Behavioral and Brain Functions最新文献

Besides deficits in social communication and interaction, repetitive behavior patterns are core manifestations of autism spectrum disorder (ASD). Phenotypes are heterogeneous and can range from simple lower-order motor stereotypies to more complex higher-order cognitive inflexibility and fixated interests. Due to ASD's multifaceted etiology, animal models are often generated from monogenic diseases associated with ASD, such as Tuberous Sclerosis Complex (TSC), and are expected to copy behavioral core deficits to increase the model´s translational value for ASD disease research and novel treatment development. The global haploinsufficient Tsc2^+/- Eker rat model has been shown to display ASD core symptoms in the social domain. However, the presence and extent of aberrant repetitive behavior patterns in the Eker rat remain to be investigated. Thus, the present study applied a set of behavioral tests to determine the repetitive behavioral profile in Tsc2^+/- Eker rats and used brain-region-specific neurotransmitter analysis to support findings on a molecular level. Tsc2^+/- animals demonstrated lower-order repetitive behavior in the form of excessive self-grooming and nestlet shredding under non-stressful conditions that co-occurred alongside social interaction deficits. However, no higher-order repetitive behavior was detected in Tsc2^+/- rats. Interestingly, Tsc2^+/- rats exhibited increased levels of homeostatic dopamine in the prefrontal cortex, supporting the link between aberrant cortical dopaminergic transmission and the appearance of lower-order repetitive phenotypes. Together, our results support the Tsc2^+/- Eker rat as a model of ASD-like behavior for further investigation of ASD-related development and neurobiology.

Background: G protein-coupled estrogen receptor 1 (Gper1) is widely expressed in the brain, while its function in traumatic brain injury (TBI) remains poorly understood. This study aims to investigate the role of Gper1 in TBI pathology and the underlying mechanisms using a mouse model.

Methods: Gper1 knockout (Gper1^KO) mice were generated, and TBI was induced via controlled cortical impact (CCI). Brain water content, cell apoptosis, and neuroinflammation were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and TUNEL staining. Behavioral outcomes, including cognitive and anxiety-related behaviors, were evaluated using the open field test and Y-maze test.

Results: Gper1 expression was significantly upregulated in the brain tissues of TBI mice. Knockout of Gper1 led to exacerbated TBI-induced outcomes, including increased brain edema, blood-brain barrier disruption, and aggravated cell apoptosis and neuroinflammation in the cortex. Behaviorally, Gper1^KO mice displayed more severe cognitive impairments and anxiety-like behaviors compared to wild-type mice.

Conclusions: Gper1 inhibition exacerbates TBI-induced neurological and behavioral impairments, which suggests that Gper1 may be a potential therapeutic target for mitigating TBI-associated brain injury.

Background: The demethylase fat mass and obesity-related associated protein (FTO) is strongly associated with depression. Aging is a risk factor for synaptic plasticity damage in the brain and leads to neurocognitive dysfunctions. FTO-dependent m6A modification plays an important role in neurodevelopment and cognitive function. However, whether FTO is associated with susceptibility to depression in different age groups remains unknown.

Methods: We subjected 3-and 12-month-old C57BL/6J male mice to chronic unpredictable mild stress (CUMS) for 6 weeks, of which 3 weeks were used for hippocampal injection of FTO knockdown adeno-associated virus 9 shRNA (FTO-KD AAV9). Finally, 36 male mice in each 3-month-old and 12-month-old groups were divided into three groups (n = 12): Sham, CUMS, and FTO-KD. After 6 weeks, we assessed behavioral deficits (depressive and anxiety-like behaviors and cognitive impairment) by behavioral tests and hippocampal neuronal damage (dendritic spine density, neuronal atrophy, and expression of proteins associated with synaptic plasticity) by molecular biochemical experiments.

