Perineuronal nets (PNNs) are extracellular matrix structures that predominantly surround PV+ inhibitory interneurons. We have previously shown that PNNs in the medial prefrontal cortex (mPFC) are essential in the extinction and reconsolidation of methamphetamine (MA)-induced conditioned place preference (CPP). However, whether PNNs and PV+ interneurons in the mPFC are also involved in the acquisition phase of MA-induced CPP remains unclear. In this study, we investigated neuronal activity in the prelimbic cortex (PL) of the mPFC in relation to MA-induced CPP. The expression of c-Fos and ΔFosB dramatically increased following MA-induced CPP expression. In vivo calcium imaging demonstrated that both Ca2+ activity and event frequency, as well as the area under the curve (AUC) for calcium imaging signals in the PL, were elevated during MA-induced CPP conditioning and expression. The quantity of PNNs and PV+ neurons, along with co-labeled PNNs+/PV+ cells, dramatically rose following the CPP test and showed a positive correlation with MA preference. The elimination of PNNs from the PL by chondroitinase ABC (ChABC) diminished the expression of MA-induced CPP and lowered the quantity of PV+ and c-Fos+ neurons. Moreover, the targeted suppression of PV+ interneuron activity via an hM4D(Gi) DREADD strategy in PV-Cre animals throughout the conditioning stages markedly disrupted MA-induced CPP development and diminished Ca2+ activity in the PL. These findings indicate that both PNNs and PV+ interneurons in the PL are essential in the acquisition phase of MA-induced CPP and may serve as potential targets in treating MA addiction.

Background: Deeper understanding of ketamine’s mechanism of action would contribute to the discovery of novel therapeutic targets with fast-onset actions. To gain insight on the mechanism underlying the antidepressant-like effects of ketamine, we focused on perineuronal nets (PNNs), an extracellular matrix structure that surrounds fast-spiking parvalbumin-positive interneurons and regulates synaptic plasticity, whose integrity is known to be compromised under stress-induced depressive conditions. Methods: We first performed the description of the plastic remodeling of PNNs in the Chronic restraint stress (CRS) mice treated or un-treated with ketamine, by quantifying the number of WFA, marker of PNNs, parvalbumin (PV) and c-Fos positive cells, as a surrogate of neuronal activity. And then, we investigated the the transcripts of a number of proteins involved in the formation or degradation of PNNs with or without ketamine in CRS mice. Next, we evaluated the expression of IBA1, a microglial marker, in the hippocampus and medial prefrontal cortex after CRS treated or un-treated with ketamine. Results: We found that ketamine effectively alleviated the animals’ depression like behavior as well as attenuates CRS-induced reduction of WFA-positive cells in the hippocampus and medial prefrontal cortex of mice. Although ketamine treatment had little or no effect on the number of PV, c-Fos positive cells and the transcripts of proteins involved in the formation or degradation of PNNs. Notably, ketamine treatment lead to remarkably reduced the number of IBA1-positive cells in the hippocampus and medial prefrontal cortex after CRS. Conclusion: Our findings suggest that PNNs is characterized by region-specific changes in chronic stress mouse brain and provide extensive evidence that ketamine exposure initiates microglia to remodel PNN, instead of the PNN accumulation and degradation enzymes.

Methamphetamine (MA) addiction is characterized by persistent drug-associated memory and high relapse risk. Perineuronal nets (PNNs), which mainly surround PV interneurons, are specialized extracellular matrix structures involved in synaptic stabilization and memory regulation. Our previous studies have shown that PNNs in the medial prefrontal cortex (mPFC) are essential for MA-induced conditioned place preference (CPP) memory, but the role of hippocampal PNNs in MA-associated contextual memory remains unclear. Here, a CPP paradigm was employed in female mice to investigate the role and underlying mechanisms of hippocampal PNNs in MA-induced reward memory. During MA-induced CPP acquisition, the number of c-Fos and PNNs in the hippocampal CA1 was significantly increased. Digestion of PNNs using chondroitinase ABC (ChABC) or knockdown of the key PNNs component Aggrecan in the ventral CA1 (vCA1) but not dorsal CA1 (dCA1) suppressed the acquisition of MA-induced CPP and reduced the immunoreactivity of PV and c-Fos. In addition, chemogenetic inhibition of PV interneurons in the vCA1 of Pvalb-IRES-Cre mice using the hM4D(Gi) DREADD strategy also suppressed CPP acquisition, supporting a critical role for PV interneuron activity in this process. Together, our findings indicate that MA-induced increased PNNs in the vCA1 promote the formation of CPP memory by regulating PV interneuron activity. This study provides new evidence for the region-specific role of hippocampal PNNs in drug-associated memory and suggests that targeting vCA1 PNNs and PV interneurons may represent a potential therapeutic strategy for MA addiction.

