An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits.

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

Sensory ASIC3 channel exacerbates psoriatic inflammation via a neurogenic pathway in female mice.

Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.

Gut microbiota-derived cholic acid mediates neonatal brain immaturity and white matter injury under chronic hypoxia.

Chronic hypoxia, common in neonates, disrupts gut microbiota balance, which is crucial for brain development. This study utilized cyanotic congenital heart disease (CCHD) patients and a neonatal hypoxic rat model to explore the association. Both hypoxic rats and CCHD infants exhibited brain immaturity, white matter injury (WMI), brain inflammation, and motor/learning deficits. Through 16s rRNA sequencing and metabolomic analysis, a reduction in B. thetaiotaomicron and P. distasonis was identified, leading to cholic acid accumulation. This accumulation triggered M1 microglial activation and inflammation-induced WMI. Administration of these bacteria rescued cholic acid-induced WMI in hypoxic rats. These findings suggest that gut microbiota-derived cholic acid mediates neonatal WMI and brain inflammation, contributing to brain immaturity under chronic hypoxia. Therapeutic targeting of these bacteria provides a non-invasive intervention for chronic hypoxia patients.

Genetically Encoded Photocatalysis Enables Spatially Restricted Optochemical Modulation of Neurons in Live Mice.

Light provides high temporal precision for neuronal modulations. Small molecules are advantageous for neuronal modulation due to their structural diversity, allowing them to suit versatile targets. However, current optochemical methods release uncaged small molecules with uniform concentrations in the irradiation area, which lack spatial specificity as counterpart optogenetic methods from genetic encoding for photosensitive proteins. Photocatalysis provides spatial specificity by generating reactive species in the proximity of photocatalysts. However, current photocatalytic methods use antibody-tagged heavy-metal photocatalysts for spatial specificity, which are unsuitable for neuronal applications. Here, we report a genetically encoded metal-free photocatalysis method for the optochemical modulation of neurons via deboronative hydroxylation. The genetically encoded photocatalysts generate doxorubicin, a mitochondrial uncoupler, and baclofen by uncaging stable organoboronate precursors. The mitochondria, nucleus, membrane, cytosol, and ER-targeted drug delivery are achieved by this method. The distinct signaling pathway dissection in a single projection is enabled by the dual optogenetic and optochemical control of synaptic transmission. The itching signaling pathway is investigated by photocatalytic uncaging under live-mice skin for the first time by visible light irradiation. The cell-type-specific release of baclofen reveals the GABABR activation on NaV1.8-expressing nociceptor terminals instead of pan peripheral sensory neurons for itch alleviation in live mice.

Neuronal and synaptic adaptations underlying the benefits of deep brain stimulation for Parkinson's disease.

Deep brain stimulation (DBS) is a well-established and effective treatment for patients with advanced Parkinson's disease (PD), yet its underlying mechanisms remain enigmatic. Optogenetics, primarily conducted in animal models, provides a unique approach that allows cell type- and projection-specific modulation that mirrors the frequency-dependent stimulus effects of DBS. Opto-DBS research in animal models plays a pivotal role in unraveling the neuronal and synaptic adaptations that contribute to the efficacy of DBS in PD treatment. DBS-induced neuronal responses rely on a complex interplay between the distributions of presynaptic inputs, frequency-dependent synaptic depression, and the intrinsic excitability of postsynaptic neurons. This orchestration leads to conversion of firing patterns, enabling both antidromic and orthodromic modulation of neural circuits. Understanding these mechanisms is vital for decoding position- and programming-dependent effects of DBS. Furthermore, patterned stimulation is emerging as a promising strategy yielding long-lasting therapeutic benefits. Research on the neuronal and synaptic adaptations to DBS may pave the way for the development of more enduring and precise modulation patterns. Advanced technologies, such as adaptive DBS or directional electrodes, can also be integrated for circuit-specific neuromodulation. These insights hold the potential to greatly improve the effectiveness of DBS and advance PD treatment to new levels.

The applied principles of EEG analysis methods in neuroscience and clinical neurology.

