Dexmedetomidine (Dex), an α2-adrenergic receptor (α2-AR) agonist, is widely used for its antihyperalgesic effects in perioperative pain management, yet its underlying mechanisms remain largely undefined. Here, we identify a rapid, circuit-specific mechanism by which Dex reverses stress-induced hyperalgesia (SIH) in mice. Stress exposure strengthens excitatory drive from the orbitofrontal cortex (OFC) to the anterior insula cortex (AIC), shifting the excitatory/inhibitory balance toward excitation and increasing the intrinsic excitability of AIC glutamatergic neurons. Viral tracing and optogenetics reveal a direct OFC-AIC glutamatergic projection. Optogenetic or chemogenetic activation of this pathway in otherwise naïve mice potentiates glutamatergic synaptic transmission and is sufficient to induce hyperalgesia, phenotyping SIH. Dex rapidly suppresses these effects by engaging presynaptic α2-ARs on OFC terminals, thereby reducing transmitter release at OFC-AIC synapses. Consistently, chemogenetic silencing of AIC neurons or of the OFC-AIC projection alleviates hyperalgesia in SIH mice. These findings define the OFC-AIC glutamatergic circuit as a key substrate for stress-related pain amplification and uncover a rapid presynaptic α2-AR "brake" as the mechanism underlying Dex's antihyperalgesic action, highlighting a tractable therapeutic entry point for stress-exacerbated pain states.

Interleukin-17 (IL-17) is a pleiotropic cytokine produced mainly by peripheral T helper 17 cells. Yet, the brain functions of IL-17 derived from central nervous cells remain poorly understood. Here, we find an aberrant IL-17A signaling in the cerebellum of Fmr1-KO mice, a well-established genetic model for autism spectrum disorder (ASD). Cerebellar IL-17A, derived exclusively from microglia, is essential for the regulation of social behaviors by maintaining neuronal excitability and selectively suppressing inhibitory neurotransmission of Purkinje cells (PCs) in the cerebellar Crus I, a brain region critically involved in social cognition. Specific downregulation of IL-17 receptor-mediated signaling in cerebellar PCs recapitulates ASD-like social deficits and repetitive behaviors. Notably, both direct administration of IL-17A and induction of IL-17A release from cerebellar microglia by poly(I:C) effectively restore PC excitability and ameliorate ASD-like symptoms. The findings uncover an indispensable role of microglia-derived IL-17A for cerebellar social processing and suggest potential therapeutic strategies targeting IL-17A signaling for ASD.

Yawning coupled with penile erection is a conserved neurobehavioral syndrome mediated by the paraventricular hypothalamus (PVH). However, the distinct roles of oxytocin and its co-transmitters remain unresolved. Using chemogenetics, we showed that activation of PVH oxytocin neurons was sufficient to elicit both responses, whereas silencing these neurons abolished them. Viral tracing revealed that these neurons project collaterally to the brainstem reticular nucleus and spinal cord to spatially coordinate autonomic and somatic motor outputs. By dissecting the molecular mechanisms using CRISPR-Cas9, we found that vesicular glutamate transporter 2 (VGLUT2)-dependent glutamatergic transmission provides the primary drive for both behaviors, whereas the oxytocin peptide is selectively required for yawning but dispensable for erection. Comparative analyses across rats, hamsters, and mice demonstrated that while the glutamatergic erectile circuit was conserved, mice lacked spontaneous yawning and were resistant to apomorphine-induced yawning. These findings suggest a hierarchical co-transmission framework in which fast glutamatergic signaling provides the core drive, while oxytocin confers behavioral specificity.

