Baicalein alleviates anxiety symptom in Parkinson's disease by targeting Sema3A-mediated parvalbumin interneuron dysfunction.

Molecular and neural circuit mechanisms of parvalbumin (PV) neurons in depression: Insights and advances.

The primate anterior entorhinal cortex (EC) receives rich projections from the amygdala and from multimodal association areas, including the medial prefrontal, anterior cingulate, and orbitofrontal cortices. Axon terminations from these structures on the anterior EC facilitate processing of the emotional aspects of stimuli and events. The EC projects to hippocampus, which is associated with episodic memory. Processing in the anterior EC is modulated by inhibitory neurons, which in primates express the calcium-binding proteins (CBPs): calretinin (CR), or calbindin (CB) or parvalbumin (PV), which collectively account for most inhibitory neurons in the primate cortex. Here, stereological analysis of these neurochemical classes of inhibitory neurons in the anterior half of EC in humans revealed similar patterns as in rhesus monkeys. In both primate species, the densest neuronal subpopulation of presumed inhibitory neurons expressed CR, followed by CB, and lastly by PV. In both species CR neurons were most prevalent in layers I and II, CB neurons in layers II and III and PV neurons in the middle-deep layers. Moreover, the medial and lateral sectors of the anterior EC had different densities of neurons expressing these CBPs. Further analysis revealed that in the human anterior EC, virtually all PV neurons expressed the GABAergic marker GAD67/GAD1 (glutamate decarboxylase 67/glutamate decarboxylase 1), whereas only two-thirds of CB neurons and only one-third of CR neurons colocalized with GAD67/GAD1. In the entire neuronal population of the anterior half of human EC estimated by stereology, 10% expressed GAD67/GAD1, comparable to the collective population of CBP-positive neurons that colocalized with GAD67/GAD1. These findings reveal that the medial and lateral sectors of anterior EC have distinct inhibitory microenvironments, which likely affect the processing of input and output of hippocampus.

Agomelatine alleviates depressive-like behaviors in mice by promoting mitophagy in parvalbumin-expressing neurons of the hippocampal ventral dentate gyrus.

This study aimed to investigate the regulatory roles of distinct neuronal subtypes within the anterior cingulate cortex (ACC) in acute seizures and to identify cell type-specific mechanisms underlying seizure modulation in this region. Acute seizure models were established in mice via pentylenetetrazol injection. Invivo fiber photometry and miniscope calcium imaging were employed to monitor neuronal calcium activity, and multichannel electroencephalography was used to record brain electrical signals simultaneously. Subsequently, bidirectional chemogenetic and optogenetic manipulations were performed on calcium/calmodulin-dependent protein kinase II (CaMKII) excitatory neurons and vesicular γ-aminobutyric acid (GABA) transporter (vGAT)-expressing GABAergic interneurons, as well as parvalbumin (PV) and somatostatin (SST) interneuron subpopulations. Calcium recordings demonstrated that both excitatory and inhibitory neurons in the ACC exhibited significant, temporally coordinated hyperactivity during acute seizures. Inhibition of CaMKII neurons significantly reduced seizure severity, whereas their activation induced spontaneous seizurelike activity. Enhancing GABAergic interneuron activity significantly decreased seizure frequency and severity. Notably, inhibition of GABAergic interneurons resulted in markedly more severe seizures. Further examination of interneuron subtypes revealed functional heterogeneity; activation of SST interneurons effectively suppressed seizures, whereas PV activation did not produce significant antiseizure effects. Critically, inhibition of either PV or SST interneurons triggered spontaneous seizurelike activity, indicating that both subtypes are necessary for maintaining network stability. This study elucidates the differential roles of ACC neuronal populations in acute seizure dynamics. Activating GABAergic interneurons or inhibiting CaMKII-positive neurons effectively suppresses seizure activity. Among interneuron subtypes, SST activation reduces seizures, whereas PV activation does not. However, inhibiting either subtype triggers spontaneous epileptiform activity, indicating both are indispensable and play complementary roles in maintaining network homeostasis. These findings reveal the microcircuit mechanisms by which the ACC modulates acute seizures, highlighting that cortical stability relies on both the classical excitation-inhibition balance and the cooperative interplay of multiple interneuron subtypes.