Drug addiction is characterized by compulsive drug use despite significant negative consequences. N-acetyltransferase 10 (NAT10), a member of the Gcn5-related N-acetyltransferases (GNAT) family, has been associated with depression, anxiety-like behaviors, and cognitive dysfunction. However, its role in addiction remains largely unknown. In the present study, we observed increased expression of NAT10 in the nucleus accumbens (NAc) of mice treated either singly or repeatedly with 2 mg/kg methamphetamine (METH). To assess the role of NAT10 in addiction-related behaviors, we established mouse models of conditioned place preference (CPP) and hyperlocomotion. Using intraperitoneal administration of 0.1 mg/kg SCH23390, a dopamine D1 receptor (D1R) antagonist, we found that D1R antagonism significantly suppressed the METH-induced upregulation of NAT10 in the NAc and inhibited hyperlocomotion. Furthermore, stereotaxic delivery of a short hairpin RNA (shRNA)-based adeno-associated virus (AAV-shNAT10) into the NAc reduced both METH-induced hyperlocomotion and CPP. AAV-shNAT10 also inhibited METH-induced upregulation of PSD95 and preserved dendritic morphology in the NAc. These findings suggest that NAT10 contributes to the development of METH-induced reward-related behaviors by modulating dendritic plasticity in the NAc.

Extracellular Tau determines the progression of Alzheimer’s disease, yet therapeutic strategies targeting it are hindered by poor brain delivery and limited clearance. Here we developed a Tau-clearing cell therapy based on monocytes functionalized with a high-affinity Tau-specific aptamer. The aptamer was covalently conjugated to the surface of monocytes (derived from bone marrow leucocytes and cultured under monocyte-inducing conditions) via bioorthogonal chemistry without affecting their viability or function. Upon intravenous administration in mice expressing mutant and disease-relevant human Tau, the engineered monocytes actively crossed the blood–brain barrier and accumulated in Tau-rich brain regions such as the hippocampus and striatum. They efficiently phagocytosed extracellular Tau, leading to a significant reduction in Tau burden. As a result, glial activation was suppressed, neuroinflammation was alleviated, and neuronal and mitochondrial integrity was preserved. Long-term treatment improved memory and spatial learning, without inducing toxicity or behavioural side effects. These results demonstrate that aptamer-guided monocytes can achieve targeted delivery, effective clearance and sustained neuroprotection, offering a promising strategy for therapeutic intervention in Alzheimer’s disease. Monocytes derived from bone marrow leucocytes are chemically conjugated with a Tau-specific aptamer via bioorthogonal chemistry, enabling systemic delivery across the blood–brain barrier and targeted clearance of extracellular Tau in Alzheimer’s disease mouse models.