Results: The results showed that 12-month-old C57BL/6J mice were more likely to develop depression-like behavior and spatial learning and memory impairment induced by CUMS than 3-month-old mice. Chronic stress-induced depression-like behavior and cognitive impairment worsened after the FTO-KD intervention. In the hippocampus of 3- and 12-month-old mice, CUMS induced the downregulation of FTO, nerve growth factor (NGF), reelin, and synaptic plasticity-related proteins. It also caused abnormal brain-derived neurotrophic factor (BDNF)- the tropomyosin-related kinase B (TrkB) signaling, reduced density of dendritic spines, and an increased number of neuronal pyknotic nuclei, leading to neuronal disarray, which was more significant in 12-month-old animals. FTO deficiency accelerated neuronal damage in the hippocampus of 12-month-old CUMS mice.

Conclusions: This study provides rodent evidence that FTO deficiency may increase the susceptibility to depression in older adults by impairing hippocampal neuronal function and neuronal synaptic plasticity in an age-dependent manner. This suggests that the development of FTO activators may be an effective treatment for depression in older adults.

Background: In addition to classical gastrointestinal symptoms, patients with inflammatory bowel disease (IBD) often exhibit neurological manifestations, such as mood disorders and cognitive dysfunctions, which are frequently overlooked. However, the potential pathogenesis of IBD-related encephalopathy remains unclear, and few studies have explored the influence of interactions between the gut microbiota and the host gut-brain metabolome on the emergence of brain diseases in IBD mice. In this study, we conducted a comprehensive analysis of gut microbiome and metabolome alterations in dextran sulfate sodium salt (DSS)-induced IBD mice compared to control mice, focusing on colonic contents and hippocampal tissue. Our aim was to investigate the putative mechanisms underlying the microbiota-gut-brain axis in IBD-induced encephalopathy.

Results: IBD mice showed depression-like behaviors and cognitive deficits. Metabolic profiling revealed distinct patterns in the colonic contents and hippocampal areas of IBD mice, marked by decreased energy metabolism, amino acid levels, short-chain fatty acids (SCFAs), and choline metabolism. These metabolic changes were negatively associated with the abundance of Bacteroides, Turicibacter, Ruminococcus, and Akkermansia, while Desulfovibrio and Lactobacillus showed positive correlations.

Conclusions: This study identifies unique microbial and gut-brain metabolite signatures associated with DSS-induced changes and offers new metabolic insights into the microbiota-gut-brain axis in IBD-related brain disorders. It highlights the potential of targeting gut microbiota to modulate host metabolism as a therapeutic approach for IBD-related neurological complications.

Background: The primary protein components of white matter include myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). Alterations in their expression are significantly implicated in depression. This study investigated changes in MBP and CNP expression associated with depressive-like behaviors induced by chronic unpredictable stress (CUS) and evaluated therapeutic interventions using fluoxetine (FLU), an enriched environment (EE), or their combination.

Methods: Male Sprague Dawley rats were randomly assigned to a control group and four CUS-exposed groups undergoing 6 weeks of stress. During the final 3 weeks of CUS, rats received daily fluoxetine (CUS + FLU group), were housed in EE (CUS + EE group), or received combined EE and fluoxetine (CUS + FLU + EE group). Depression-like behaviors were assessed through sucrose preference, forced swimming, and open field tests after CUS completion and at the end of weeks 4-6. Protein and mRNA expression levels of MBP and CNP in the prefrontal cortex were quantified via immunohistochemistry, western blot, and qRT-PCR.

Results: Three weeks following CUS exposure, rats demonstrated significant depression-like behavioral phenotypes. By the fifth week, these behavioral deficits were ameliorated in the CUS + FLU + EE, whereas the CUS + FLU and CUS + EE groups exhibited comparable behavioral recovery by week 6. Parallel molecular analyses revealed diminished protein and mRNA expression levels of MBP and CNP in the prefrontal cortex of CUS-exposed animals, accompanied by a pronounced elevation in IL-1β expression. Therapeutic interventions with FLU, EE, or their combination significantly attenuated these CUS-induced molecular alterations.

Conclusions: The antidepressant effects correlated with restored MBP, CNP, and IL-1β expression levels, suggesting that MBP/CNP deficiencies in depression may involve IL-1β elevation. In particular, combined enriched environment and fluoxetine accelerated behavioral recovery.

