Mouse Prefrontal Cortex Research Articles

Retraction Note: Xiaoyaosan exerts antidepressant-like effects by regulating the functions of astrocytes and EAATs in the prefrontal cortex of mice

Retraction Note: Xiaoyaosan exerts antidepressant-like effects by regulating the functions of astrocytes and EAATs in the prefrontal cortex of mice

Aging disrupts the link between network centrality and functional properties of prefrontal neurons during memory-guided behavior

The prefrontal cortex (PFC) is vital for higher cognitive functions and displays neuronal heterogeneity, with neuronal activity varying significantly across individual neurons. Using calcium imaging in the medial PFC (mPFC) of mice, we investigate whether differences in degree centrality—a measure of connectivity strength within local circuits—could explain this neuronal diversity and its functional implications. In young adults, neurons with high degree centrality, inferred from resting-state activity, exhibit reliable and stable action-plan selectivity during memory-guided tasks, suggesting that connectivity strength is closely linked to functional heterogeneity. This relationship, however, deteriorates in middle-aged and older mice. A computational model simulating age-related declines in synaptic plasticity reproduces these results. In young adults, degree centrality also predicts cross-modal action-plan selectivity, but this predictive power diminishes with age. Furthermore, neurons with high action-plan selectivity are spatially clustered, a pattern that fades with aging. These findings reveal the significant aging impact on the network properties in parallel with the functional and spatial organization of the mPFC.

Sleep fragmentation impairs cognitive function and exacerbates Alzheimer's disease-related pathology in a mouse model by disrupting mitochondrial biogenesis.

A large proportion of Alzheimer's disease (AD) patients suffer from various types of chronic sleep disturbances, including sleep fragmentation (SF). In addition, impaired mitochondrial biogenesis is an important feature of AD, but whether it is altered in sleep disorders has not been fully elucidated. Hence, we aimed to investigate the relationship between SF and mitochondrial biogenesis and the possible impact of SF on AD-related pathology. In this study, thirty-six 9-month-old 3xTgAD model mice and thirty-six 9-month-old wild-type (WT) C57BL/6J mice were divided into a control group (6weeks of normal sleep), a SF group (6weeks of SF) and a SF+recovery sleep group (6weeks of SF followed by 2weeks of recovery sleep). Cognitive functions were assessed by behavioural experiments. Mitochondrial structure and function and the activity of a classic mitochondrial biogenesis signalling pathway were investigated using transmission electron microscopy (TEM), reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence and Western blotting. Markers of AD-related pathology, including the levels of amyloid β (Aβ) and tau proteins, were assessed by immunofluorescence and Western blotting. The expression of insulin-degrading enzyme (IDE) was assessed by Western blotting. We found that long-term SF impaired the cognitive functions of the mice. In addition, chronic SF reduced the expression of mitochondrial respiratory chain components, the number of mitochondria, the fluorescence intensity of COX-IV, the level of mitochondrial DNA (mtDNA) and the expression of crucial regulators of the AMPK/SIRT-1/PGC-1α signalling pathway in the mouse prefrontal cortex and hippocampus, while recovery sleep could partly abrogate these effects. Moreover, SF reduced the protein level of IDE and increased the Aβ burden and tau hyperphosphorylation. This study demonstrates that chronic SF can negatively regulate the AMPK/SIRT-1/PGC-1α signalling pathway to disrupt mitochondrial biogenesis in the brains of mice, which may subsequently exacerbate AD-related pathology by decreasing the expression of IDE.

Nobiletin-rich kososan, a Kampo formula, prevents the onset of apathy-like behavior and neuroinflammation in sickness behavior mouse model induced by increasing doses of lipopolysaccharide.