Electroencephalography (EEG) is a non-invasive measurement method for brain activity. Due to its safety, high resolution, and hypersensitivity to dynamic changes in brain neural signals, EEG has aroused much interest in scientific research and medical fields. This article reviews the types of EEG signals, multiple EEG signal analysis methods, and the application of relevant methods in the neuroscience field and for diagnosing neurological diseases. First, three types of EEG signals, including time-invariant EEG, accurate event-related EEG, and random event-related EEG, are introduced. Second, five main directions for the methods of EEG analysis, including power spectrum analysis, time-frequency analysis, connectivity analysis, source localization methods, and machine learning methods, are described in the main section, along with different sub-methods and effect evaluations for solving the same problem. Finally, the application scenarios of different EEG analysis methods are emphasized, and the advantages and disadvantages of similar methods are distinguished. This article is expected to assist researchers in selecting suitable EEG analysis methods based on their research objectives, provide references for subsequent research, and summarize current issues and prospects for the future.

Memory Trace for Fear Extinction: Fragile yet Reinforceable.

Fear extinction is a biological process in which learned fear behavior diminishes without anticipated reinforcement, allowing the organism to re-adapt to ever-changing situations. Based on the behavioral hypothesis that extinction is new learning and forms an extinction memory, this new memory is more readily forgettable than the original fear memory. The brain's cellular and synaptic traces underpinning this inherently fragile yet reinforceable extinction memory remain unclear. Intriguing questions are about the whereabouts of the engram neurons that emerged during extinction learning and how they constitute a dynamically evolving functional construct that works in concert to store and express the extinction memory. In this review, we discuss recent advances in the engram circuits and their neural connectivity plasticity for fear extinction, aiming to establish a conceptual framework for understanding the dynamic competition between fear and extinction memories in adaptive control of conditioned fear responses.

Synaptic scaling of corticostriatal circuits underlies hyperactivity in GABA Transporter-1 deficient mice.

Homeostatic synaptic scaling entails adjustment of synaptic strength on a cell to prolonged changes of neuronal activity, which is postulated to participate in neuropsychiatric disorders in vivo. Here, we find that sustained elevation in ambient GABA levels, by either genetic deletion or pharmacological blockade of GABA transporter-1 (GAT1), leads to synaptic scaling up of corticostriatal pathways, which underlies locomotor hyperactivity. Meanwhile, medium spiny neurons of the dorsal striatum exhibit an aberrant increase in excitatory synaptic transmission and corresponding structural changes in dendritic spines. Mechanistically, GAT1 deficiency dampens the expression and function of metabotropic glutamate receptors (mGluRs) and endocannabinoid (eCB)-dependent long-term depression of excitatory transmission. Conversely, restoring mGluR function in GAT1 deficient mice rescues excitatory transmission. Lastly, pharmacological potentiation of mGluR-eCB signaling or inhibition of homomeric-GluA1 AMPA receptors eliminates locomotor hyperactivity in the GAT1 deficient mice. Together, these results reveal a synaptic scaling mechanism in corticostriatal pathways that regulate locomotor activity.

Lidocaine alleviates inflammation and pruritus in atopic dermatitis by blocking different population of sensory neurons.