Autism spectrum disorder (ASD) presents a wide range of cognitive and language impairments. In this study, we investigated the genetic basis of non-verbal status in ASD using a comprehensive genomic approach. We identified a novel common variant, rs1944180 in CNTN5, significantly associated with non-verbal status through family-based Transmission Disequilibrium Testing. Polygenic risk score (PRS) analysis further showed that higher ASD PRS was significantly linked to non-verbal status (p = 0.034), specific to ASD and not related to other conditions such as bipolar disorder, schizophrenia and three language-related traits. Using structural equation modeling (SEM), we found two causal SNPs, rs1247761 located in KCNMA1 and rs2524290 in RAB3IL1, linking ASD with language traits. The model indicated a unidirectional effect, with ASD driving language impairments. Additionally, de novo mutations (DNMs) were found to be related with ASD and interaction between common variants and DNMs significantly impacted non-verbal status (p = 0.038). Our findings also identified 5 high-risk ASD genes, and DNMs were enriched in glycosylation-related pathways. These results offer new insights into the genetic mechanisms underlying language deficits in ASD.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects dopaminergic neurons in the substantia nigra pars compacta. It is a complex disease that is strongly influenced by environmental and genetic factors. While the exact causes of PD are not well understood, research on the effects of toxic substances that induce neuronal death has shed some light on the etiology of the disease. In addition, studies have implicated protein aggregation and impaired mitochondrial, endoplasmic reticulum (ER), proteasome, and/or lysosomal function in the pathogenesis of PD. This review focuses on the alterations in intraneuronal organelles and the role of toxic agents that lead to organelle damage and neurodegeneration that characterize PD. We describe in vivo and in vitro models that have been used to elucidate the factors that lead to the death of dopaminergic neurons and summarize the molecular mechanisms that may underlie the changes that promote neurodegeneration. A deeper understanding of the mechanisms of neuronal death may help us to develop new therapies and interventions to delay or prevent the progression of PD.

Background: Ligand of NUMB protein-X 1 (LNX1) and LNX2 proteins are closely related PDZ domain-containing E3 ubiquitin ligases that interact with and potentially modulate numerous synaptic and neurodevelopmentally important proteins. While both LNX1 and LNX2 are expressed in neurons, it is noteworthy that neuronal LNX1 isoforms lack the catalytic domain responsible for ubiquitination of substrates. Thus, the shared interaction partners of LNX1 and LNX2 might be differentially regulated by these proteins, with LNX1 acting as a stabilizing scaffold while LNX2 may promote their ubiquitination and degradation. Despite the identification of many LNX interacting proteins and substrates, our understanding of the distinct in vivo functions of LNX1 and LNX2 remains very incomplete.

Results: We previously reported that mice lacking both LNX1 in the central nervous system and LNX2 globally exhibit decreased anxiety-related behaviour. Here we significantly extend this work by examining anxiety-related and risk-taking behaviours in Lnx1^-/- and Lnx2^-/- single knockout animals for the first time and by analysing previously unexplored aspects of behaviour in both single and double knockout animals. While the absence of both LNX1 and LNX2 contributes to the decreased anxiety-related behaviour of double knockout animals in the open field and elevated plus maze tests, the elimination of LNX2 plays a more prominent role in altered behaviour in the dark-light emergence test and wire beam bridge risk-taking paradigms. By contrast, Lnx knockout mice of all genotypes were indistinguishable from wildtype animals in the marble burying, stress-induced hyperthermia and novel object recognition tests. Analysis of the ultrasonic vocalizations of pups following maternal separation revealed significant differences in call properties and vocal repertoire for Lnx1^-/- and Lnx1^-/-;Lnx2^-/- double knockout animals. Finally, decreased body weight previously noted in double knockout animals could be attributed largely to Lnx1 gene knockout.