The extracellular matrix (ECM) performs several functions during development and in mature nervous tissue plasticity; ECM concentrates in lattice-like envelopes called perineuronal nets (PNNs), which surround the cell bodies and proximal dendrites, mainly of parvalbumin (PV) γ-aminobutyric acidergic interneurons. PNNs are proposed to serve synaptic plasticity regulation, synapse stabilization, and neuron protection, by forming a physical barrier from potentially damaging neurochemical stimuli. We analyzed aggrecan expression, a major component of adult PNNs, in human specimens obtained from epilepsy surgery. Postsurgical tissues were obtained from 20 patients with drug-resistant epilepsy: six cases with no histological alterations (cryptogenic epilepsy) and 14 patients showing type IIa and IIb focal cortical dysplasia (FCDII). For comparison, cortices from three autoptic controls with short postmortem delay were analyzed. Immunohistochemistry, confocal microscopy, and RNAscope technique were applied. Control autoptic cases showed high aggrecan expression in the cortex, with a clear decreasing expression gradient from occipital to frontal and temporal areas. This expression gradient was lost in cryptogenic cases, which showed severe aggrecan loss, with residual immunoreactive arrangements mainly around PV interneurons. In FCDII, altered immunolabeling was evident in the core of the dysplastic lesion, and PNNs were identified around both PV interneurons and dysmorphic neurons (DNs) presenting abnormal vGLUT1 and vGAT perisomatic basket formations. Diffuse weak staining of the white matter without PNNs was also found in FCDII. As for cryptogenic cases, FCDII perilesional cortex showed a marked aggrecan staining loss. RNAscope findings confirmed that aggrecans are produced by FCDII pathological neurons, such as DNs. These data support the notion that etiology-specific PNN remodeling is part of the epileptogenic process. FCDII tissues show altered PNN expression in DNs suggestive of a pathogenic role within the FCD lesion, and the disappearance of histochemical PNN labeling in cryptogenic and FCDII perilesional area suggests a possible role mediated by seizure activity.

Projectomic profiles of calbindin D28K-expressing neurons in the mediodorsal thalamic nucleus of mouse.

Aggregates of α-synuclein (α-syn), a hallmark of synucleinopathies, accumulate in the cerebral cortex accompanied by the emergence of motor symptoms, which are associated with altered cortical neuronal activity. However, the mechanism by which α-syn pathology drives cortical network dysfunction, and how these alterations contribute to impaired motor execution and learning, remain unknown. Here, we adopted a multi-disciplinary approach to elucidate the pathophysiological characteristics in transgenic mice that express mutant human α-syn, with minimal nigrostriatal degeneration. In vivo two-photon imaging revealed distinct alteration patterns in excitatory and parvalbumin (PV)-expressing inhibitory cortical neurons accompanying fine motor deficits during learning. Cell type specific ex vivo whole-cell recording further revealed selectively altered intrinsic properties in excitatory but not PV neurons, consistent with the preferential accumulation of α-syn inclusions in excitatory rather than PV neurons within the same cortical region. These results indicate cell-type selective vulnerability in motor cortex of early stage synucleinopathy, leading to disrupted excitatory/inhibitory balance and dysregulated cortical plasticity, driving early-stage motor symptoms. This study provides evidence for selective vulnerability of excitatory neurons in cortical synucleinopathy.

Physical exercise effectively relieves anxiety disorders, and the underlying mechanisms are mostly studied in the regulation of glutamatergic transmission. The potential role of the GABAergic inhibitory pathway, however, is largely underappreciated. The current study found that chronic restraint stress (CRS) induces hyperactivation of parvalbumin (PV)-expressing interneurons (INs) in the prelimbic (PrL) region of male C57BL/6 J mice, and 14-day treadmill exercise effectively reduces PV-IN activity. Such modulation of the inhibitory transmission restores synaptic structure and functions in cortical pyramidal neurons, and chemogenetic manipulation confirmed the necessary role of PV-IN modulation in exercise-mediated anxiolytic effects. Our work broadens the knowledge of cortical inhibitory circuits in exercise intervention against mental illness and provides more targets for the neuromodulation of anxiety disorders.