Infectious diseases are often concomitant with symptoms of lassitude and emotional disturbances, including depression, the so-called sickness behavior. Kososan, a Kampo (traditional Japanese herbal) formula, has been clinically used for depressive mood, with demonstrated efficacy in stress-induced depressive-like behavior mouse models. Additionally, our previous study has shown that nobiletin-rich kososan (NKS) prevents aging-related depressive-like behaviors and neuroinflammation in mice. Here, we examined whether NKS alleviates depressive-like behavior and neuroinflammation in a mouse model of sickness behavior induced by lipopolysaccharide (LPS). Repeated oral administration of NKS and the positive control antidepressant paroxetine (Paro) significantly prevented this behavior. NKS and Paro significantly increased the anti-inflammatory milieu in the hippocampus and prefrontal cortex (PFC), as well as brain microglia, of LPS-injected mice. The expression of the vascular tight junction protein claudin-5 was also significantly increased by the treatment with NKS, but not with Paro, in the hippocampus and PFC of LPS-injected mice. In vitro analysis using brain microvascular endothelial cells (BMVECs) showed that incubation with 5% serum derived from mice orally administered NKS resulted in a significant increase in the expression of anti-inflammatory heme oxygenase 1 as well as autophagic flux markers. Moreover, the claudin-5 levels in BMVECs were also increased under LPS-stimulated conditions. These results suggest that NKS exerts prophylactic effects against the LPS-induced apathy-like behavior, partly mediated by the increase in the anti-inflammatory milieu and in the levels of tight junction proteins in the brain. This study provides scientific evidence supporting the potential efficacy of NKS in preventing post-infection depression.

Metalomics Revealed that Changes of Serum Elements were Associated with Oxidative Stress-Induced Inflammation of Cortex in a Mouse Model of Autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder emerging during early childhood. However, the mechanism underlying the pathogenesis of ASD remains unclear. This study investigated the alterations of elements in serum and prefrontal cortex of BTBR T + tf/J (BTBR) mice and potential mechanisms. The male BTBR mice were used for experimental group and C57BL/6J (C57) mice were used for control group (n = 15). After behavioral tests were monitored, serum and prefrontal cortex of mice were analyzed by ICP-MS. The results demonstrated that the level of copper (Cu) was increased, and the levels of calcium (Ca), magnesium (Mg), selenium (Se), cobalt (Co), iron (Fe) and zinc (Zn) were decreased in BTBR mice compared to C57 mice (p < 0.01). The levels of above differential elements in serum demonstrated positive correlations with those in prefrontal cortex. Meanwhile, differential elements in prefrontal cortex had correlations with the total distance traveled (open field test) and the number of marbles buried (marble burying test) in BTBR mice (p < 0.05 or p < 0.01). The abnormally changed elements in serum might cross blood-brain-barrier into the brain and lead to oxidative stress, causing inflammation. Furtherly, the levels of inflammation-related indicators including tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-B (NF-κB), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were increased in prefrontal cortex of BTBR mice (p < 0.01), which were consistent with the aforementioned results. Our study suggested that the abnormal elements in the serum of BTBR mice may cause oxidative stress and inflammation in prefrontal cortex, which might contribute to increase the understanding of ASD pathogenesis.

DNMT3a Downregulation Ttriggered Upregulation of GABAA Receptor in the mPFC Promotes Paclitaxel-Induced Pain and Anxiety in Male Mice.

Chemotherapeutic agents, such as paclitaxel (PTX), induce neuroplastic changes and alter gene expression in the prefrontal cortex (PFC), which may be associated with chemotherapy-induced pain and negative emotions. Notably, DNA methylation undergoes adaptive changes in neurological disorders, emerging as a promising target for neuromodulation. In this study, systemic administration of PTX leads to a decrease in the expression of the DNA methyltransferase DNMT3a, while concurrently upregulating the expression of Gabrb1 mRNA and its encoded GABAARβ1 protein in the medial PFC (mPFC) of male mice. Overexpression of DNMT3a in the mPFC alleviates PTX-induced pain hypersensitivity, and anxiety-like behavior in these mice. Additionally, it reverses the PTX-induced increase in inhibitory synaptic transmission in the pyramidal neurons of the mPFC. Mechanistically, the upregulation of GABAARβ1 in the mPFC is linked to the reduced expression of DNMT3a and DNA hypomethylation at the promoter region of the Gabrb1 gene. Furthermore, a long-term diet rich in methyl donors alleviates PTX-induced pain hypersensitivity and anxiety-like behavior in mice. These findings suggest that the DNMT3a-mediated upregulation of GABAARβ1 in the mPFC contributes to PTX-induced neuropathic pain and anxiety, highlighting DNA methylation-dependent epigenetic regulation as a potential therapeutic target for addressing chemotherapy-induced cortical dysfunction.