This cross-sectional study assessed the well-being of family members affected (AFMs) by substance use disorder (SUD) of other family members. Mental symptoms, social avoidance, and quality of life (QoL) were measured for 775 Chinese AFMs and 206 controls. Saliva from 65 AFMs and 31 controls was analyzed for cortisol, BDNF, proBDNF, and mRNA levels of BDNF and its receptors (TrkB, P75NTR, Sortilin). AFMs had significantly higher SCL-90 scores (t = 3.45, p < 0.01) and lower SF-36 scores (t = -4.70, p < 0.01). Of AFMs, 22.1

Acute lung injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition marked by severe inflammatory responses and disruption of the alveolar-capillary barrier, leading to high mortality rates and lack of effective treatments. Recent research has underscored the crucial role of programmed cell death pathways-pyroptosis, apoptosis, and necroptosis-in exacerbating inflammation and barrier dysfunction in ALI/ARDS. However, effective therapeutic agents targeting this process remain scarce. In this study, we reveal that PANoptosis, which integrates these cell death pathways through the PANoptosome complex, plays a central role in the pathogenesis and progression of ALI/ ARDS. The levels of PANoptosis-related molecules were significantly elevated in both the ALI mice and the clinical ARDS patient samples, highlighting it as a novel therapeutic target. Building on this insight, we developed a multifunctional nanomedicine, TPNs/Sal B, which integrates tea polyphenol-based nanoparticles (TPNs), a bioactive nanomaterial with anti-pyroptotic and anti-necroptotic properties, with salvianolic acid B (Sal B), known for its anti-apoptotic effects. Our results demonstrate that the nanomedcine TPNs/Sal B effectively inhibit PANoptosis, thereby attenuating lung tissue pathological damage, reducing inflammation, and improving lung epithelial barrier function in ALI models. Moreover, we identified LIM and SH3 protein 1 (LASP1) which may play an critical role in modulating alveolar epithelial barrier function during ALI/ARDS progression, and treatment with TPNs/Sal B effectively restored LASP1 levels. Our findings underscore the therapeutic potential of TPNs/Sal B as a targeted treatment for ALI/ARDS, offering a promising strategy for modulating PANoptosis and preserving lung function.

Methamphetamine (METH) is a highly addictive and widely abused drug that causes complex adaptive changes in the brain's reward system, such as the nucleus accumbens (NAc). LASP1 (LIM and SH 3 domain protein 1) as an actin-binding protein, regulates synaptic plasticity. However, the role and mechanism by which NAc LASP1 contributes to METH addiction remains unclear. In this study, adult male C57BL/6J mice underwent repeated METH exposure or METH-induced conditioned place preference (CPP). Western blotting and immunohistochemistry were used to determine LASP1 expression in the NAc. Furthermore, LASP1 knockdown or overexpression using adeno-associated virus (AAV) administration via stereotactic injection into the NAc was used to observe the corresponding effects on CPP. We found that repeated METH exposure and METH-induced CPP upregulated LASP1 expression in the NAc. LASP1 silencing in the NAc reversed METH-induced CPP and reduced PSD95, NR2A, and NR2B expression, whereas LASP1 overexpression in the NAc enhanced CPP acquisition, accompanied by increased PSD95, NR2A, and NR2B expression. Our findings demonstrate an important role of NAc LASP1 in modulating METH induced drug-seeking behavior and the underlying mechanism may be related to regulate the expression of synapse-associated proteins in the NAc. These results reveal a novel molecular regulator of the actions of METH on the NAc and provide a new strategy for treating METH addiction.

The high rate of relapse to compulsive methamphetamine (MA)-taking and seeking behaviors after abstinence constitutes a major obstacle to the treatment of MA addiction. Perineuronal nets (PNNs), essential components of the extracellular matrix, play a critical role in synaptic function, learning, and memory. Abnormalities in PNNs have been closely linked to a series of neurological diseases, such as addiction. However, the exact role of PNNs in MA-induced related behaviors remains elusive. Here, we established a MA-induced conditioned place preference (CPP) paradigm in female mice and found that the number and average optical density of PNNs increased significantly in the medial prefrontal cortex (mPFC) of mice during the acquisition, extinction, and reinstatement stages of CPP. Notably, the removal of PNNs in the mPFC via chondroitinase ABC (ChABC) before extinction training not only facilitated the extinction of MA-induced CPP and attenuated the relapse of extinguished MA preference but also significantly reduced the activation of c-Fos in the mPFC. Similarly, the ablation of PNNs in the mPFC before reinstatement markedly lessened the reinstatement of MA-induced CPP, which was accompanied by the decreased expression of c-Fos in the mPFC. Collectively, our results provide more evidence for the implication of degradation of PNNs in facilitating extinction and preventing relapse of MA-induced CPP, which indicate that targeting PNNs may be an effective therapeutic option for MA-induced CPP memories.

