synaptic CAMs such as the immunoglobulin superfamily, N-cadherin, leucine-rich repeat proteins, and neuroligin-1 in the pathogenesis of FXS and found that they contribute to defects in dendritic spines and synaptic plasticity in FXS animal models. This review systematically summarizes the biological associations between nine representative synaptic CAMs and FMRP, as well as the functional consequences of the interaction, to provide new insights into the mechanisms of abnormal synaptic development in FXS.

Behavioral neuroscience's inevitable SABV growing pains.

The field of rodent behavioral neuroscience is undergoing two major sea changes: an ever-growing technological revolution, and worldwide calls to consider sex as a biological variable (SABV) in experimental design. Both have enormous potential to improve the precision and rigor with which the brain can be studied, but the convergence of these shifts in scientific practice has exposed critical limitations in classic and widely used behavioral paradigms. While our tools have advanced, our behavioral metrics - mostly developed in males and often allowing for only binary outcomes - have not. This opinion article explores how this disconnect has presented challenges for the accurate depiction and interpretation of sex differences in brain function, arguing for the expansion of current behavioral constructs to better account for behavioral diversity.

Cerebellar Roles in Motor and Social Functions and Implications for ASD.

The cerebellum, traditionally linked to voluntary motor coordination, is now recognized for its role in nonmotor functions, including cognitive and social behaviors. This expanded understanding is vital for identifying neurodevelopmental disorders such as autism spectrum disorder (ASD), where cerebellar abnormalities are common. Recent research has identified specific cerebellar circuits contributing to these diverse functions, revealing interconnected pathways that regulate both motor and social behaviors. The cerebellum communicates extensively with the cerebral cortex, thalamus, and limbic structures through converging and diverging pathways, integrating sensory and motor information to fine-tune outputs and influence higher-order functions. Mouse models have been instrumental in dissecting cerebellar functions, with studies using genetic and neuroanatomical techniques to manipulate specific circuits and observe behavioral outcomes. Disruptions in cerebellar pathways can lead to motor deficits and social impairments, mirroring human neurodevelopmental disorders. This review explores the anatomical and functional organization of cerebellar pathways in mice, their role in behavior, and the implications of cerebellar dysfunction in disorders such as ASD. Understanding these pathways enhances knowledge of cerebellar contributions to behavior and informs therapeutic strategies for cerebellar and neurodevelopmental disorders, emphasizing the integral role of the cerebellum in motor and social functions.

Burst firing in Output-Defined Parallel Habenula Circuit Underlies the Antidepressant Effects of Bright Light Treatment.

Research highlights the significance of increased bursting in lateral habenula (LHb) neurons in depression and as a focal point for bright light treatment (BLT). However, the precise spike patterns of LHb neurons projecting to different brain regions during depression, their roles in depression development, and BLT's therapeutic action remain elusive. Here, LHb neurons are found projecting to the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and median raphe nucleus (MnR) exhibit increased bursting following aversive stimuli exposure, correlating with distinct depressive symptoms. Enhanced bursting in DRN-projecting LHb neurons is pivotal for anhedonia and anxiety, while concurrent bursting in LHb neurons projecting to the DRN, VTA, and MnR is essential for despair. Remarkably, reducing bursting in distinct LHb neuron subpopulations underlies the therapeutic effects of BLT on specific depressive behaviors. These findings provide valuable insights into the mechanisms of depression and the antidepressant action of BLT.

Neural circuits for taste sensation.

The sense of taste arises from the detection of chemicals in food by taste buds, the peripheral cellular detectors for taste. Although numerous studies have extensively investigated taste buds, research on neural circuits from primary taste neurons innervating taste buds to the central nervous system has only recently begun owing to recent advancements in neuroscience research tools. This minireview focuses primarily on recent reports utilizing advanced neurogenetic tools across relevant brain regions.

BLA-involved circuits in neuropsychiatric disorders.

The basolateral amygdala (BLA) is the subregion of the amygdala located in the medial of the temporal lobe, which is connected with a wide range of brain regions to achieve diverse functions. Recently, an increasing number of studies have focused on the participation of the BLA in many neuropsychiatric disorders from the neural circuit perspective, aided by the rapid development of viral tracing methods and increasingly specific neural modulation technologies. However, how to translate this circuit-level preclinical intervention into clinical treatment using noninvasive or minor invasive manipulations to benefit patients struggling with neuropsychiatric disorders is still an inevitable question to be considered. In this review, we summarized the role of BLA-involved circuits in neuropsychiatric disorders including Alzheimer's disease, perioperative neurocognitive disorders, schizophrenia, anxiety disorders, depressive disorders, posttraumatic stress disorders, autism spectrum disorders, and pain-associative affective states and cognitive dysfunctions. Additionally, we provide insights into future directions and challenges for clinical translation.