Kaixin San ameliorating doxorubicin-induced neurotoxicity by activating AMPK signaling pathway

The study explored the pathological mechanism of doxorubicin chemotherapy-induced neurotoxicity and the intervention methods of traditional Chinese medicine. BALB/c mice were selected to establish tumor-bearing mouse models by orthotopic injection of 4T1 triple-negative breast cancer cells. After randomization, the mice were treated with doxorubicin chemotherapy or doxorubicin chemotherapy + Kaixin San(KXS). The lesions in the prefrontal cortex of mice were observed by pathological examination, and the lesion information was obtained by long non-coding RNA sequencing. The occurrence of lesions was determined by Western blot and biochemical indicators. In addition, neuroblastoma cells and microglia cells were used to construct in vitro models, and drug-containing serum and p-AMPK dephosphorylation inhibitors were used to further verify the accuracy of animal experiments. Pathological results showed that KXS could alleviate doxorubicin-induced neuronal degeneration in the prefrontal cortex. The long non-coding RNA sequencing suggested that neuronal degeneration and the intervention process of KXS were related to ferroptosis, immune diseases, AMPK signaling pathway, etc. Western blot and biochemical indicators confirmed that this process was directly related to the activation of the AMPK/HIF-1α/ACSL4 signaling pathway to alleviate ferroptosis of neurons and immune response of glial cells. In conclusion, KXS could alleviate doxorubicin-induced neurotoxicity by activating the AMPK signaling pathway and reducing the ferroptosis of neurons and immune response of glial cells.

Dysbindin-1 Mutation Alters Prefrontal Cortex Extracellular Glutamate and Dopamine In Vivo.

Elevated risk for schizophrenia is associated with a variation in the DTNBP1 gene encoding dysbindin-1, which may underpin cognitive impairments in this prevalent neuropsychiatric disorder. The cognitive symptoms of schizophrenia involve anomalies in glutamate and dopamine signaling, particularly within the prefrontal cortex (PFC). Indeed, mice with Dtnbp1 mutations exhibit spatial and working memory deficits that are associated with deficits in glutamate release and NMDA receptor function as determined by slice electrophysiology. The present study extended the results from ex vivo approaches by examining how the Dtnbp1 mutation impacts high K+- and NMDA receptor-evoked glutamate release within the PFC using in vivo microdialysis procedures. Dntbp1 mutant mice are also reported to exhibit blunted K+-evoked dopamine release within the PFC. Thus, we examined also K+- and NMDA-evoked dopamine release within this region. Perfusion of high-concentration K+ or NMDA solutions increased the PFC levels of both dopamine and glutamate in wild-type (WT) but not in Dtnbp1 mutants (MUT), whereas mice heterozygous for the Dtnbp1 mutation (HET) exhibited blunted K+-evoked dopamine release. No net-flux microdialysis procedures confirmed elevated basal extracellular content of both glutamate and dopamine within the PFC of HET and MUT mice. These in vivo microdialysis results corroborate prior indications that Dtnbp1 mutations perturb evoked dopamine and glutamate release within the PFC, provide in vivo evidence for impaired NMDA receptor function within the PFC, and suggest that these neurochemical anomalies may be related to abnormally elevated basal neurotransmitter content.

Application of TCM network pharmacology and experimental verification to explore the mechanism of kaempferol against epilepsy

BackgroundKaempferol (KF), the main active ingredient in identifying the authenticity of safflower, has a variety of pharmacological activities and neuroprotective effects. However, the mechanism of KF in the treatment of epilepsy remains unclear. This study aimed to investigate the protective effects of KF on epilepsy and its related mechanisms. MethodsNetwork pharmacology was used to explore the targets and mechanisms of safflower antiepileptic action. The protective effect of KF on epilepsy was assessed in the behavior and tissues of epileptic mice. Additionally, the impact of KF on the excitability and calcium transients of rat cortical neurons and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) were investigated using patch clamp and calcium imaging techniques. ResultsNetwork pharmacology indicated safflower could be involved in calcium signaling pathways and calcium channel inhibitor activity. Experimental validation demonstrated that KF delayed seizure onset and mitigated neuronal damage in the prefrontal cortex of mice. It also reduced neuronal excitability, as indicated by action potential parameters, and suppressed Glutamate (Glu)-induced calcium transients. In tsA201 cells, KF inhibited AMPAR-mediated currents, suggesting a role in regulating [Ca2+]i homeostasis. ConclusionThese results indicate that KF's anticonvulsant properties may arise from its neuroprotection against cell injury, edema, and necrosis, its reduction of neuronal hyperexcitability, and its prevention of calcium-induced cytotoxicity, potentially involving AMPAR modulation. This study positions KF as a promising candidate for epilepsy therapy, offering a scientific foundation for its clinical investigation.