Sepsis-associated encephalopathy (SAE), a devastating neurological complication of systemic inflammation, affects approximately 70% of patients with sepsis. It not only increases mortality but also leaves survivors with persistent cognitive deficits. However, the mechanisms underlying SAE progression remain incompletely understood. Here, using a lipopolysaccharide (LPS)-induced mouse model of SAE, we identify microglial galectin-3 (Gal-3) as a central pathogenic mediator driving systemic inflammation-induced cognitive impairment. Mechanistically, systemic LPS challenge robustly upregulates microglial Gal-3, which in turn activates Toll-like receptor 2 (TLR2) signaling and promotes NLRP3/AIM2 inflammasome assembly. This microglia-driven inflammatory cascade substantially exacerbates local oxidative stress, leading to selective structural and functional impairment of hippocampal parvalbumin (PV) interneurons. Dysfunction of these critical interneurons disrupts theta/gamma oscillations, impairs excitatory/inhibitory (E/I) balance and synaptic plasticity, and ultimately results in severe cognitive decline. Supporting this pathogenic cascade, pharmacological inhibition of Gal-3 with TD139 effectively suppresses TLR2/inflammasome activation, attenuates oxidative stress, and prevents memory deficits. Conversely, targeted rAAV-mediated overexpression of Gal-3 in microglia is sufficient to recapitulate neuroinflammation, PV-interneuron injury, oscillatory abnormalities, and cognitive impairment. Finally, chemogenetic reactivation of hippocampal PV interneurons using DREADDs restores theta/gamma oscillations and ameliorates LPS-induced cognitive deficits. Together, our findings define a coherent pathogenic axis linking microglial Gal-3 upregulation to PV interneuron-dependent network desynchronization and highlight Gal-3 as a promising therapeutic target for inflammation-associated cognitive disorders.

Prenatal alcohol exposure differently affects seizure susceptibility and severity depending on its mechanism of induction: role of excitatory synapses and parvalbumin-positive interneurons.

Classic theoretical models of cortical oscillations are based on the interactions between two populations of excitatory and inhibitory neurons. Nevertheless, experimental studies and network simulations suggest that interneuron subclasses such as parvalbumin (PV) and somatostatin (SOM) exert distinct control over oscillatory dynamics. Yet, we lack a theoretical understanding of the mechanisms underlying oscillations in E-PV-SOM circuits and of the differences with respect to the classical mechanisms for oscillations in simpler E-I networks. Here, we derive a biologically realistic mean-field model of a canonical three-population E-PV-SOM circuit. This model robustly generates oscillations whose features are consistent with experimental observations, including the relative timing of PV and SOM activity and the effects of optogenetic perturbations. By reducing the model to a linear analytical form, we demonstrate that gamma oscillations emerge directly from the cell-specific connectivity of the three-population circuit. This connectivity motif alone accounts for experimentally observed phase relationships, with PV activity consistently leading that of SOM neurons. Together, this mean field model identifies a distinct structural mechanism giving rise to oscillations in canonical E-PV-SOM circuits and provides theoretical primitives for constructing large-scale, cell-type-specific models of cortical dynamics.

Clinical trials suggest that a single dose of psilocybin may be an effective treatment for substance use disorders. Choice impulsivity is a value-based decision-making bias that predicts drug-intake escalation and is commonly associated with substance use disorders. The dorsomedial prefrontal cortex regulates choice impulsivity and is enriched with 5-HT2A receptors that mediate effects of psilocybin. We hypothesized that psilocybin has long-term (≥ 48 h) effects on choice impulsivity in association with dorsomedial prefrontal cortex inhibitory interneurons with perineuronal nets (PNNs). Male Long Evans rats were trained in a delay discounting task where rats chose between delayed large rewards and immediate small rewards. Forty-eight hours after psilocybin or vehicle injections, delay discounting was assessed and rats' brains processed for microscopy analysis of extracellular matrix (PNNs) together with inhibitory parvalbumin (PV) interneurons and c-Fos as a marker of neuronal activity. Psilocybin acutely increased head-twitch responses. Psilocybin decreased large reward choices and increased the latency to large reward choices 48 h after administration. These effects were independent of delay and therefore not consistent with changes in impulsivity. Psilocybin also increased the density of triple-labelled neurons (PNN + PV + cFos) in the dorsomedial prefrontal cortex. These results suggest that psilocybin decreases appetitive motivation through the increased activation of PV interneurons with PNNs in the dorsomedial prefrontal cortex.

