Neuroplasticity and synaptic dysfunction are central to the pathophysiology of depression, yet their underlying mechanisms remain not fully understood. Here, we identify the m6A reader protein YTHDF1 as a key regulator of depression pathogenesis. Mice with genetic deletion of Ythdf1 exhibited anterior cingulate cortex (ACC) hyperactivity, hyperalgesia, heightened social stress sensitivity, and anxiodepressive-like behaviors following acute social stress. Using multi-omics approaches, we linked these effects to dysregulated actin cytoskeleton dynamics and identified cyclase-associated protein 1 (CAP1) as a downstream effector of YTHDF1. YTHDF1 deficiency reduced CAP1 expression from early postnatal stages, leading to F-actin accumulation, impaired synaptic function, and behavioral deficits. Strikingly, early postnatal re-expression of YTHDF1 in the ACC normalized CAP1 levels, restored synaptic integrity, and reversed depressive-like phenotypes. Similarly, CAP1 re-expression was sufficient to alleviate stress-induced psychomotor retardation and anxiety. Our findings establish the YTHDF1-CAP1 axis as a critical pathway governing synaptic function and depressive behaviors.

Mitochondrial quality is crucial for maintaining brain homeostasis. BNIP3L/NIX, a mitophagy receptor, has been linked to neurological disorders, yet its specific function in the brain remains unclear. We found BNIP3L highly expressed in basolateral amygdala (BLA) neurons. Selective deletion of bnip3l in BLA glutamatergic neurons (BLAGLU) impaired contextual fear memory, accompanied by reduced neuronal excitation and mitochondrial respiration. Notably, fear conditioning did not invariably activate mitophagy in BLAGLU neurons. Overexpression of both wild-type and a mitophagy-deficient mutant (BNIP3LΔLIR) in BLAGLU neurons was sufficient to rescue the contextual fear memory deficits in bnip3l-/- mice, suggesting a non-mitophagy role. Instead, we detected a prompt mitochondrial fission in BLAGLU neurons after foot-shock conditioning, an effect abolished by bnip3l deletion. Inhibition of Drp1 with Mdivi-1 disrupted memory formation, whereas optogenetic activation of Drp1 restored neuronal excitation and rescued memory deficits in bnip3l-/- mice. These data indicated an essential role of BNIP3L-mediated mitochondrial fission in modulating contextual fear memory. Mechanistically, BNIP3L and Drp1 competitively interact with AMPK, leading to reduced Drp1 phosphorylation and increased Drp1 accumulation on mitochondria, thereby promoting mitochondrial fission. Taken together, the present study revealed a previously uncharacterized, non-mitophagy-dependent role for BNIP3L in contextual fear memory conditioning.

Abstract Objectives Substance abuse and addiction represent a critical yet frequently overlooked component of toxicology education within preventive medicine curricula in China. Despite their significant public health burden, these topics are often absent from standard toxicology courses, leading to a gap in professional training. This study addresses this deficit by developing an instructional module focused specifically on the neurobiological mechanisms and social implications of drug addiction, aiming to equip students with evidence-based knowledge and intervention strategies. Methods The module integrates problem-based learning (PBL) and inquiry-based learning (IBL) within a BOPPPS (Bridge-in, Objective/Outcome, Pre-assessment, Participatory learning, Post-assessment, and Summary) and Storyline framework, structured around outcome-based education (OBE) principles. Core content covers addiction concepts, substance classification, and neural mechanisms, incorporating frontier research to clarify complex topics and foster critical thinking. Guided by the student-centered and problem-oriented philosophy, the instructional activities are designed to encourage active participation, foster intrinsic motivation, and cultivate a dynamic teacherstudent interaction within a progressive and logically coherent class environment. Results By incorporating frontier research, the module helps clarify complex topics and foster critical thinking among students. This innovative pedagogy enhances standard toxicology content and supports the attainment of teaching objectives. Conclusions The instructional module improves educational outcomes in both knowledge acquisition and professional skill development for preventive medicine students, effectively filling the training gap related to substance abuse and addiction in traditional toxicology education.

