Molecular Brain最新文献

We previously demonstrated that ibrutinib has therapeutic efficacy against AD pathologies when injected intraperitoneally at a lower dosage (10 mg/kg, daily for 2 weeks) or orally at a higher dosage (30 mg/kg, daily for 1 month) in AD mice models. However, the effect of chronic lower dose of ibrutinib by oral administration on AD pathologies has not been investigated yet. Therefore, we investigated whether long-term oral administration of ibrutinib at a lower dose (1 or 10 mg/kg, daily for 5 months) on AD pathology and in vivo toxicity in 5xFAD mice. We found ibrutinib enhanced cognitive function and alleviated Aβ pathology in 5xFAD mice without hepatotoxicity. Furthermore, ibrutinib-treated 5xFAD mice decrease tau hyperphosphorylation, p-GSK3α/β levels, and markers of neuroinflammation such as Iba-1, GFAP, and NLRP3. Collectively, these translational studies indicate chronic oral administration of ibrutinib at low doses improves cognitive function and suppresses AD pathology/neuroinflammation in an AD mice model thereby having potential as an effective multitarget AD therapeutic in clinical application.

Postoperative nausea and vomiting (PONV) after orthognathic surgery is a serious postoperative complication. The cholinergic receptor muscarinic 3 (CHRM3) rs2165870 and tachykinin receptor 1 (TACR1) rs3755468 single-nucleotide polymorphisms (SNPs) have been reported to be involved in PONV. We evaluated the impact of these SNPs on PONV in a Japanese population who underwent orthognathic surgery under PONV prophylaxis with the 5-hydroxytryptamine (serotonin) receptor 3A receptor antagonist ondansetron. In 121 patients, dexamethasone was administered after intubation, followed by ondansetron before the end of surgery. An 11-point numeric rating scale (NRS) score for PONV (0-2 h or 2-24 h after anesthesia endpoint [a.a.e.]) and the presence or absence of metoclopramide administration (0-2 h or 2-24 h a.a.e.) were evaluated. If patients complained of PONV and had an NRS score ≥ 4, then metoclopramide was administered intravenously for PONV rescue. Patients were genotyped for the CHRM3 rs2165870 and TACR1 rs3755468 SNPs, followed by the statistical analysis of associations between these SNPs and phenotypes. AA carriers of CHRM3 rs2165870 received metoclopramide at a significantly higher rate (P = 2.48 × 10^- 2) and had higher NRS scores (P = 3.40 × 10^- 2) under a diminished influence of ondansetron than GG and GA carriers. CC carriers of TACR1 rs3755468 had significantly higher NRS scores under the sufficient influence of ondansetron than CT and TT carriers (P = 9.97 × 10^- 3). Numeric rating scale scores showed a significant interaction between "time" (the effect of ondansetron) and "genotype" (two-way analysis of variance, P = 4.39 × 10^- 2). AA carriers of CHRM3 rs2165870 were significantly associated with "time" (P = 3.26 × 10^- 2), and CC carriers of TACR1 rs3755468 were not (P > 0.05). These results suggest that ondansetron significantly affects nausea that is associated with CHRM3, whereas it has a minimal effect on nausea that is associated with TACR1. This indicates that nausea that is associated with CHRM3 is qualitatively different from nausea that is associated with TACR1. Ondansetron mainly exerts its effects outside the blood-brain barrier, which may lead to differential impacts on nausea that is associated with CHRM3 and TACR1. These findings may provide future directions for tailor-made preventive measures against PONV that depend on high-risk genotypes of the CHRM3 rs2165870 and TACR1 rs3755468 SNPs.