Estrogen fluctuations have been implicated in various mood disorders, including perimenopausal and postpartum depression (PPD), likely through complex neural networks. γ-aminobutyric acid-ergic (GABAergic) neurons in the medial preoptic area (MPOA) that express estrogen receptor 1 (ESR1) are essential for the development and expression of depressive-like behaviors in ovarian hormone withdrawal (HW) mice. However, the precise circuit mechanisms through which MPOA GABAergic neurons influence behavior remain incompletely understood. Here, we identified robust projections from MPOA GABAergic neurons to the paraventricular nucleus of the hypothalamus (PVN). In HW mice, chemogenetic activation of MPOA GABAergic neurons targeting PVN attenuated depressive-like behaviors. Conversely, in nonhormone withdrawal (NHW) control mice (which received continuous estrogen), suppression of MPOA GABAergic projections to PVN exacerbated depressive-like behaviors. Further analyses using quantitative polymerase chain reaction and immunostaining identified arginine vasopressin (AVP) as a key neuropeptide in this pathway in the HW mouse model. Chemogenetic inhibition of PVN AVP neurons significantly alleviated depressive-like behaviors in HW mice, while their activation in NHW mice worsened depressive-like behaviors. These behaviors were dependent on AVP expression in PVN AVP neurons. Moreover, in HW mice, chemogenetic inhibition of PVN AVP neurons receiving MPOA input mitigated depressive-like behaviors. Conversely, in NHW mice, activation of these neurons exacerbated depressive-like behaviors. Electrophysiological recordings demonstrated that MPOA GABAergic neurons directly inhibit PVN AVP neurons. Thus, our findings suggest that PVN AVP neurons serve as downstream effectors of MPOA GABAergic neurons via monosynaptic inhibitory signaling to regulate depressive-like behaviors. Targeting this circuit may offer a novel therapeutic strategy for PPD.

Neuronal hyperexcitability is a common pathophysiological feature of many neurological diseases. Neuron-glia interactions underlie this process but the detailed mechanisms remain unclear. Here, we reveal a critical role of microglia-mediated selective elimination of inhibitory synapses in driving neuronal hyperexcitability. In epileptic mice of both sexes, hyperactive inhibitory neurons directly activate surveilling microglia via GABAergic signaling. In response, these activated microglia preferentially phagocytose inhibitory synapses, disrupting the balance between excitatory and inhibitory synaptic transmission and amplifying network excitability. This feedback mechanism depends on both GABA-GABAB receptor-mediated microglial activation and complement C3-C3aR-mediated microglial engulfment of inhibitory synapses, as pharmacological or genetic blockage of both pathways effectively prevents inhibitory synapse loss and ameliorates seizure symptoms in mice. Additionally, putative cell-cell interaction analyses of brain tissues from males and females with temporal lobe epilepsy reveal that inhibitory neurons induce microglial phagocytic states and inhibitory synapse loss. Our findings demonstrate that inhibitory neurons can directly instruct microglial states to control inhibitory synaptic transmission through a feedback mechanism, leading to the development of neuronal hyperexcitability in temporal lobe epilepsy.

Vestibular compensation, the spontaneous recovery from vestibular dysfunction following unilateral vestibular loss, serves as a valuable model for investigating post-lesion plasticity in the adult central nervous system. Elucidating the mechanisms underlying vestibular compensation also offers promising therapeutic avenues for treating vestibular disorders. While most studies have focused on the dynamics of GABAergic synaptic plasticity and intrinsic cellular adaptations in the ipsilesional medial vestibular nucleus (MVN) after unilateral labyrinthectomy (UL), the role of glutamatergic synaptic plasticity in this process remains largely unexplored. Here, we employed Golgi staining, immunofluorescence, whole-cell patch-clamp recordings, and behavioral assessments to examine the structural and functional dynamics of glutamatergic synapses during vestibular compensation. Our results reveal rapid structural and functional plasticity of glutamatergic transmission in response to UL. Specifically, dendritic spine density and morphology in the ipsilesional MVN recovered to baseline levels within 6 to 24 h post-UL. Furthermore, UL-induced postsynaptic depression of glutamatergic synaptic strength, reflected by a reduced AMPA/NMDA ratio, was reversed within 24 h, likely due to an upregulation of Ca2+-permeable AMPA receptors. In contrast, presynaptic glutamate release probability, as indicated by a reduced frequency of spontaneous excitatory postsynaptic currents, was not fully compensated during this period. These results suggest that while presynaptic properties recover more slowly in ipsilesional MVN neurons following UL, postsynaptic glutamatergic transmission undergoes rapid structural and functional reorganization. The findings highlight glutamatergic synaptic plasticity as a critical driver for vestibular compensation and suggest that pharmacological interventions targeting these mechanisms may accelerate functional recovery, offering potential therapeutic avenues for vestibular disorders.