CNSC-64. BEYOND THE LOCAL TUMOR MICROENVIRONMENT: CHARACTERIZING CHANGES TO NEURONAL ACTIVITY INDUCED BY PEDIATRIC HIGH-GRADE GLIOMA

Abstract Bidirectional electrochemical signaling between neurons and tumor cells is emerging as a critical regulator of pediatric high-grade glioma (HGG) pathology. Neuron-tumor interactions are known to induce local neuronal hyperactivity. However, recent work tracing the projections of these neuron-tumor networks revealed that HGG neuronal recruitment extends beyond the local tumor microenvironment (TME). These findings suggest that tumor-induced hyperexcitability may spread beyond the local TME and drive brain-wide circuit-level changes. To elucidate how non-tumor innervated brain regions are affected by TME hyperactivity we first characterized neuronal hyperactivity induced by a cortical patient-derived pediatric high-grade cell line in vitro on human iPSC-derived neurons. In vitro calcium imaging experiments demonstrated an increase in the number of calcium fluctuations in glioma co-cultured neurons. In parallel, multi-electrode recordings revealed increased population spiking activity and amplitude in neurons co-cultured with glioma cells. We then xenografted these HGG cells into the prefrontal cortex of mice and performed whole brain-clearing and cFos staining on tumor-bearing vs saline-injected control samples. As cFos is an immediate early gene activated by neuronal activity, we utilized the density of cFos expression as a readout-out of neuronal activation in our atlas-aligned segmented brain section analyses. We expectedly observed increased cFos expression within the ipsilateral primary and secondary motor region, which collectively comprise the local TME. Interestingly, we additionally observed elevated cFos in non-tumor bearing brain regions on both the ipsilateral and contralateral hemispheres, largely in layer 2/3 cortical neurons. These neurons form extensive cortico-cortical projections, and we coincidingly observed increased cFos expression in known cortical projection targets of the prefrontal xenograft location, such as somatosensory, visual, and retrosplenial cortices. Our findings suggest that tumor-induced neuronal hyperactivity extends beyond the local TME in a brain-wide manner and potentially follows established neuronal circuits, rendering these connected regions vulnerable to alterations in neuronal activity.

Decreased Brain pH Underlies Behavioral and Brain Abnormalities Induced by Chronic Exposure to Glucocorticoids in Mice

Depressed patients may exhibit glucocorticoid hypersecretion, suggesting that elevated levels of glucocorticoids may play an important role in the pathophysiology of depression. Some postmortem brain studies have shown decreased pH and increased lactate levels in psychiatric patients, implying involvement of these factors in the pathogenesis. To investigate the effects of glucocorticoids on brain pH and lactate levels, and their roles in depressive symptoms, brain pH and lactate were examined in mice treated with corticosterone (CORT), the major bioactive glucocorticoid in rodents. A single administration of CORT decreased hippocampal pH after 24 h. Three weeks of CORT treatment decreased pH in the prefrontal cortex (PFC), striatum, and hippocampus (HC), whereas intake of pH 9.0 drinking water increased pH in these brain regions. pH and lactate levels were correlated in the PFC and HC of mice treated with CORT for 3 weeks. The suppression of body weight gain and decrease in adrenal weight observed after 3 weeks of CORT treatment were not alleviated by pH 9.0 water. However, an increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus were alleviated. The decrease in brain pH and increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus induced by CORT treatment were abolished by co-treatment with the glucocorticoid receptor (GR) antagonist mifepristone. These findings indicate that decreased brain pH via GRs may be related to glucocorticoid-induced depression-like behavior and decreased hippocampal neurogenesis.

