Behavioral And Brain Functions[JOURNAL]
Sun
200 papers
Chronic lipopolysaccharide exposure promotes cognitive impairments by activating TRPC6-AIM2 inflammasome signaling and the regulation of ginsenoside Rg1 in Trpc6 mice.
Fu Y, Zhang H, Zhu X … +5 more , Liang H, Fan L, Su Y, Li W, Li W
Behav Brain Funct · 2025 Jul · PMID 40696361 · Full text
BACKGROUND: Chronic neuroinflammation is a pivotal pathogenesis in neurodegenerative diseases (NDDs). Transient receptor potential canonical protein 6 (TRPC6) has an essential role in the maintenance of calcium homeostas...
BACKGROUND: Chronic neuroinflammation is a pivotal pathogenesis in neurodegenerative diseases (NDDs). Transient receptor potential canonical protein 6 (TRPC6) has an essential role in the maintenance of calcium homeostasis in cells. Our previous study indicated that TRPC6 signaling is involved in Aβ deposition and NLRP1 inflammasome activation in type 2 diabetes mellitus-associated cognitive dysfunction. However, whether TRPC6 signaling contributes to chronic lipopolysaccharide (LPS)-induced neuroinflammatory injury and the mechanism remain unclear. METHODS: In this study, male mice received intraperitoneal injections of LPS (200 µg/kg) for 21 days to induce a chronic neuroinflammation model. The open field test, hole-board test, and Morris water maze were conducted to evaluate cognitive function. The H&E and Nissl staining was employed to examine neuronal injury. The immunofluorescence, western blotting, or q-PCR were used to analyze TRPC6, AIM2 inflammasome expression, and Nrf2 activation. The fluorescent probes and calcium imaging were performed to assess ROS accumulation and calcium dysregulation in LPS-induced HT22 neuron cells. RESULTS: Chronic LPS exposure induced behavioral deficits in locomotion, exploratory behavior, and learning and memory, and neuronal damages with less expressions of PSD95 and Synaptophysin in mice. Mechanistically, LPS exposure significantly increased ROS production, TRPC6 expression and calcium overload, and induced AIM2 inflammasome activation in vivo or in vitro. While Trpc6 knockout could significantly improve LPS-induced cognitive dysfunction and neuronal injuries, inhibit TRPC6-mediated calcium overload, and downregulate the expressions of AIM2, caspase-1, IL-1β, IL-6, caspase-3 and Bax in vivo or in vitro. Additionally, Rg1 treatment significantly inhibited calcium overload and AIM2 inflammasome activation in LPS-induced HT22 cells. More importantly, Rg1 significantly activated Nrf2 signaling and reduced ROS production in LPS-induced mice or HT22 cells. CONCLUSIONS: Trpc6 knockout can improve chronic LPS-induced neuroinflammation and injury by inhibiting TRPC6-AIM2 inflammasomes. While Rg1 treatment can alleviate LPS-induced neuroinflammation and injury not only by inhibiting TRPC6-AIM2 inflammasomes activation but also activating Nrf2 signaling.
Knockout of Bmal1 in dopaminergic neurons induces ADHD-like symptoms via hyperactive dopamine signaling in male mice.
Zhang Y, Li X, Liu Y … +7 more , Li X, Liu D, Han Q, Liu X, Wang X, Li JD, Deng S
Behav Brain Funct · 2025 Jul · PMID 40646562 · Full text
BACKGROUND: The central circadian clock coordinates daily oscillations in physiology, metabolism and behavior. Disruptions to core circadian clock genes not only perturb sleep-wake rhythms but also contribute to psychiat...
BACKGROUND: The central circadian clock coordinates daily oscillations in physiology, metabolism and behavior. Disruptions to core circadian clock genes not only perturb sleep-wake rhythms but also contribute to psychiatric disorders. While dopaminergic dysfunction is strongly associated with mental illnesses, the mechanistic connection between circadian clock genes and dopamine signaling remains elusive. In the current study, we directly examine the role of the core circadian gene Bmal1 in dopamine neurons, investigating its effects on behavioral outcomes and dopamine signaling. RESULTS: Bmal1 conditional knockout (cKO) mice specific to dopamine neuron were generated by crossing Bmal1-flox strain with the Dat-Cre strain, with knockout efficiency validated through immunofluorescence. BMAL1 deficiency in dopaminergic neurons induces attention-deficit hyperactivity disorder (ADHD)-like phenotypes, including hyperactivity, impairments in attention and working memory. Dopamine sensor detection revealed increased dopamine release in Bmal1-cKO mice. Additionally, electrophysiological recording showed that striatal neurons in Bmal1 knockout mice exhibited increased neuronal excitability. Amphetamine and dopamine D1 receptor antagonist SCH23390 treatment attenuated the hyperactivity behavior in cKO mice. CONCLUSIONS: This study finds that BMAL1 ablation in dopaminergic neurons induces ADHD-like phenotypes in male mice, identifying hyperactive dopamine signaling as a potential mediator of these phenotypes. It unveils a novel role for BMAL1 in regulating dopamine signaling and provide insights into circadian gene-driven psychiatric pathophysiology.