Refractory hypertension often involves centrally driven sympathetic augmentation. Yet effective central targets for the treatment of hypertension are still scarce. Here, the role of the histamine H4 receptor (H4R) is explored, the newest member of the histamine receptor family, in central cardiovascular regulation. Analysis of single-nucleus RNA-sequencing datasets of human brains and RNAscope assays of rat brains reveal a conservative expression of H4R in the rostral ventromedial medulla (RVMM), a key sympathetic cardiovascular center. Optoactivation of RVMM histaminergic afferents evokes depressor and bradycardic responses via H4R, whose activation excites GABAergic presympathetic neurons by transient receptor potential vanilloid 1 (TRPV1). Intranasal delivery of H4R agonist produces sustained blood pressure-lowering effects in free-moving spontaneously hypertensive rats and stress-induced hypertensive rats. The findings reveal an antihypertensive role of RVMM histamine H4R and a potential central therapeutic target for hypertension.

Accumulating evidence has identified disrupted oxytocin signaling in both autistic patients and animal models of autism. Nevertheless, the specific timing of the impact of oxytocin on social behavior has remained unclear. Using mouse strains from oxytocin-Cre mice crossed with Cre-dependent chemogenetic mice, oxytocinergic neuronal activity is selectivity manipulated during the early or late postnatal stages and revealed, for the first time, that the suppression of oxytocinergic neurons in the early rather than late postnatal stage led to the emergence of autistic-like behaviors. Notably, significantly reduced oxytocin levels are identified specifically during the early postnatal stage in both valproic acid (VPA)-exposed and Fmr1-KO mouse brains, along with an impairment of the GABA reversal potential and downregulation of the Na+-K+-2Cl- cotransporter (NKCC1) post-birth. Furthermore, chemogenetic activation of oxytocinergic neurons during the early rather than late postnatal stage effectively restored the aberrant NKCC1 expression and GABAA receptor reversal potential and consequently alleviated autistic-like behaviors in VPA-exposed mice. Overall, the results demonstrate that the early postnatal stage may be the unique critical period for oxytocin signaling to regulate GABA reversal potential and promote brain development for prosocial behaviors. These findings suggest an earlier intervention window and strategy for the clinical oxytocin treatment of autism.

The brain consists of local and large-scale functional neural networks that must tightly communicate to allow information processing and integration. Neuronal avalanches are neural activities occurring at near-critical state of the brain, which enhances its capacity to carry and process information. However, the relationship between functional networks and neuronal avalanches remains largely unknown. Here, human magnetoencephalography data containing information of both cortical-wide avalanches and oscillatory phases of information flow were utilized to explore this relationship. We found that cortical-wide avalanches of specific frequency bands are strongly associated with information flow across anteroposterior cortical gradients, which connect important hubs within known functional networks. Also, long-range memories of local oscillatory activities at these network hubs strongly influence global avalanche activities. By computer modelling, we demonstrated that periodic, but not aperiodic, oscillations of specific frequencies generated at network hubs along a cortical gradient could explain the occurrence of avalanches. This study represents the first attempt to integrate previously disparate explorations of functional networks and neuronal avalanches under a unified framework. Consequently, it provides mechanistic insights into how oscillatory information flow underlies neuronal avalanches to facilitate cortical-wide communication, which also implicates the significance of different frequencies of brain activities in health and neuropsychiatric conditions.