A mesocorticolimbic insulin receptor gene co-expression network moderates the association between early life adversity and food approach eating behaviour style in childhood

Insulin receptors, located in brain regions associated with reward sensitivity and decision-making, facilitate insulin action in the brain, modulating intracellular signaling cascades, gene expression, and neural activity. Here, we tested if variations in the expression of the insulin receptor gene network in the prefrontal cortex (PFC) and striatum (STR) moderate the association between early life adversity and eating behaviour in childhood and if this moderation is sex-specific. Participants from the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and Basal Influences on the Baby's Development (BIBO) were included as two independent cohorts. A biologically-informed polygenic score reflecting functional variation of the mesocorticolimbic insulin receptor gene network was created by using insulin receptor co-expression data from the PFC and STR in mice, and validated in humans through filtering by homologous expression in PFC using well-known databases. Early life adversity exposure was measured as a composite score. Eating behaviour was characterized using the Child Eating Behaviour Questionnaire administered to mothers of children aged 4 and 6 years in MAVAN, and 6 years in BIBO. We found that only in those with high expression of the mesocorticolimbic insulin receptor gene network a higher early adversity score associated with a higher desire to drink in 4-year boys and 6-year girls, as well as a higher food approach score and food approach/food avoidance ratio in 4-year girls. Also, a higher early life adversity was associated with higher food responsiveness, food approach score and food approach/food avoidance ratio at 6 years in the MAVAN full sample. The moderation observed on desire to drink was partially replicated in BIBO children aged 6 years. Identifying individual differences in response to early adversity may help to prioritize individuals at high risk for long-term disease and design suitable interventions.

Perisomatic Synaptic Targeting by Cholecystokinin-Basket Interneurons through NrCAM and Ankyrin B.

The perisomatic region of cortical pyramidal neurons (PNs) integrates local and long-range inputs and regulates firing.This domain receives GABAergic inputs from cholecystokinin (CCK)- and parvalbumin (PV)-expressing basket cells (BCs) but how synaptic contacts are established is unclear. Neuron-glial related cell adhesion molecule (NrCAM) is a homophilic transmembrane protein that binds the scaffold protein Ankyrin B. Here we show that NrCAM and Ankyrin B mediate perisomatic synaptic contact between CCK-BCs and PNs in mouse prefrontal cortex (PFC). Immunolabeling of CCK-BC terminals for vesicular glutamate transporter-3 (VGlut3) or vesicular glutamate transporter (VGAT) revealed a significant decrease in CCK-BC synaptic puncta on PN soma in NrCAM-null mice, however no decrease in PV-BC puncta, or cell loss. VGlut3+ CCK-BC puncta were also decreased by Ankyrin B deletion from PNs in Nex1Cre-ERT2:Ank2 flox/flox :EGFP mice. A novel CCK-BC reporter mouse expressing tdTomato (tdT) at the Synuclein-γ ( Sncg ) locus showed NCAM localized to presynaptic Sncg+ CCK-BCs, as well as to postsynaptic PN soma of WT mice. Results implicate NrCAM homophilic interactions and Ankyrin B binding with development of inhibitory connectivity between CCK-BCs and excitatory neurons of the PFC.

MK-801-exposure induces increased translation efficiency and mRNA hyperacetylation of Grin2a in the mouse prefrontal cortex

ABSTRACT Acute exposure to MK-801, the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, induces schizophrenia-like behavioural changes in juvenile male mice. However, the effects of acute MK-801 exposure on brain gene expression at the translation level remain unclear. Here, we conducted ribosome profiling analysis on the prefrontal cortex (PFC) of acute MK-801-exposed juvenile male mice. We found 357 differentially translated genes, with the N 4-acetylcytidine (ac4C) consensus motif enriched in the transcripts with increased translation efficiency. Acetylated RNA immunoprecipitation sequencing revealed 148 differentially acetylated peaks, of which 121 were hyperacetylated, and 27 were hypoacetylated. Genes harbouring these peaks were enriched in pathways related to axon guidance, Hedgehog signalling pathway, neuron differentiation, and memory. Grin2a encodes an NMDA receptor subunit NMDAR2A, and its human orthologue is a strong susceptibility gene for schizophrenia. Grin2a mRNA was hyperacetylated and exhibited significantly increased translation efficiency. NMDAR2A protein level was increased in MK-801-exposed PFC. Pretreatment of Remodelin, an inhibitor of N-acetyltransferase 10, returned the NMDAR2A protein levels to normal and partially reversed schizophrenia-like behaviours of MK-801-exposed mice, shedding light on the possible role of mRNA acetylation in the aetiology of schizophrenia.