BACKGROUND AND PURPOSE: Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro-immune communication. Neuronal mechanism-based therapeutic treatments remain lacking. We investigated the efficacy of intravenous lidocaine therapy on atopic dermatitis and the underlying neuro-immune mechanism. EXPERIMENTAL APPROACH: Pharmacological intervention, immunofluorescence, RNA-sequencing, genetic modification and immunoassay were performed to dissect the neuro-immune basis of itch and inflammation in atopic dermatitis-like mouse model and in patients. KEY RESULTS: Lidocaine alleviated skin lesions and itch in both atopic dermatitis patients and calcipotriol (MC903)-induced atopic dermatitis model by blocking subpopulation of sensory neurons. QX-314, a charged NaV blocker that enters through pathologically activated large-pore ion channels and selectivity inhibits a subpopulation of sensory neurons, has the same effects as lidocaine in atopic dermatitis model. Genetic silencing NaV 1.8-expressing sensory neurons was sufficient to restrict cutaneous inflammation and itch in the atopic dermatitis model. However, pharmacological blockade of TRPV1-positive nociceptors only abolished persistent itch but did not affect skin inflammation in the atopic dermatitis model, indicating a difference between sensory neuronal modulation of skin inflammation and itch. Inhibition of activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons by lidocaine largely accounts for the therapeutic effect of lidocaine in the atopic dermatitis model. CONCLUSION AND IMPLICATIONS: NaV 1.8+ sensory neurons play a critical role in pathogenesis of atopic dermatitis and lidocaine is a potential anti-inflammatory and anti-pruritic agent for atopic dermatitis. A dissociable difference for sensory neuronal modulation of skin inflammation and itch contributes to further understanding of pathogenesis in atopic dermatitis.

SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

Social deficits via dysregulated Rac1-dependent excitability control of prefrontal cortical neurons and increased GABA/glutamate ratios.

Identifying symptom-specific convergent mechanisms for neurodevelopmental disorders is a promising strategy in advancing therapies. Here, we show that bidirectional dysregulation of Rac1 activity in the medial prefrontal cortex (mPFC) dictates shared social deficits in mice. Selective upregulation or downregulation of Rac1 activity in glutamatergic or fast-spiking GABAergic neurons results in excessive or inadequate control of excitability combined with a decrease in glutamate or an increase in GABA concentrations and an increase in the GABA/glutamate ratio, which is responsible for social deficits. Notably, the autism model of Shank3B knockout mice exhibits aberrantly enhanced Rac1 activity, reduced glutamate concentrations, and pyramidal neuron excitability in mPFC accompanied with social deficits, which were corrected by either excitatory-neuron-specific downregulation of Rac1 activity or upregulation of neuronal excitability. Thus, this work shows a convergence between genetic autism risk factors, dysregulation of Rac1 signaling, and excitation-inhibition imbalance, enabling mechanism-based stratification of patients with social deficits.

Insular cortical circuits as an executive gateway to decipher threat or extinction memory via distinct subcortical pathways.

Threat and extinction memories are crucial for organisms' survival in changing environments. These memories are believed to be encoded by separate ensembles of neurons in the brain, but their whereabouts remain elusive. Using an auditory fear-conditioning and extinction paradigm in male mice, here we discovered that two distinct projection neuron subpopulations in physical proximity within the insular cortex (IC), targeting the central amygdala (CeA) and nucleus accumbens (NAc), respectively, to encode fear and extinction memories. Reciprocal intracortical inhibition of these two IC subpopulations gates the emergence of either fear or extinction memory. Using rabies-virus-assisted tracing, we found IC-NAc projection neurons to be preferentially innervated by intercortical inputs from the orbitofrontal cortex (OFC), specifically enhancing extinction to override fear memory. These results demonstrate that IC serves as an operation node harboring distinct projection neurons that decipher fear or extinction memory under the top-down executive control from OFC.

Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory.

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

Nanoformulated Bumetanide Ameliorates Social Deficiency in BTBR Mice Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with few medication options. Bumetanide, an FDA-approved diuretic, has been proposed as a viable candidate to treat core symptoms of ASD, however, neither the brain region related to its effect nor the cell-specific mechanism(s) is clear. The availability of nanoparticles provides a viable way to identify pharmacological mechanisms for use in ASD. Here, we found that treatment with bumetanide, in a systemic and medial prefrontal cortex (mPFC) region-specific way, attenuated social deficits in BTBR mice. Furthermore, using poly (ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles [NP(bumetanide)], we showed that the administration of NP(bumetanide) in a mPFC region-specific way also alleviated the social deficits of BTBR mice. Mechanistically, the behavioral effect of NP(bumetanide) was dependent on selective microglia-specific targeting in the mPFC. Pharmacological depletion of microglia significantly reduced the effect of nanoencapsulation and depletion of microglia alone did not improve the social deficits in BTBR mice. These findings suggest the potential therapeutic capabilities of nanotechnology for ASD, as well as the relevant link between bumetanide and immune cells.