Estrogen fluctuations have been implicated in various mood disorders, including perimenopausal and postpartum depression (PPD), likely through complex neural networks. γ-aminobutyric acid-ergic (GABAergic) neurons in the medial preoptic area (MPOA) that express estrogen receptor 1 (ESR1) are essential for the development and expression of depressive-like behaviors in ovarian hormone withdrawal (HW) mice. However, the precise circuit mechanisms through which MPOA GABAergic neurons influence behavior remain incompletely understood. Here, we identified robust projections from MPOA GABAergic neurons to the paraventricular nucleus of the hypothalamus (PVN). In HW mice, chemogenetic activation of MPOA GABAergic neurons targeting PVN attenuated depressive-like behaviors. Conversely, in nonhormone withdrawal (NHW) control mice (which received continuous estrogen), suppression of MPOA GABAergic projections to PVN exacerbated depressive-like behaviors. Further analyses using quantitative polymerase chain reaction and immunostaining identified arginine vasopressin (AVP) as a key neuropeptide in this pathway in the HW mouse model. Chemogenetic inhibition of PVNAVP neurons significantly alleviated depressive-like behaviors in HW mice, while their activation in NHW mice worsened depressive-like behaviors. These behaviors were dependent on AVP expression in PVNAVP neurons. Moreover, in HW mice, chemogenetic inhibition of PVNAVP neurons receiving MPOA input mitigated depressive-like behaviors. Conversely, in NHW mice, activation of these neurons exacerbated depressive-like behaviors. Electrophysiological recordings demonstrated that MPOA GABAergic neurons directly inhibit PVNAVP neurons. Thus, our findings suggest that PVNAVP neurons serve as downstream effectors of MPOA GABAergic neurons via monosynaptic inhibitory signaling to regulate depressive-like behaviors. Targeting this circuit may offer a novel therapeutic strategy for PPD.

The cumulative evidence suggests that oxytocin is involved in the male sexual behaviors. However, no significant sexual impairments were observed in oxytocin gene knock-out (KO) mice, suggesting that oxytocin is not necessary for sexual behavior in male mice. To better understand the role of oxytocin in male erection, two types of oxytocin gene KO mice were created. In the first type, the oxytocin gene was deleted in the zygote, while in the second type, the oxytocin gene was mutated in adulthood by injecting the CRISPR/Cas9 AAVs. The results showed that disrupting the oxytocin gene at either the embryonic or adult stage did not affect erection, indicating that oxytocin is not necessary for penile erection. Pharmacologically, injecting oxytocin receptor agonist Carbetocin into the VTA of the oxytocin gene KO mice still evoked penile erection. By employing the Oxt-Ires-Cre mice, we found that specifically activating oxytocinergic neurons through chemogenetics strongly induced penile erection, while inhibiting these neurons blocked the erection responses. Furthermore, ablating PVN oxytocinergic neurons abolished the male erection response. In conclusion, although the neuropeptide oxytocin is not essential for male erection, the activity of oxytocinergic neurons is required. Our results might reflect the redundancy in the central nerve system in the sense that many signals contribute to the activation of oxytocinergic neurons to evoke penile erection during sexual behaviors.

The cerebellum has long been associated with motor control. However, its role in cognitive functions has attracted increasing attention recently. The uniformity of cerebellar internal structure seems at odds with its involvement in such diverse cognitive functions. Nonetheless, in cerebellar diseases such as ataxia, there is a comorbidity of motor and cognitive impairments, raising essential questions about how and to what extent the cerebellum participates in cognitive functions. This review begins by tracing the historical development of cerebellar research, suggesting that the diverse connections between the cerebellum and cerebral cortex, basal ganglia, and other subcortical nuclei form the basis for the cerebellum’s role in regulating cognitive functions. We then delve into its involvement in language, reward-based learning, working memory, and spatial cognition. Additionally, we summarize the changes in the cerebellum observed in Alzheimer’s disease (AD), Parkinson’s disease (PD), and ataxias and their impact on cognitive functions. By discussing the role and mechanism of the cerebellum in cognition in physiology and pathology from the aspects of structure and function, we aim to shed light on promising new therapeutic targets related to the cerebellum for cognitive impairment.