PFOS sub-chronic exposure selectively activates Aβ clearance pathway to improve the cognitive ability of AD mice

Perfluorooctane sulfonate (PFOS), an emerging persistent organic pollutant, has been controversial in its impact on cognitive functions. Our previous research has confirmed that the sub-chronic PFOS exposure leads to neuronal apoptosis in the cerebral cortex, impairing cognitive functions in normal mice. However, our current study presents a surprising finding: sub-chronic exposure to PFOS effectively reduces cognitive impairments in Alzheimer's disease (AD) mice and significantly retards the disease's progression. Our results indicate that PFOS exposure upregulates the expression level of insulin-degrading enzyme (IDE) in the prefrontal cortex (PFC) of AD mice, thereby selectively enhancing the amyloid-beta (Aβ) clearance pathway without affecting the Aβ production. Moreover, PFOS exposure inhibits microglial proliferation and reduces inflammatory cytokines levels in the PFC of AD mice, providing further supporting for the pivotal role of IDE in attenuating AD progression under PFOS exposure. Collectively, our study is the first to demonstrate that sub-chronic PFOS exposure can alleviates cognitive impairments in AD pathology, with the IDE-mediated Aβ clearance pathway potentially playing a critical role.

Mitochondrial small RNA alterations associated with increased lysosome activity in an Alzheimer's Disease Mouse Model uncovered by PANDORA-seq.

Emerging small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in various biological processes, such as neurological diseases. Traditional sncRNA-sequencing (seq) protocols often miss these sncRNAs due to their modifications, such as internal and terminal modifications, that can interfere with sequencing. We recently developed panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq), a method enabling comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we revealed a novel sncRNA profile enriched by tsRNAs/rsRNAs in the mouse prefrontal cortex and found a significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimer's disease (AD) mouse model compared to wild-type controls, while this pattern is not present in the genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs negatively correlate with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provide insights for future mechanistic study of AD with potential therapeutic strategies.

Synaptic communication within the microcircuits of pyramidal neurons and basket cells in the mouse prefrontal cortex.

Basket cells are inhibitory interneurons in cortical structures with the potential to efficiently control the activity of their postsynaptic partners. Although their contribution to higher order cognitive functions associated with the medial prefrontal cortex (mPFC) relies on the characteristics of their synaptic connections, the way that they are embedded into local circuits is still not fully uncovered. Here, we determined the synaptic properties of excitatory and inhibitory connections between pyramidal neurons (PNs), cholecystokinin-containing basket cells (CCKBCs) and parvalbumin-containing basket cells (PVBCs) in the mouse mPFC. By performing paired recordings, we revealed that PVBCs receive larger unitary excitatory postsynaptic currents from PNs with shorter latency and faster kinetic properties compared to events evoked in CCKBCs. Also, unitary inhibitory postsynaptic currents in PNs were more reliably evoked by PVBCs than by CCKBCs, yet the former connections showed profound short-term depression. Moreover, we demonstrated that CCKBCs and PVBCs in the mPFC are connected with each other. Because alterations in PVBC function have been linked to neurological and psychiatric conditions such as Alzheimer's disease and schizophrenia and CCKBC vulnerability might play a role in mood disorders, a deeper understanding of the general features of basket cell synapses could serve as a reference point for future investigations with therapeutic objectives. KEY POINTS: Cholecystokinin- (CCKBCs) and parvalbumin-expressing basket cells (PVBCs) have distinct passive and active membrane properties. Pyramidal neurons give rise to larger unitary excitatory postsynaptic currents in PVBCs compared to events in CCKBCs. Unitary inhibitory postsynaptic currents in pyramidal neurons are more reliably evoked by PVBCs than by CCKBCs. Basket cells form chemical synapses and gap junctions with their own cell type. The two basket cell types are connected with each other.