Impaired theta and low-gamma directed information flow in the hippocampal-prefrontal circuit underlies working memory deficits in APP/PS1 mice.
Ai H, Zhang S, Si C … +4 more , Liu T, Zheng X, Tian X, Bai W
Behav Brain Funct · 2025 Jul · PMID 40618096 · Full text
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Working memory impairment, a hallmark of early-stage AD, is hypothesized to arise from deficits in encoding process...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Working memory impairment, a hallmark of early-stage AD, is hypothesized to arise from deficits in encoding processes. Given the critical role of hippocampal-prefrontal interactions in working memory, we investigated whether disrupted encoding mechanisms in this circuit contribute to AD-related deficits. We performed simultaneous local field potential (LFP) recordings in the ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC) of APP/PS1 transgenic mice during a spatial working memory task. We analyzed oscillatory dynamics and directed information flow between these two regions across distinct task phases. Wild-type mice exhibited task-phase-specific enhancement of theta (4-12 Hz) and low-gamma (30-40 Hz) information flow from vHPC to mPFC during encoding, which correlated with performance accuracy. APP/PS1 mice showed a significant reduction in the theta and low-gamma flow and impaired task performance. Decoding analyses revealed a robust correlation between the strength of directed information flow and performance accuracy. These findings provide compelling evidence for a neurophysiological mechanism linking vHPC-mPFC circuit dynamics to encoding processes, offering new insights into the neural basis of working memory impairment in AD.
Behavioral phenotyping identifies autism-like repetitive stereotypies in a Tsc2 haploinsufficient rat model.
Ramme A, Zachow M, Habelt B … +4 more , Vojtechova I, Petrasek T, Waltereit R, Bernhardt N
Behav Brain Funct · 2025 Jul · PMID 40611277 · Full text
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 s...
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.
Gper1 inhibition exacerbates traumatic brain injury-induced neurological impairments in mice.
Xue YF, Wu YX, Zhang YZ … +1 more , Zhao TZ
Behav Brain Funct · 2025 Jul · PMID 40605012 · Full text
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 i...
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) 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 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.
FTO (fat-mass and obesity-associated protein) deficiency aggravates age-dependent depression-like behaviors and cognitive impairment.
Li M, Yang Y, Chen T … +4 more , Luo Y, Zhang Y, Liu H, Maes M
Behav Brain Funct · 2025 Jun · PMID 40518522 · Full text
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 dys...
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.
The gut microbiome and metabolomic alterations underlying colitis-induced encephalopathy in mice: mechanistic insight.
Cai A, Shen D, Xiong Q … +9 more , Li S, Qiu C, Li L, Chen Z, Lin X, Yao Q, Zhang Y, Chen R, Kou L
Behav Brain Funct · 2025 Jun · PMID 40506791 · Full text
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 frequ...
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.
Combined enriched environment and fluoxetine enhance myelin protein expression in the prefrontal cortex of a chronic unpredictable stress depression model.
Gu J, Liu C, Li Y … +8 more , Feng L, Geng M, Dong J, Han J, Zhao L, Shao Q, Wang HY, Wang CH
Behav Brain Funct · 2025 Jun · PMID 40500721 · Full text
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 depres...
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.
Unraveling genetic risk contributions to nonverbal status in autism spectrum disorder probands.
Liu H, Wang S, Cao B … +17 more , Zhu J, Huang Z, Li P, Zhang S, Liu X, Yu J, Huang Z, Lv L, Cai F, Liu W, Song Z, Liu Y, Pang T, Chang S, Chen Y, Chen J, Chen WX
Behav Brain Funct · 2025 Jun · PMID 40483526 · Full text
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 identifi...
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.
Neurodegeneration models in Parkinson's disease: cellular and molecular paths to neuron death.
Álvarez-Luquín DD, González-Fernández RR, Torres-Velasco ME … +6 more , Ichikawa-Escamilla E, Arce-Sillas A, Martínez-Martínez E, Miranda-Narvaez CL, Rodríguez-Ramírez JF, Adalid-Peralta L
Behav Brain Funct · 2025 May · PMID 40450319 · Full text
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 genet...