Chronic stress induces neurobiological adaptations that manifest as altered behavioral patterns in both humans and animal models. To enhance the translational value of preclinical research, we systematically evaluated chronic restraint stress (CRS) protocols in mice through longitudinal tracking of behavioral outcomes across multiple validated assays. By comparing various CRS parameters, we identified specific protocols that elicited persistent behavioral adaptations across distinct measurements in male mice. Short-duration, high-intensity CRS (6 h/day for 3 days) induced persistent phenotypes of avoidance-related and repetitive behaviors in multiple assays of approach-avoidance conflict, whereas prolonged CRS exposure (2 h/day for 10-14 days) progressively disrupted reward-seeking and behavioral coping phenotypes. When prolonging CRS exposure, we observed a behavioral transition from the initial phenotypes of avoidance/repetitive behavior to the later deficits of reward seeking/behavioral coping, accompanied by a progressive dissociation between these behavioral domains. The 10-day CRS protocol represents a critical threshold for inducing reward-seeking deficit, as well as a comorbid model of avoidance-related response and reward-processing impairment. Rapid antidepressant ketamine reversed impairments of reward seeking and behavioral coping, and typical antidepressant/anxiolytic paroxetine alleviated both repetitive/avoidance-related behaviors and coping/reward-seeking deficits. These findings demonstrated the face, construct, and predictive validity of CRS as a male mouse model of stress-related neuropsychiatric disorders. Leveraging comprehensive behavioral characterization across diverse CRS protocols, our study provides standardized protocols for recapitulating clinically-relevant behavioral adaptations to chronic stress.

Accumulating evidence has shown that various brain functions are associated with experience-activated neuronal ensembles. However, whether such neuronal ensembles are engaged in the pathogenesis of stress-induced depression remains elusive. Utilizing activity-dependent viral strategies in mice, we identified a small population of stress-responsive neurons, primarily located in the middle part of the lateral hypothalamus (mLH) and the medial part of the lateral habenula (LHbM). These neurons serve as "starter cells" to transmit stress-related information and mediate the development of depression-like behaviors during chronic stress. Starter cells in the mLH and LHbM form dominant connections, which are selectively potentiated by chronic stress. Silencing these connections during chronic stress prevents the development of depression-like behaviors, whereas activating these connections directly elicits depression-like behaviors without stress experience. Collectively, our findings dissect a core functional unit within the LH-LHb circuit that mediates the development of depression-like behaviors in mice.

Post-stroke pain (PSP) and post-stroke depression (PSD) frequently co-occur after thalamic hemorrhage and may mutually exacerbate one another, with persistent pain contributing to affective dysfunction and depression altering sensory processing. Because current symptom-specific treatments often provide limited benefit, identifying shared neural mechanisms underlying PSP–PSD comorbidity may offer a more clinically relevant framework for developing targeted circuit-based therapies. Twelve patients with isolated anterior or posterior thalamic hemorrhage underwent parallel multimodal assessments, including standardized pain, mood, anxiety, and cognitive evaluations together with structural MRI, diffusion tensor imaging, and resting-state functional MRI to characterize lesion topography and thalamocortical connectivity. Guided by the clinical findings, we subsequently established nucleus-specific murine models of thalamic hemorrhage using stereotactic collagenase injection. Mice underwent sequential behavioral phenotyping, fiber photometry recording, and viral tracing analyses to investigate the circuit mechanisms underlying pain–depression comorbidity. In patients, posterior thalamic hemorrhage was the exclusive locus for PSP-PSD comorbidity and exhibited severe disruption of thalamocortical functional connectivity, with right-sided lesions having the most profound effect. In mice, focal hemorrhage confined to the posterior thalamic nucleus (PO), but not adjacent parafascicular or ventral posterolateral nuclei, recapitulated both mechanical hyperalgesia and delayed depression-like behaviors. In the murine model, we uncovered a striking hemispheric specialization: left PO lesions induced anhedonia, while right PO lesions led to behavioral despair. PO neurons became hyperexcitable to pain after hemorrhage, a state amplified with PSD onset. Viral tracing revealed lateralized PO projections to somatosensory cortices. The posterior thalamic nucleus represents a lateralized thalamocortical substrate for post-stroke pain–depression comorbidity after hemorrhagic stroke. These findings support the potential value of lesion-topography-based prognostic stratification and circuit-guided neuromodulation strategies targeting both sensory and affective symptoms. A major limitation of this study is the relatively small but carefully phenotyped clinical cohort, which warrants validation in larger longitudinal studies.

Synaptic plasticity, which is thought to underlie learning and memory, is commonly induced in experimental settings with regular activity patterns. However, such regularity strongly differs from natural in vivo firing statistics. Therefore, it remains unclear how in vivo-like patterns, such as irregular and bursty activity, shape synaptic plasticity. We combined mathematical modeling and ex vivo patch-clamp experiments inducing naturalistic spike-timing-dependent plasticity (STDP) at cortico-striatal synapses. We found that irregular spike-pair stimulation diminished LTD occurrence and widened the LTP temporal window compared to regular patterns at low firing rate. Furthermore, increasing the firing rate abolished LTD to the profit of LTP. Our modeling and experimental data indicate that bursts of action potentials are key contributors to this effect. These results highlight the importance of naturalistic firing statistics and show that irregular and bursty firings extend the typical compressed STDP expression temporal window toward timescales relevant for behavior.