Multifarious astrocyte-neuron dialog in shaping neural circuit architecture.

Astrocytes are multifaceted glial cell types that perform structural, functional, metabolic, and homeostatic roles in the brain. Recent studies have revealed mechanisms underlying the diversity of bidirectional communication modes between astrocytes and neurons - the fundamental organizing principle shaping synaptic properties at tripartite synapses. These astrocyte-neuron interactions are critical for the proper functioning of synapses and neural circuits. This review focuses on molecular mechanisms that direct these interactions, highlighting the versatile roles of multiple adhesion-based paths that likely modulate them, often in a context-dependent manner. It also describes how astrocyte-mediated processes go awry in certain brain disorders and provides a timely insight on the pivotal roles of astrocyte-neuron interactions in synaptic integrity and their relevance to understanding and treating neurological disorders.

Compensatory enhancement of input maintains aversive dopaminergic reinforcement in hungry Drosophila.

Hungry animals need compensatory mechanisms to maintain flexible brain function, while modulation reconfigures circuits to prioritize resource seeking. In Drosophila, hunger inhibits aversively reinforcing dopaminergic neurons (DANs) to permit the expression of food-seeking memories. Multitasking the reinforcement system for motivation potentially undermines aversive learning. We find that chronic hunger mildly enhances aversive learning and that satiated-baseline and hunger-enhanced learning require endocrine adipokinetic hormone (AKH) signaling. Circulating AKH influences aversive learning via its receptor in four neurons in the ventral brain, two of which are octopaminergic. Connectomics revealed AKH receptor-expressing neurons to be upstream of several classes of ascending neurons, many of which are presynaptic to aversively reinforcing DANs. Octopaminergic modulation of and output from at least one of these ascending pathways is required for shock- and bitter-taste-reinforced aversive learning. We propose that coordinated enhancement of input compensates for hunger-directed inhibition of aversive DANs to preserve reinforcement when required.

Dual circuits originating from the ventral hippocampus independently facilitate affective empathy.

Affective empathy enables social mammals to learn and transfer emotion to conspecifics, but an understanding of the neural circuitry and genetics underlying affective empathy is still very limited. Here, using the naive observational fear between cagemates as a paradigm similar to human affective empathy and chemo/optogenetic neuroactivity manipulation in mouse brain, we investigate the roles of multiple brain regions in mouse affective empathy. Remarkably, two neural circuits originating from the ventral hippocampus, previously unknown to function in empathy, are revealed to regulate naive observational fear. One is from ventral hippocampal pyramidal neurons to lateral septum GABAergic neurons, and the other is from ventral hippocampus pyramidal neurons to nucleus accumbens dopamine-receptor-expressing neurons. Furthermore, we identify the naive observational-fear-encoding neurons in the ventral hippocampus. Our findings highlight the potentially diverse regulatory pathways of empathy in social animals, shedding light on the mechanisms underlying empathy circuity and its disorders.

Loss of postnatal Arx transcriptional activity in parvalbumin interneurons reveals non-cell autonomous disturbances in CA1 pyramidal cells.

Maintenance of proper electrophysiological and connectivity profiles in the adult brain may be a perturbation point in neurodevelopmental disorders (NDDs). How these profiles are maintained within mature circuits is unclear. We recently demonstrated that postnatal ablation of the Aristaless (Arx) homeobox gene in parvalbumin interneurons (PVIs) alone led to dysregulation of their transcriptome and alterations in their functional as well as network properties in the hippocampal cornu Ammoni first region (CA1). Here, we characterized CA1 pyramidal cells (PCs) responses in this conditional knockout (CKO) mouse to further understand the circuit mechanisms by which postnatal Arx expression regulates mature CA1 circuits. Field recordings of network excitability showed that CA1 PC ensembles were less excitable in response to unpaired stimulations but exhibited enhanced excitability in response to paired-pulse stimulations. Whole-cell voltage clamp recordings revealed a significant increase in the frequency of spontaneous inhibitory postsynaptic currents onto PCs. In contrast, excitatory drive from evoked synaptic transmission was reduced while that of inhibitory synaptic transmission was increased. Current clamp recordings showed increase excitability in several sub- and threshold membrane properties that correlated with an increase in voltage-gated Na+ current. Our data suggest that, in addition to cell-autonomous disruption in PVIs, loss of Arx postnatal transcriptional activity in PVIs led to complex dysfunctions in PCs in CA1 microcircuits. These non-cell autonomous effects are likely the product of breakdown in feedback and/or feedforward processes and should be considered as fundamental contributors to the circuit mechanisms of NDDs such as Arx-linked early-onset epileptic encephalopathies.