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.
Differential neuronal functions of LNX1 and LNX2 revealed by behavioural analysis in single and double knockout mice.
Cioccarelli L, Lenihan JA, Erwin LG … +1 more , Young PW
Behav Brain Funct · 2025 Apr · PMID 40269869 · Full text
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 import...
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.
Imaging-validated correlates and implications of the pathophysiologic mechanisms of ageing-related cerebral large artery and small vessel diseases: a systematic review and meta-analysis.
Ackah JA, Li X, Zeng H … +1 more , Chen X
Behav Brain Funct · 2025 Apr · PMID 40264233 · Full text
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), compro...
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.
Acute high-intensity noise exposure exacerbates anxiety-like behavior via neuroinflammation and blood brain barrier disruption of hippocampus in male rats.
Song Y, Zhang H, Wang X … +6 more , Huang L, Kang Y, Feng Z, Zhao F, Zhuang H, Zhang J
Behav Brain Funct · 2025 Apr · PMID 40264210 · Full text
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 i...
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.
A comprehensive review on the impact of polyphenol supplementation and exercise on depression and brain function parameters.
Jie S, Fu A, Wang C … +1 more , Rajabi S
Behav Brain Funct · 2025 Mar · PMID 40140839 · Full text
The objective of this review study is to examine the combined antidepressant effects of exercise and polyphenol supplementation, with a focus on specific polyphenolic compounds such as crocin, curcumin, and quercetin, as...
The objective of this review study is to examine the combined antidepressant effects of exercise and polyphenol supplementation, with a focus on specific polyphenolic compounds such as crocin, curcumin, and quercetin, as well as different forms of physical exercise, including aerobic and resistance training. The research examines how these interventions influence depressive-like behaviors, cognitive function, and neurochemical markers in animal models and human participants. The findings demonstrate that both exercise and polyphenols independently contribute to mood enhancement, reduced anxiety, and improved cognitive function through mechanisms such as neurogenesis, neurotransmitter modulation, and anti-inflammatory effects. Notably, the combined interventions showed a synergistic effect, providing more significant benefits in reducing symptoms of depression and anxiety, enhancing cognitive performance, and supporting overall mental well-being. These results suggest that integrating exercise and polyphenol supplementation could be a promising non-pharmacological approach to managing depression and related disorders.
The role of cerebellar-cortical connectivity in modulating attentional abilities: insight from football athletes.
Wang J, Gao S, Tian J … +2 more , Hong H, Zhou C
Behav Brain Funct · 2025 Mar · PMID 40128842 · Full text
Neuroplasticity, a phenomenon present throughout the lifespan, is thought to be influenced by physical training. However, the relationship between neuroplastic differences and attentional abilities remains unclear. This...
Neuroplasticity, a phenomenon present throughout the lifespan, is thought to be influenced by physical training. However, the relationship between neuroplastic differences and attentional abilities remains unclear. This study explored the differences in brain function and attentional abilities between professional football athletes and novices, and further investigated the relationship between the two. To address this question, we included 49 football athletes and 63 novices in our study, collecting data on resting-state functional connectivity and Attention Network Test (ANT). Behavioral results from the ANT indicated that football experts had superior orienting attention but weaker alerting functions compared to novices, with no difference in executive control attention. fMRI results revealed that football experts exhibited higher fractional Amplitude of Low-Frequency Fluctuations (fALFF) values in the bilateral anterior cerebellar lobes, bilateral insula, and left superior temporal gyrus. Functional connectivity analysis showed increased connectivity between the left anterior cerebellar lobe and various cortical regions, including the right supramarginal gyrus, left precuneus, left superior frontal gyrus, bilateral posterior cerebellar lobes, and bilateral precentral gyri in experts compared to novices. More importantly, in the expert group but not in novice group, functional connectivity differences significantly predicted attentional orienting scores. Graph theoretical analysis showed that experts exhibited higher betweenness centrality and node efficiency in the right cerebellar lobule III (Cerebelum_3_R) node. Our findings demonstrate that long-term professional football training may significantly affect neuroplasticity and attentional functions. Importantly, our analysis reveals a substantive connection between these two aspects, suggesting that the integration of neuroplastic and attentional changes is likely mediated by cerebellar-cortical connectivity.
Neonatal maternal separation causes depressive-like behavior and potentiates memory impairment induced by amyloid-β oligomers in adult mice.