N6-methyladenosine (m6A) modification intricately regulates mRNA transportation, localization, and translation, significantly influencing learning and memory processes. However, the specific role of YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2)-mediated m6A mRNA degradation in learning and memory remains elusive. Utilizing a forebrain-specific conditional knockout mice model, it is discovered that the absence of YTHDF2 impedes the decay of m6A-modified mRNAs, resulting in heightened synaptic transmission in hippocampal neurons and improved hippocampus-dependent learning and memory. Unexpectedly, an increase in activity-dependent protein synthesis is also observed. Reintroduction of YTHDF2 expression or reduction of its downstream target, Semaphorin 4B (SEMA4B), in the hippocampus reverses the enhanced memory in conditional knockout mice, while augmenting YTHDF2 in wild-type mice impairs memory performance. These findings underscore the pivotal role of YTHDF2-mediated mRNA degradation in regulating learning and memory processes.

In this issue of Neuron, Fulton et al.1 discover ZBTB7A, a chromatin regulator in orbitofrontal astrocytes, drives neuronal hyperactivity to promote depression susceptibility.

Depression, a prevalent psychiatric disorder of ambiguous etiology and high heterogeneity, has been recently linked to the primary visual cortex (V1). However, the precise circuits mediating the impact of V1 on depressive-like behaviors are poorly understood. Here, we demonstrate that the V1, specifically the lateral posterior nucleus of the thalamus (LP)-projecting V1 glutamatergic subpopulation (GluV1→LP neurons), shows reduced activity after chronic restraint stress (CRS) in male mice, leading to depressive-like behaviors. Optogenetic or chemogenetic activation of these neurons ameliorated depressive-like behaviors in CRS-depressed mice, whereas reducing activity exacerbated these behaviors. This reduction in GluV1→LP neurons activity was predominantly due to a decrease in the guanine nucleotide-binding protein subunit gamma-4 (Gγ4). Overexpression of Gγ4 in the GluV1→LP neurons produced antidepressant-like effects, suggesting that Gγ4 is a crucial regulator of mood. Collectively, these results reveal a V1→LP circuit that modulates depressive-like behaviors, suggesting potential targets for therapeutic interventions. Depression has been recently linked to the visual cortex. Here, the authors identify a glutamatergic primary visual corticallateral posterior thalamic nucleus circuit and its key regulator, Gγ4, as modulators of depressive-like behaviors in male mice.

>Dear Editor,Manipulating neuronal activities by exogenous means is always much desired in the field of neuroscience and beyond. Though many optogenetics and chemogenetics tools, such as channelrhodopsins and DREADDs(Armbruster et al., 2007; Sternson and Roth, 2014), have been developed and widely used, there are several limitations in these tools. For optogenetics, the invasiveness of implanted optical fiber is unavoidable.

Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders1. As a key modulator of brain homeostasis2, it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity by means of on-demand degradation of glutamate receptors. Collectively, this study shows a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a new antidepressant strategy.

Stress has been considered as a major risk factor for depressive disorders, triggering depression onset via inducing persistent dysfunctions in specialized brain regions and neural circuits. Among various regions across the brain, the lateral habenula (LHb) serves as a critical hub for processing aversive information during the dynamic process of stress accumulation, thus having been implicated in the pathogenesis of depression. LHb neurons integrate aversive valence conveyed by distinct upstream inputs, many of which selectively innervate the medial part (LHbM) or lateral part (LHbL) of LHb. LHb subregions also separately assign aversive valence via dissociable projections to the downstream targets in the midbrain which provides feedback loops. Despite these strides, the spatiotemporal dynamics of LHb-centric neural circuits remain elusive during the progression of depression-like state under stress. In this review, we attempt to describe a framework in which LHb orchestrates aversive valence via the input-output specific neuronal architecture. Notably, a physiological form of Hebbian plasticity in LHb under multiple stressors has been unveiled to incubate neuronal hyperactivity in an input-specific manner, which causally encodes chronic stress experience and drives depression onset. Collectively, the recent progress and future efforts in elucidating LHb circuits shed light on early interventions and circuit-specific antidepressant therapies.