The striatum is a critical component of the basal ganglia and plays a central role in regulating motor initiation and action selection. How cortical and subcortical inputs converging at the striatum regulate locomotion remains unclear. By examining gait changes in head-fixed mice running on a treadmill, we found that mice were capable of performing forward, but not backward, rhythmic locomotion using their forelimbs when the striatum and motor cortex were inactivated. The striatal activity is critical for adjusting initially disorganized gait to efficient rhythmic locomotion during forward running training, as well as for increasing the stride width during forward locomotion. The inputs from the motor cortex to striatum are important for the rhythmic locomotion, but not for changes of stride length and width during forward running training. In addition, D1 and D2 dopamine receptor activity in striatum are both important for efficient rhythmic locomotion, while exerting opposite effects on the stride width. Together, these results reveal multifactorial control of efficient and rhythmic gait by motor cortical and dopaminergic inputs converging at the striatum.

For social animals, social isolation is a potential threat to survival, and therefore can be considered innately aversive. Long-term social isolation induces a variety of social and affective deficits and has been used as a stress model in animal studies, with increasing insight into its underlying neural mechanisms. In contrast, short-term social isolation is known to elicit prosocial behaviors such as rebound social interactions, yet the neural basis of these adaptive responses remains poorly understood. Here, we investigated the effects of short-term social isolation on social and appetitive behaviors and examined the role of the insular cortex in modulating social preference in male mice. Three days of social isolation increased social contacts in a three-chamber social preference test. Additionally, socially isolated mice showed higher food intake in the home cage compared with the group-housed mice, and those exhibiting a higher social preference following social isolation also tended to consume more food during the isolation, postulating a potential correlation of social craving and food craving. Furthermore, chemogenetic suppression of the insular cortex during social isolation reduced rebound social interactions. We propose that the insular cortex modulates social valence by serving as an alert center for social deprivation. Our findings may help advance understanding of the neuronal mechanisms that underlie adaptive social and appetitive behaviors in response to social isolation.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including deficits in social interaction, repetitive and stereotyped behaviors, along with higher levels of anxiety and cognitive impairments. Previous studies demonstrate pronounced reduced density of calretinin (CR)-expressing GABAergic interneurons in both ASD patients and animal models. The object of the current study was to determine the role of CR in ASD-relevant behavioral aberrations. Herein, the mRNA and protein levels of CR in the prefrontal cortex (PFC) of mouse model of ASD based on prenatal exposure to valproic acid (VPA) were determined by qRT-PCR and Western blot analysis, respectively. Moreover, the behavioral abnormalities in naive mice with CR deficiency mediated by recombinant adeno-associated virus (rAAV) were evaluated in a comprehensive testing battery including social interaction, marble burying, self-grooming, open-field, elevated plus maze and novel object recognition tests. Furthermore, the action potential changes caused by CR deficiency were examined in neurons within the PFC in naive mouse. The results show that the mRNA and protein levels of PFC CR of VPA-induced mouse ASD model were reduced. Concomitantly, mice with CR knockdown displayed ASD-like behavioral aberrations, such as social impairments, elevated stereotypes, anxiety and memory defects. Intriguingly, patch-clamp recordings revealed that CR knockdown provoked decreased neuronal excitability by increasing action potential discharge frequencies together with decreased action potential threshold and rheobase. Our findings support a notion that CR knockdown might contribute to ASD-like phenotypes, with the pathogenesis most likely stemming from increased neuronal excitability.

Passage of molecules across the central nervous system is tightly regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), which restrict entry of many substances, including opioid medications. Here, we examined the effects of opioid withdrawal on BBB and BSCB integrity by measuring extravascular levels of peripherally injected dyes - Evans Blue (high molecular weight) and sodium fluorescein (NaFl, low molecular weight) - in the brain and spinal cord. In morphine-dependent male and female mice, repeated naloxone challenge induced robust withdrawal behaviors concomitant with region specific dye extravasation. In a fixed dose morphine paradigm, Evans Blue extravasation was highest within the cortex, hippocampus, cerebellum, and brainstem (pons and medulla) in male mice, and in the hypothalamus in female mice. By contrast, NaFl extravasation remained unchanged in both sexes. In an escalating dose morphine paradigm, Evans Blue extravasation was most prominent in the brainstem (pons and medulla) of both sexes, as well as in the lumbar of male mice and cervical spinal cord of female mice. NaFl extravasation in these regions was unchanged in male but reduced in female mice. These findings suggest that repeated opioid withdrawal alters permeability of the BBB and BSCB in discrete regions of the brain and spinal cord.