Prefrontal TNRC6A mediates anxiety-like behaviour by regulating CRF through the maintenance of miR-21-3p stability

Anxiety is an emotional response to a potential threat. It is characterized by worry, feelings of tension, and physical changes. Trinucleotide repeat containing adaptor 6A (TNRC6A) binds to argonaute (AGO) proteins and microRNAs to form the miRNA-induced silencing complex (miRISC), which mediates mRNA degradation, storage, and translational repression functions. However, whether TNRC6A is involved in anxiety regulation remains unknown.In this study, TNRC6A was downregulated in the prefrontal cortex (PFC) of mice exposed to acute restraint stress. Inhibition of TNRC6A in PFC induced anxious behaviour. RNA immunoprecipitation, RNA pull-down and real-time quantitative PCR revealed that TNRC6A directly binds to miR-21-3p and maintains its stability. Intriguingly, miR-21-3p was downregulated in the PFC of acute stress mice, whereas overexpression of miR-21-3p significantly reduced anxiety-like behaviour. Furthermore, miR-21-3p knockdown significantly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the PFC pyramidal neurons. Dual luciferase assay and western blotting confirmed that miR-21-3p binds to the 3 ‘UTR region of corticotropin-releasing factor (CRF) mRNA and regulates CRF and cAMP-response element binding protein (CREB) expression. These results confirm that low levels of TNRC6A in the PFC decrease the stability of miR-21-3p which promotes the up-regulation of CRF, leading to the development of anxiety-like behaviours. This research provides insight into a novel molecular mechanism by which TNRC6A regulates anxiety behaviour through the miR-21-3p/CRF signalling axis.

Autism spectrum disorder-like behaviors induced by hyper-glutamatergic NMDA receptor signaling through hypo-serotonergic 5-HT1A receptor signaling in the prefrontal cortex in mice exposed to prenatal valproic acid.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, social deficits, and cognitive impairments. Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in offspring. The prevailing pathophysiological hypothesis for ASD involves excitation/inhibition (E/I) imbalances and serotonergic dysfunction. Here, we investigated the association between glutamatergic-serotonergic neuronal interactions and ASD-like behaviors in mice exposed to prenatal VPA. Prenatal VPA exposure induced excessive repetitive self-grooming behavior and impaired social behavior and object recognition memory in young adult period. Prenatal VPA mice showed hyper-glutamatergic function (increase in basal extracellular glutamate levels and CaMKII phosphorylation) and hypo-serotonergic function (decrease in 5-hydroxyindoleacetic acid and stimulation-induced serotonin [5-HT] release, but an increase in 5-HT transporter expression) in the prefrontal cortex. Treatment with a low-affinity NMDA receptor antagonist (memantine), a selective 5-HT reuptake inhibitor (fluoxetine), and a 5-HT1A receptor agonist (tandospirone) attenuated both the increase in CaMKII phosphorylation and ASD-like behavior of prenatal VPA mice. Opto-genetic activation of the serotonergic neuronal system attenuated impairments in social behavior and object recognition memory in prenatal VPA mice. WAY-100635-a 5-HT1A receptor antagonist-antagonized the effect of fluoxetine on impaired social behavior and object recognition memory. These results suggest that E/I imbalance and ASD-like behavior are associated with hypo-serotonergic receptor signaling through 5-HT1A receptors in prenatal VPA mice.

Comparative single-cell multiome identifies evolutionary changes in neural progenitor cells during primate brain development.

Understanding the cellular and genetic mechanisms driving human-specific features of cortical development remains a challenge. We generated a cell-type resolved atlas of transcriptome and chromatin accessibility in the developing macaque and mouse prefrontal cortex (PFC). Comparing with published human data, our findings demonstrate that although the cortex cellular composition is overall conserved across species, progenitor cells show significant evolutionary divergence in cellular properties. Specifically, human neural progenitors exhibit extensive transcriptional rewiring in growth factor and extracellular matrix (ECM) pathways. Expression of the human-specific progenitor marker ITGA2 in the fetal mouse cortex increases the progenitor proliferation and the proportion of upper-layer neurons. These transcriptional divergences are primarily driven by altered activity in the distal regulatory elements. The chromatin regions with human-gained accessibility are enriched with human-specific sequence changes and polymorphisms linked to intelligence and neuropsychiatric disorders. Our results identify evolutionary changes in neural progenitors and putative gene regulatory mechanisms shaping primate brain evolution.