Hyperfunction of the dopamine system has been implicated in manic episodes in bipolar disorders. How dopaminergic neuronal function is regulated in the pathogenesis of mania remains unclear. Histaminergic neurons project dense efferents into the midbrain dopaminergic nuclei. Here, we present mice lacking dopaminergic histamine H2 receptor (H2R) in the ventral tegmental area (VTA) that exhibit a behavioral phenotype mirroring some of the symptoms of mania, including increased locomotor activity and reduced anxiety- and depression-like behavior. These behavioral deficits can be reversed by the mood stabilizers lithium and valproate. H2R deletion in dopaminergic neurons significantly enhances neuronal activity, concurrent with a decrease in the γ-aminobutyric acid (GABA) type A receptor (GABAAR) membrane presence and inhibitory transmission. Conversely, either overexpression of H2R in VTA dopaminergic neurons or treatment of H2R agonist amthamine within the VTA counteracts amphetamine-induced hyperactivity. Together, our results demonstrate the engagement of H2R in reducing VTA dopaminergic activity, shedding light on the role of H2R as a potential target for mania therapy.

Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitochondrial performance. Here, we identified an age-dependent coupling between neuronal and synaptic excitation and mitochondrial DNA transcription (E-TC mito ), which operates differently compared to classic excitation-transcription coupling in the nucleus (E-TC nuc ). We demonstrated that E-TC mito repurposes molecules traditionally associated with E-TC nuc to regulate mitochondrial DNA expression in areas closely linked to synaptic activation. The effectiveness of E-TC mito weakens with age, contributing to age-related neurological deficits in mice. Boosting brain E-TC mito in aged animals ameliorated these impairments, offering a potential target to counteract age-related cognitive decline.

Long-term synaptic plasticity is critical for adaptive function of the brain, but presynaptic mechanisms of functional plasticity remain poorly understood. Here, we show that changes in synaptic efficacy induced by activation of the cannabinoid type-1 receptor (CB1R), one of the most widespread G-protein coupled receptors in the brain, requires contractility of the neuronal actomyosin cytoskeleton. Specifically, using a synaptophysin-pHluorin probe (sypH2), we show that inhibitors of non-muscle myosin II (NMII) ATPase as well as one of its upstream effectors Rho-associated kinase (ROCK) prevent the reduction of synaptic vesicle release induced by CB1R activation. Using 3D STORM super-resolution microscopy, we find that activation of CB1R induces a redistribution of synaptic vesicles within presynaptic boutons in an actomyosin dependent manner, leading to vesicle clustering within the bouton and depletion of synaptic vesicles from the active zone. We further show, using sypH2, that inhibitors of NMII and ROCK specifically restore the release of the readily releasable pool of synaptic vesicles from the inhibition induced by CB1R activation. Finally, using slice electrophysiology, we find that activation of both NMII and ROCK is necessary for the long-term, but not the short-term, form of CB1R induced synaptic plasticity at excitatory cortico-striatal synapses. We thus propose a novel mechanism underlying CB1R-induced plasticity, whereby CB1R activation leads to a contraction of the actomyosin cytoskeleton inducing a reorganization of the functional presynaptic vesicle pool, preventing vesicle release and inducing long-term depression.

Repeated reward intake decreases its subjective pleasantness, which is a common phenomenon called reward devaluation. In this issue of Neuron, Yuan et al.1 unravel that blunted inhibitory response of anterior cingulate cortex (ACC) encodes this process, whose hypersensitization leads to anhedonia.

BACKGROUND:The ventromedial prefrontal cortex has been viewed as a locus for storage and recall of extinction memory. However, the synaptic and cellular mechanisms underlying these processes remain elusive.METHODS:We combined transgenic mice, electrophysiological recording, activity-dependent cell labeling, and chemogenetic manipulation to analyze the role of adaptor protein APPL1 in the ventromedial prefrontal cortex in fear extinction retrieval.RESULTS:We found that both constitutive and conditional APPL1 knockout decreased NMDA receptor (NMDAR) function in the ventromedial prefrontal cortex and impaired fear extinction retrieval. Moreover, APPL1 undergoes nuclear translocation during extinction retrieval. Blocking APPL1 nucleocytoplasmic translocation reduced NMDAR currents and disrupted extinction retrieval. We also identified a prefrontal neuronal ensemble that is both necessary and sufficient for the storage of extinction memory. Inducible APPL1 knockout in this ensemble abolished NMDAR-dependent synaptic potentiation and disrupted extinction retrieval, while chemogenetic activation of this ensemble simultaneously rescued the impaired behaviors.CONCLUSIONS:Our results indicate that a prefrontal neuronal ensemble stores extinction memory, and APPL1 signaling supports these neurons in retrieving extinction memory by controlling NMDAR-dependent potentiation.

Ketamine, an N -methyl- d -aspartate receptor (NMDAR) antagonist 1 , has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects 2 – 4 . Although the elimination half-life of ketamine is only 13 min in mice 5 , its antidepressant activities can last for at least 24 h 6 – 9 . This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine–NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine–NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.