Excessive or inappropriate fear responses can lead to anxiety-related disorders, such as post-traumatic stress disorder (PTSD). Studies have shown that microglial activation occurs after fear conditioning and that microglial inhibition impacts fear memory. However, the role of microglia in fear memory recall remains unclear. In this study, we investigated the activated profiles of microglia after the recall of remote-cued fear memory and the role of activated microglia in the extinction of remote-cued fear in adult male C57BL/6 mice. The results revealed that the expression of the microglia marker Iba1 increased in the medial prefrontal cortex (mPFC) at 10 min and 1 h following remote-cued fear recall, which was accompanied by amoeboid morphology. Inhibiting microglial activation through PLX3397 treatment before remote fear recall did not affect recall, reconsolidation, or regular extinction but facilitated recall-extinction and mitigated spontaneous recovery. Moreover, our results demonstrated reduced co-expression of Iba1 and postsynaptic density protein 95 (PSD95) in the mPFC, along with decreases in the p-PI3K/PI3K ratio, p-Akt/Akt ratio, and KLF4 expression after PLX3397 treatment. Our results suggest that microglial activation after remote fear recall impedes fear extinction through the pruning of synapses in the mPFC, accompanied by alterations in the expression of the PI3K/AKT/KLF4 pathway. This finding can help elucidate the mechanism involved in remote fear extinction, contributing to the theoretical foundation for the intervention and treatment of PTSD.

Autism spectrum disorder (ASD) is neurodevelopmental disorder with a high incidence rate, characterized by social deficits and repetitive behaviors. There is currently no effective management available to treat the core symptoms of ASD; however, oxidative stress has been implicated in its pathogenesis. Edaravone (EDA), a free-radical scavenger, is used to treat amyotrophic lateral sclerosis (ALS) and acute ischemic stroke (AIS). Here, we hypothesized that an oral formula of EDA may have therapeutic efficacy in the treatment of core ASD symptoms. A rat model of autism was established by prenatal exposure to valproic acid (VPA), and the offsprings were orally treated with EDA at low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg) doses once daily for 28 days starting from postnatal day 25 (PND25). Oral EDA administration alleviated the core symptoms in VPA rats in a dose-dependent manner, including repetitive stereotypical behaviors and impaired social interaction. Furthermore, oral administration of EDA significantly reduced oxidative stress in a dose-dependent manner, as evidenced by a reduction in oxidative stress markers and an increase in antioxidants in the blood and brain. In addition, oral EDA significantly attenuated downstream pathologies, including synaptic and mitochondrial damage in the brain. Proteomic analysis further revealed that EDA corrected the imbalance in brain oxidative reduction and mitochondrial proteins induced by prenatal VPA administration. Overall, these findings demonstrate that oral EDA has therapeutic potential for ASD by targeting the oxidative stress pathway of disease pathogenesis and paves the way towards clinical studies.

Cognitive behavioral therapy, rooted in exposure therapy, is currently the primary approach employed in the treatment of anxiety-related conditions, including post-traumatic stress disorder (PTSD). In laboratory settings, fear extinction in animals is a commonly employed technique to investigate exposure therapy; however, the precise mechanisms underlying fear extinction remain elusive. Casein kinase 2 (CK2), which regulates neuroplasticity via phosphorylation of its substrates, has a significant influence in various neurological disorders, such as Alzheimer’s disease and Parkinson’s disease, as well as in the process of learning and memory. In this study, we adopted a classical Pavlovian fear conditioning model to investigate the involvement of CK2 in remote fear memory extinction and its underlying mechanisms. The results indicated that the activity of CK2 in the medial prefrontal cortex (mPFC) of mice was significantly upregulated after extinction training of remote cued fear memory. Notably, administration of the CK2 inhibitor CX-4945 prior to extinction training facilitated the extinction of remote fear memory. In addition, CX-4945 significantly upregulated the expression of p-ERK1/2 and p-CREB in the mPFC. Our results suggest that CK2 negatively regulates remote fear memory extinction, at least in part, by inhibiting the ERK-CREB pathway. These findings contribute to our understanding of the underlying mechanisms of remote cued fear extinction, thereby offering a theoretical foundation and identifying potential targets for the intervention and treatment of PTSD.