The immuno-behavioural covariation associated with the treatment response to bumetanide in young children with autism spectrum disorder.

Bumetanide, a drug being studied in autism spectrum disorder (ASD) may act to restore gamma-aminobutyric acid (GABA) function, which may be modulated by the immune system. However, the interaction between bumetanide and the immune system remains unclear. Seventy-nine children with ASD were analysed from a longitudinal sample for a 3-month treatment of bumetanide. The covariation between symptom improvements and cytokine changes was calculated and validated by sparse canonical correlation analysis. Response patterns to bumetanide were revealed by clustering analysis. Five classifiers were used to test whether including the baseline information of cytokines could improve the prediction of the response patterns using an independent test sample. An immuno-behavioural covariation was identified between symptom improvements in the Childhood Autism Rating Scale (CARS) and the cytokine changes among interferon (IFN)-γ, monokine induced by gamma interferon and IFN-α2. Using this covariation, three groups with distinct response patterns to bumetanide were detected, including the best (21.5%, n = 17; Hedge's g of improvement in CARS = 2.16), the least (22.8%, n = 18; g = 1.02) and the medium (55.7%, n = 44; g = 1.42) responding groups. Including the cytokine levels significantly improved the prediction of the best responding group before treatment (the best area under the curve, AUC = 0.832) compared with the model without the cytokine levels (95% confidence interval of the improvement in AUC was [0.287, 0.319]). Cytokine measurements can help in identifying possible responders to bumetanide in ASD children, suggesting that immune responses may interact with the mechanism of action of bumetanide to enhance the GABA function in ASD.

Alterations of gut microbiota diversity, composition and metabonomics in testosterone-induced benign prostatic hyperplasia rats.

BACKGROUND: Studies had shown many diseases affect the stability of human microbiota, but how this relates to benign prostatic hyperplasia (BPH) has not been well understood. Hence, this study aimed to investigate the regulation of BPH on gut microbiota composition and metabonomics. METHODS: We analyzed gut samples from rats with BPH and healthy control rats, the gut microbiota composition and metabonomics were detected by 16S rDNA sequencing and liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: High-throughput sequencing results showed that gut microbiota beta-diversity increased (P < 0.01) in the BPH group vs. control group. Muribaculaceae (P < 0.01), Turicibacteraceae (P < 0.05), Turicibacter (P < 0.01) and Coprococcus (P < 0.01) were significantly decreased in the BPH group, whereas that of Mollicutes (P < 0.05) and Prevotella (P < 0.05) were significantly increased compared with the control group. Despite profound interindividual variability, the levels of several predominant genera were different. In addition, there were no statistically significant differences in several bacteria. BPH group vs. control group: Firmicutes (52.30% vs. 57.29%, P > 0.05), Bacteroidetes (46.54% vs. 41.64%, P > 0.05), Clostridia (50.89% vs. 54.66%, P > 0.05), Ruminococcaceae (25.67% vs. 20.56%, P > 0.05). LC-MS/MS of intestinal contents revealed that differential metabolites were mainly involved in cellular processes, environmental information processing, metabolism and organismal systems. The most important pathways were global and overview maps, lipid metabolism, amino acid metabolism, digestive system and endocrine system. Through enrichment analysis, we found that the differential metabolites were significantly enriched in metabolic pathways, steroid hormone biosynthesis, ovarian steroidogenesis, biosynthesis of unsaturated fatty acids and bile secretion. Pearson correlation analysis (R = 0.94) showed that there was a strong correlation between Prevotellaceae, Corynebacteriaceae, Turicibacteraceae, Bifidobacteriaceae and differential metabolites. CONCLUSION: Our findings suggested an association between the gut microbiota and BPH, but the causal relationship between the two groups is unclear. Thus, further studies are warranted to elucidate the potential mechanisms and causal relationships between BPH and gut microbiota.