Excitatory synaptic scaling regulates network dynamics by proportionally adjusting excitatory synaptic strengths after sensory perturbations. During associative learning, blocking excitatory scaling in conditioned taste aversion paradigms prolongs generalized aversive responses and delays memory specificity. Recent evidence also implicates inhibitory synaptic scaling in the regulation of network dynamics. Specifically, parvalbumin (PV)-expressing inhibitory neurons, targeting perisomatic regions of excitatory (E) pyramidal neurons, and somatostatin (SST)-expressing neurons, targeting distal dendrites, exhibit distinct scaling responses. This leaves open the question of how complex plasticity mechanisms regulate recurrent excitatory-inhibitory circuit dynamics in associative learning. Using computational approaches, we demonstrate that Hebbian plasticity drives memory generalization to novel stimuli not presented during conditioning. Following conditioning, diverse synaptic scaling mechanisms progressively induce memory specificity, which can be regulated by top-down inputs. Our results reveal that, in the absence of excitatory scaling, PV-to-E scaling can effectively compensate and rescue memory specificity, highlighting the presence of degenerate mechanisms in the brain. Notably, in the process of establishing memory specificity, excitatory scaling and PV-to-E scaling function synergistically, while concurrently opposing SST-to-E scaling. The synergistic and antagonistic plasticity mechanisms are orchestrated to shape the temporal evolution of memory representations, from generalized to precise.Significance statement Associative learning is a fundamental brain function that allows us to link experiences, adapt behavior, and form lasting memories. During this process, memory representations are shaped by synaptic scaling, a homeostatic plasticity mechanism that provides slow, negative feedback to regulate synaptic strengths and adjust network excitability. Operating at the synapses of diverse excitatory and inhibitory cell types, multiple forms of homeostatic plasticity influence the dynamics of associative learning. Here, we demonstrate that synergistic and antagonistic cell-type-specific synaptic scaling mechanisms operate at different types of inhibitory synapses to jointly govern the temporal evolution of memory representations. Through their interaction, they guide the transition from generalized to precise memories.

Effects of ethanol exposure in neonatal mice on retinoic acid signaling in forebrain neurons and astrocytes

Prenatal exposure to valproic acid (VPA), a widely prescribed antiepileptic and mood‑stabilizing drug, is a well-established environmental risk factor for autism spectrum disorder (ASD). Although behavioral and anatomical abnormalities have been reported in VPA-exposed animal models, the underlying molecular mechanisms within specific brain regions remain unclear. In this study, we used tandem mass tag (TMT)-based quantitative proteomics to profile protein expression in the striatum of 9-10-week-old mice prenatally exposed to VPA. Behavioral assessment confirmed core ASD-like phenotypes, including reduced body and brain weights and increased repetitive self-grooming behavior. Proteomic profiling identified 101 differentially expressed proteins (DEPs), with 47 upregulated and 54 downregulated in VPA-exposed mice. Functional enrichment analysis revealed significant involvement of pathways related to synaptic transmission, neuronal development, metal ion homeostasis, oxidative stress response, and excitation/inhibition (E/I) balance. Notably, proteins such as parvalbumin (PVALB), NR2F1, and metallothioneins (MT1, MT2, MT3) were markedly downregulated, implicating impaired inhibitory signaling and redox regulation. Importantly, quantitative PVALB immunofluorescence analysis provided histological validation of the proteomic findings, revealing a significant reduction of PVALB immunoreactivity in the dorsolateral striatum, with a non-significant trend toward reduction in the dorsomedial striatum. Additionally, protein-protein interaction network analysis identified PVALB and MT2 as central hub proteins linking synaptic, glial, and oxidative stress-related modules, highlighting disrupted striatal network organization. Collectively, these findings provide subregion-specific molecular and histological insight into how prenatal VPA exposure alters striatal neurobiology and contributes to ASD-like behavioral phenotypes. Proteomic data are available via ProteomeXchange (PXD067574).