ObjectiveThe relationship between post-traumatic stress disorder (PTSD) and autoimmune thyroid disease (AITD) needs further evaluation. This study employs Mendelian randomization (MR) to investigate the causal correlations of PTSD with autoimmune thyroiditis (AIT) and Graves’ disease (GD).MethodsDatasets for PTSD, AIT, and GD were obtained from FinnGen. The exposure-outcome causal relationship was assessed using inverse variance weighted, MR-Egger, and weighted median. Horizontal pleiotropy was evaluated through the MR-Egger intercept, heterogeneity was examined using Cochran’s Q test, and robustness was assessed via leave-one-out sensitivity analysis.ResultsMR analysis indicated no significant causal relationship between PTSD and AIT (OR 0.920, 95% CI 0.832 to 1.017, p = 0.103), but a potential increase in the risk of GD associated with PTSD (OR 1.056, 95% CI 1.008 to 1.105, p = 0.021). MR-Egger intercept showed no horizontal pleiotropy (p > 0.05), and Cochran’s Q showed no heterogeneity (p > 0.05). Sensitivity analysis suggested the MR results were robust.ConclusionsEvidence of an MR association between genetic liability to PTSD and an increased risk of GD were provided, but no evidence of association between PTSD and AIT. The findings indicate that individuals with PTSD may have an increased likelihood of developing GD, underscoring the importance of further research to comprehend the intricate interplay between PTSD and thyroid disorders.

Methamphetamine (Meth), a commonly used central nervous system stimulant, is highly addictive. Currently, there is no effective treatment for Meth dependence and abuse, although cell adhesion molecules (CAMs) have been shown to play an important role in the formation and remodeling of synapses in the nervous system while also being involved in addictive behavior. Contactin 1 (CNTN1) is a CAM that is widely expressed in the brain; nevertheless, its role in Meth addiction remains unclear. Therefore, in the present study, we established mouse models of single and repeated Meth exposure and subsequently determined that CNTN1 expression in the nucleus accumbens (NAc) was upregulated in mice following single or repeated Meth exposure, whereas CNTN1 expression in the hippocampus was not significantly altered. Intraperitoneal injection of the dopamine receptor 2 antagonist haloperidol reversed Meth-induced hyperlocomotion and upregulation of CNTN1 expression in the NAc. Additionally, repeated Meth exposure also induced conditioned place preference (CPP) in mice and upregulated the expression levels of CNTN1, NR2A, NR2B, and PSD95 in the NAc. Using an AAV-shRNA-based approach to specifically silence CNTN1 expression in the NAc via brain stereotaxis reversed Meth-induced CPP and decreased the expression levels of NR2A, NR2B, and PSD95 in the NAc. These findings suggest that CNTN1 expression in the NAc plays an important role in Meth-induced addiction, and the underlying mechanism may be related to the expression of synapse-associated proteins in the NAc. The results of this study improved our understanding of the role of cell adhesion molecules in Meth addiction.

MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression at the post-transcriptional level and are involved in the pathogenesis of epilepsy. Here, we provide strong evidence in support of a pathogenic association of miRNA-32-5p (miR-32-5p) with epilepsy. Levels of miR-32-5p were elevated in the plasma of epilepsy patients, as well as in the hippocampus and plasma of pentylenetetrazol (PTZ)-induced seizure mice. Systemic knockout and hippocampal-specific knockdown of miR-32-5p mitigated seizure discharge and neuronal hyperactivity in the experimental mice. Mechanically, we found that RNA N6-methyl-adenosine (m6A) modification of hippocampal pri-miR-32-5p via the METTL14-YTHDC1 axis promoted the mature of miR-32, which then targeted KCC2 to weaken the inhibitory effect of GABAergic neurons. Together, this study discovered a link between m6A modification and miRNA maturation in epileptic pathogenesis, and specifically identified miR-32-5p as a putative biomarker and therapeutic target for hippocampus-related epilepsy.Trial Registration: Registered on the Chinese Clinical Trial Registry (Registration No: ChiCTR2200065002).Funding: This work was supported by the National Natural Science Foundation of China (No. (grants: 82271506 to Xuyu Zu, 81873651 and 82270939 to Jianghua Liu and 81901147 to Xiaolin Zhong).Declaration of Interest: The authors declare no competing interests.Ethical Approval: The human project was approved by the Ethics Committee of the First Affiliated Hospital of University of South China. All patients and healthy volunteers signed the informed consent. The animal project was approved by the Ethics Committee of the University of South China (2022usc05xs07). The experimental protocol was approved by the Animal Care and Use Committee of the University of South China in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

As social beings, animals and humans alike make real life decisions that are often influenced by other members. Most current research has focused on the influence of same-sex peers on individual decision-making, with potential opposite sex effect scarcely explored. Here, we developed a behavioral model to observe food foraging decision-making in female rats under various social situations. We found that female rats preferred to forage food from male over female rats or from the no-rat storage side. Female rats were more likely to forage food from familiar males than from unfamiliar. This opposite-sex preference was not altered by the lure of sweet food, or with estrous cycle, nor under stress conditions. These results suggest that the opposite sex influences food foraging decision-making in female rats. The behavioral model established could facilitate future investigation into the underlying neurobiological mechanisms.

A wealth of knowledge regarding glial cell-mediated neuroinflammation, which contributes to cognitive deficits in Alzheimer’s disease (AD) has emerged in recent years. Contactin 1(CNTN1), a member of the cell adhesion molecule and immunoglobulin supergene family, is centrally involved in axonal growth regulation and is also a key player in inflammation-associated disorders. However, whether CNTN1 plays a role in inflammation-related cognitive deficits and how this process is triggered and orchestrated remain to be fully elucidated. In this study, we examined postmortem brains with AD. CNTN1 immunoreactivity was markedly increased, particularly in the CA3 subregion, as compared with non-AD brains. Furthermore, by applying an adeno-associated virus-based approach to overexpress CNTN1 directly via stereotactic injection in mice, we demonstrated that hippocampal CNTN1 overexpression triggered cognitive deficits detected by novel object-recognition, novel place-recognition and social cognition tests. The mechanisms underlying these cognitive deficits could be attributed to hippocampal microglia and astrocyte activation, which led to aberrant expression of excitatory amino acid transporters (EAAT)1/EAAT2. This resulted in long-term potentiation (LTP) impairment that could be reversed by minocyline, an antibiotic and the best-known inhibitor of microglial activation. Taken together, our results identified Cntn1 as a susceptibility factor involved in regulating cognitive deficits via functional actions in the hippocampus. This factor correlated with microglial activation and triggered astrocyte activation with abnormal EAAT1/EAAT2 expression and LTP impairment. Overall, these findings may significantly advance our understanding of the pathophysiological mechanisms underlying the risk of neuroinflammation related cognitive deficits.

Traditional Chinese medicine (TCM) is one of the two mainstream medical practices in China's healthcare system. Postgraduate students largely determine the development and advancement of TCM; therefore, their mental health and academic achievement are vital to their performance as practitioners. We conducted a longitudinal study to provide information on the changes in mental health before and after TCM training and the relationship between mental health and academic performance among postgraduate students. All participants were enrolled in full-time programs at a TCM university in China, and they completed our questionnaire in the first month of registering as postgraduate students and at the end of training 3 years later. The results showed that the rate of positive symptoms for mental distress among TCM postgraduates was higher (12.2%) at the beginning of the first postgraduate year than at the end of training (10.4%). Previous mental health status and comprehensive academic performance were predictors of mental health status at the second measurement. Implications of the findings are discussed.