Background: N6-methyladenosine (m6A) methylation is an essential epigenetic modification that regulates mRNA stability, splicing, and translation. Its role in neurological diseases, including epilepsy, ischemic stroke, and vascular dementia (VaD), remains poorly understood.

Methods: We integrated multi-omics data, including GWAS, m6A quantitative trait loci (QTL), expression QTL (eQTL), and protein QTL (pQTL), and using FUSION to assess the association of m6A with these diseases. Transcriptome-wide association studies (TWAS) and Mendelian Randomization (MR) were performed to identify causal relationships between m6A sites, gene expression, and disease. Differentially expressed genes (DEGs) were analyzed via RNA sequencing and enriched for biological pathways. Protein-protein interaction (PPI) networks and m6A-related gene-disease associations were constructed to reveal regulatory mechanisms.

Results: We identified 218 m6A sites significantly associated with the three diseases, highlighting 3,430 associations between m6A sites and gene expression. Functional enrichment analysis revealed key pathways, including base excision repair and chemokine-mediated signaling. MR analysis identified causal relationships, such as NBL1 in epilepsy, TPGS2 in ischemic stroke, and SERINC2 in VaD. PPI analysis revealed interactions involving critical proteins like PARP1, MCL1, and CD40, underscoring their role in neuroinflammation and apoptosis.

Conclusion: Our findings elucidate the genetic and epigenetic roles of m6A in epilepsy, ischemic stroke, and VaD, uncovering potential mechanisms by which m6A modulates gene and protein expression to influence disease outcomes. These insights highlight m6A as a promising biomarker and therapeutic target for neurological diseases.

The nucleus accumbens (NAcc) is a key brain region in reward circuitry, mediating responses to psychostimulants, such as amphetamine (AMPH), including locomotor activity. This effect is known to be enhanced by the orexigenic neuropeptide ghrelin acting through growth hormone-secretagogue receptors (GHSR) expressed in the region. Recently, liver-expressed antimicrobial peptide 2 (LEAP2) was identified as another ligand for GHSR that opposes ghrelin's action. Based on its antagonism, we hypothesized that LEAP2 modulates AMPH-induced locomotor activity in the NAcc. To examine this, we first confirmed the presence of LEAP2 protein in this NAcc and observed that its fluorescent signals were predominantly localized in neurons, including medium spiny neurons (MSNs). We then investigated whether LEAP2 microinjection alters AMPH-induced locomotor activity. Our findings showed that LEAP2 inhibited acute AMPH-induced locomotor activity in a dose-dependent manner. However, its inhibitory effects were absent following chronic AMPH exposure, indicating that the effect of LEAP2 on AMPH-induced locomotor activity varies depending on drug-exposed physiological status. These results provide new insights into a state-dependent regulatory role of LEAP2 in AMPH-induced locomotor activity.

The prefrontal cortex plays a crucial role in procedural rule learning; however, the specific neuronal mechanism through which it represents rules is unknown. We hypothesized that sequential neuronal activities in the prefrontal cortex encode these rules. To investigate this, we recorded neuronal activities in the medial prefrontal cortex of mice during rule learning using Ca²⁺ imaging. We utilized a method based on convolutional negative matrix factorization, iSeq, to automatically detect temporal neuronal sequences in the recorded data. As rule learning advanced, these neuronal sequences began to encode critical information for rule execution. In mice that had mastered the rule, the dynamics of neuronal sequences could predict success and failure of reward acquisition. Furthermore, the composition of cell populations within the neuronal sequences was rearranged throughout the learning process. These findings suggest that as animals learn a rule, the medial prefrontal cortex continually updates its neuronal sequences to assign significance to behavioural actions crucial for reward acquisition.