Most of our mechanistic understanding of threat responding and defensive fear behaviors is based on exposure to aversive stimuli in the environment. However, unpleasant, within-the body interoceptive signals can also regulate threat and emotion although underlying cell-circuit mechanisms are not well understood. Abnormal interoceptive sensitivity is associated with fear-associated psychiatric conditions such as panic disorder and PTSD. The ventromedial infralimbic (IL) subdivision of the prefrontal cortex plays a key role in threat appraisal and fear, however, IL engagement in interoceptive threat response and contributory afferent mechanisms are not known. Here, using an interoceptive clinical panicogen, carbon dioxide (CO 2 ) inhalation, we report IL-mediated regulation of fear in mice via afferents from the subfornical organ (SFO), a key viscero-humoral circumventricular organ lacking a traditional blood brain barrier. Chemogenetic inhibition of SFO-to-IL (but not SFO-to-BNST) projections regulated defensive behaviors during CO 2 inhalation and associative contextual fear. Notably, the SFO-IL circuit also modulated delayed CO 2 effects on contextual fear conditioning-extinction, but not startle, neuroendocrine response or motivated behaviors. We also established more specifically that SFO angiotensin II receptor type-1 (AT-1R) +ve neuronal afferents to the IL regulate CO 2 -associated fear and long-term deficits in contextual fear extinction. CO 2 inhalation reduced neuronal activation within the IL and optogenetic activation of SFO neurons activated inhibitory parvalbumin (PV) (but not somatostatin (SST)) interneurons in the IL. Collectively, these data reveal that aversive interoceptive signals can be directly conveyed to the IL via the SFO, a sensory hub for systemic perturbations, to regulate spontaneous and long-term fear. Our findings provide important mechanistic insights into fear-associated disorders with abnormal interoceptive threat sensitivity such as panic disorder and PTSD.

Aversive 22-kHz ultrasonic vocalization playback reveals differences in affective (dys)function following early life adversity in male and female juvenile rats

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder marked by inattention, impulsivity, and hyperactivity. Although the spontaneously hypertensive rat (SHR) is widely used to model ADHD, intra-strain behavioral heterogeneity and its neurobiological relevance remain insufficiently defined. We conducted a comprehensive multidomain behavioral assessment of male adolescent SHR and Wistar-Kyoto (WKY) rats spanning locomotion/exploration, anxiety- and risk-related behavior, compulsive-like activity, cognition, and sensorimotor gating. Across tasks, SHR rats exhibited increased impulsive and repetitive exploratory behaviors, context-dependent alterations in anxiety-related measures, reduced spontaneous alternation, and impaired prepulse inhibition. Exploratory factor analysis of 26 behavioral variables identified five interpretable latent dimensions, including exploratory-attentional engagement and impulsivity/disinhibition, and revealed substantial heterogeneity within the SHR population. Using WKY-referenced factor-score deviation, SHR were stratified into normative-range and combined-deviant subtypes. The combined-deviant subtype exhibited convergent circuit-level alterations, including reduced parvalbumin (PV)/glutamate decarboxylase 67 (GAD67)-associated inhibitory features and decreased synaptic marker signals in prelimbic and infralimbic medial prefrontal cortex, together with increased dopamine transporter expression (DAT) in the striatum without changes in tyrosine hydroxylase (TH). Complementary principal axis factoring, bootstrap resampling, and split-sample analyses supported the robustness of the factor structure. These findings link multidimensional behavioral subtypes in SHR to distinct prefrontal-striatal signatures, strengthening the translational utility of SHR-based ADHD research.

All-optical electrophysiology reveals behavior-dependent dynamics of excitation and inhibition in the hippocampus.