The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson’s disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K+ channels, or Ca2+-activated K+ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.

Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ+ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Although more than 30 different types of neuropeptides have been identified in various cell types and circuits of the cerebellum, their unique functions in the cerebellum remain poorly understood. Given the nature of their diffuse distribution, peptidergic systems are generally assumed to exert a modulatory effect on the cerebellum via adaptively tuning neuronal excitability, synaptic transmission, and synaptic plasticity within cerebellar circuits. Moreover, cerebellar neuropeptides have also been revealed to be involved in the neurogenetic and developmental regulation of the developing cerebellum, including survival, migration, differentiation, and maturation of the Purkinje cells and granule cells in the cerebellar cortex. On the other hand, cerebellar neuropeptides hold a critical position in the pathophysiology and pathogenesis of many cerebellar-related motor and psychiatric disorders, such as cerebellar ataxias and autism. Over the past two decades, a growing body of evidence has indicated neuropeptides as potential therapeutic targets to ameliorate these diseases effectively. Therefore, this review focuses on eight cerebellar neuropeptides that have attracted more attention in recent years and have significant potential for clinical application associated with neurodegenerative and/or neuropsychiatric disorders, including brain-derived neurotrophic factor, corticotropin-releasing factor, angiotensin II, neuropeptide Y, orexin, thyrotropin-releasing hormone, oxytocin, and secretin, which may provide novel insights and a framework for our understanding of cerebellar-related disorders and have implications for novel treatments targeting neuropeptide systems.

Reactive astrocytes play an important role in neurological diseases, but their molecular and functional phenotypes in epilepsy are unclear. Here, we show that in patients with temporal lobe epilepsy (TLE) and mouse models of epilepsy, excessive lipid accumulation in astrocytes leads to the formation of lipid-accumulated reactive astrocytes (LARAs), a new reactive astrocyte subtype characterized by elevated APOE expression. Genetic knockout of APOE inhibited LARA formation and seizure activities in epileptic mice. Single-nucleus RNA sequencing in TLE patients confirmed the existence of a LARA subpopulation with a distinct molecular signature. Functional studies in epilepsy mouse models and human brain slices showed that LARAs promote neuronal hyperactivity and disease progression. Targeting LARAs by intervention with lipid transport and metabolism could thus provide new therapeutic options for drug-resistant TLE.

Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the striatum, leading to dopamine (DA) deficiency in the striatum and typical motor symptoms. A small molecule as a dietary supplement for PD would be ideal for practical reasons. Hordenine (HOR) is a phenolic phytochemical marketed as a dietary supplement found in cereals and germinated barley, as well as in beer, a widely consumed beverage. This study was aimed to identify HOR as a dopamine D2 receptor (DRD2) agonist in living cells, and investigate the alleviative effect and mechanism of HOR on PD-like motor deficits in mice and nematodes. Our results firstly showed that HOR is an agonist of DRD2, but not DRD1, in living cells. Moreover, HOR could improve the locomotor dysfunction, gait, and postural imbalance in MPTP- or 6-OHDA-induced mice or Caenorhabditis elegans, and prevent α-synuclein accumulation via the DRD2 pathway in C. elegans. Our results suggested that HOR could activate DRD2 to attenuate the PD-like motor deficits, and provide scientific evidence for the safety and reliability of HOR as a dietary supplement.

Phase-locking between local field potential and spikes has been widely investigated through neurophysiological analysis. Two indices most frequently adopted traditionally include the mean resultant length and p of the Rayleigh test. However, the traditional method is found less reliable for cases with substantial sample sizes or with bimodal distribution. In this article, K we propose an entropy-based method to detect and measure phase-locking. Simulation results prove that the method can be effectively applied to cases with a relatively large sample size and it can effectively detect phase-locking even under bimodal conditions with two peaks of opposite phases. Furthermore, we propose thresholds to help measure the intensity of spike field phase-locking. We also apply the proposed method to our experimental data and find phase locking with two opposite phases, which would be left out in traditional phase-locking analysis.