Conclusions: These results identify specific roles of LNX1 and LNX2 proteins in modulating distinct aspects of anxiety and risk-taking behaviour and social communication in mice. They also reveal an unexpected role for neuronally expressed LNX1 isoforms in determining body weight. These novel insights into the differential neuronal functions of LNX1 and LNX2 proteins provide a foundation for mechanistic studies of these phenomena.

Background: Cerebral large artery and small vessel diseases are considered substrates of neurological disorders. We explored how the mechanisms of neurovascular uncoupling, dysfunctional blood-brain-barrier (BBB), compromised glymphatic pathway, and impaired cerebrovascular reactivity (CVR) and autoregulation, identified through diverse neuroimaging techniques, impact cerebral large artery and small vessel diseases.

Methods: Studies (1990-2024) that reported on neuroradiological findings on ageing-related cerebral large artery and small vessel diseases were reviewed. Fifty-two studies involving 23,693 participants explored the disease mechanisms, 9 studies (sample size = 3,729) of which compared metrics of cerebrovascular functions (CF) between participants with cerebral large artery and small vessel diseases (target group) and controls with no vascular disease. Measures of CF included CVR, cerebral blood flow (CBF), blood pressure and arterial stiffness.

Results: The findings from 9 studies (sample size = 3,729, mean age = 60.2 ± 11.5 years), revealed negative effect sizes of CVR [SMD = - 1.86 (95% CI - 2.80, - 0.92)] and CBF [SMD = - 2.26 (95% CI - 4.16, - 0.35)], respectively indicating a reduction in cerebrovascular functions in the target group compared to their controls. Conversely, there were significant increases in the measures of blood pressure [SMD = 0.32 (95% CI 0.18, 0.46)] and arterial stiffness [SMD = 0.87 (95% CI 0.77, 0.98)], which signified poor cerebrovascular functions in the target group. In the combined model the overall average effect size was negative [SMD = - 0.81 (95% CI - 1.53 to - 0.08), p < 0.001]. Comparatively, this suggests that the negative impacts of CVR and CBF reductions significantly outweighed the effects of blood pressure and arterial stiffness, thereby predominantly shaping the overall model. Against their controls, trends of reduction in CF were observed exclusively among participants with cerebral large artery disease (SMD = - 2.09 [95% CI: - 3.57, - 0.62]), as well as those with small vessel diseases (SMD = - 0.85 [95% CI - 1.34, - 0.36]). We further delineated the underlying mechanisms and discussed their interconnectedness with cognitive impairments.

Conclusion: In a vicious cycle, dysfunctional mechanisms in the glymphatic system, neurovascular unit, BBB, autoregulation, and reactivity play distinct roles that contribute to reduced CF and cognitive risk among individuals with cerebral large artery and/or small vessel diseases. Reduction in CVR and CBF points to reductions in CF, which is associated with increased risk of cognitive impairment among ageing populations ≥ 60 years.

The health risks associated with acute noise exposure are increasing, particularly the risk of mental health. This study aims to identify the association between acute high-intensity noise exposure and anxiety behavior in male rats, and to explore the associated neurobiological mechanisms. Male rats were subjected to different levels of acute high-intensity noise to determine the intensity that causes long-lasting anxiety-like behaviors. Anxiety-like behaviors were evaluated using the open field test (OFT) and the elevated plus maze test (EPMT) on the third day and 1month post-exposure, respectively. A range of techniques, including immunofluorescence staining, western blot, ELISA, and real-time quantitative PCR, were used to investigate neuronal apoptosis, glial cell activation, neuroinflammation, and blood-brain barrier (BBB) disruption in the hippocampus. Upon exposure to 135 dB of acute noise, male rats exhibited enduring anxiety-like behaviors. Subsequent investigations discovered that this noise intensity not only activated glial cells and triggered neuroinflammation within the hippocampus but also decreased the expression levels of ZO-1, claudin-5, and occludin, suggesting a disruption of the BBB. Additionally, this exposure was associated with the induction of neuronal apoptosis in the hippocampal region. In conclusion, acute exposure to 135 dB noise may cause persistent anxiety in male rats through a cyclical interaction between neuroinflammation and BBB disruption, potentially leading to neuronal apoptosis.