Suman PR, Kincheski GC, Frozza RL … +2 more , De Felice FG, Ferreira ST
Behav Brain Funct · 2025 Mar · PMID 40114204 · Full text
BACKGROUND: Alzheimer's disease (AD) is characterized by memory decline and mood alterations. A growing body of evidence implicates stress and other social determinants of health as potential contributors to the progress...
BACKGROUND: Alzheimer's disease (AD) is characterized by memory decline and mood alterations. A growing body of evidence implicates stress and other social determinants of health as potential contributors to the progressive cerebral alterations that culminate in AD. In the current study, we investigated the impact of neonatal maternal separation (MS) on the susceptibility of male and female mice to AD-associated memory impairments and depressive-like behavior in adulthood, and on brain levels of pro-inflammatory cytokines and neurotransmitters. METHODOLOGY: Male and female Swiss mice were exposed to MS for 180 min daily from post-natal day 1 to 10. Seventy days post-MS, mice received an intracerebroventricular infusion of amyloid-β oligomers (AβOs), and memory and mood were evaluated. Levels of TNF-α, IL-1β, serotonin, dopamine, and related metabolites were determined in the cortex and hippocampus. RESULTS: Previous exposure to MS alone did not cause memory impairments in adult mice. Interestingly, however, MS increased the susceptibility of adult male mice to memory impairment and depressive-like behavior induced by AβOs, and potentiated the inhibitory impact of AβOs on memory in adult females. Females were more susceptible to depressive-like behavior caused by a low dose of AβOs, regardless of MS. No changes in IL-1β were found. A decrease in TNF-α was selectively found in females exposed to MS that received an infusion of 1 pmol AβOs. MS led to an increase in serotonin (5-HT) in the hippocampus of male mice, without influencing the levels of the serotonin metabolite, 5-HIAA. Changes in serotonin turnover were predominantly observed in the cortex of female mice. No changes in dopamine or its metabolites were induced by MS or AβOs in male or female mice. CONCLUSIONS: Neonatal MS enhances the susceptibility of adult mice to AD-associated cognitive deficits and depressive-like behavior in a sex-specific manner. This suggests that early life stress may play a role in the development of AD.
Improving effects of melatonin on memory and synaptic potentiation in a mouse model of Alzheimer's-like disease: the involvement of glutamate homeostasis and mGluRs receptors.
Shabani Sadr NK, Bakhtiarzadeh F, Shahpasand K … +2 more , Mirnajafi-Zadeh J, Behmanesh M
Behav Brain Funct · 2025 Mar · PMID 40102986 · Full text
BACKGROUND: Alzheimer's disease (AD) is characterized by progressive cognitive decline and synaptic dysfunction, largely driven by amyloid plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. T...
BACKGROUND: Alzheimer's disease (AD) is characterized by progressive cognitive decline and synaptic dysfunction, largely driven by amyloid plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. These pathological hallmarks disrupt glutamate signaling, which is essential for synaptic plasticity and memory consolidation. This study investigates the therapeutic potential of melatonin on memory and synaptic plasticity in an AD-like mouse model, with a focus on its regulatory effects on glutamate homeostasis and metabotropic glutamate receptors (mGluRs). METHODS: The study began with an in-silico bioinformatics analysis of RNA-seq datasets from hippocampal tissues of AD patients to identify differentially expressed genes (DEGs) related to glutamate signaling and tau pathology. An AD-like model was induced via intra-hippocampal injection of cis-phospho tau in C57BL/6 mice. Memory function was assessed using behavioral tests. Synaptic plasticity was evaluated using in vitro field potential recording of hippocampal slices. Histological analyses included Nissl staining for neuronal density, Luxol Fast Blue for myelin integrity, and immunofluorescence for tau hyperphosphorylation. Molecular studies employed qPCR and Western blot to assess glutamate-related markers and tau phosphorylation. Melatonin (10 mg/kg) was administered intraperitoneally, starting either two weeks (early intervention) or four weeks (late intervention) post-induction. RESULTS: Key molecular targets in glutamate signaling pathways were identified using bioinformatics. AD-like mice displayed memory deficits and synaptic dysfunction. Melatonin improved cognitive function, especially with early intervention, as confirmed by behavioral tests. Histological studies revealed reduced neuronal loss, improved myelin integrity, and decreased tau hyperphosphorylation. Molecular findings showed restored mGluR expression and reduced GSK3 activity. Early intervention yielded superior outcomes, with partial restoration of synaptic plasticity observed in LTP recordings. CONCLUSIONS: These findings underscore the neuroprotective properties of melatonin, mediated by its ability to modulate glutamate signaling and mGluR activity, offering new insights into its potential as a therapeutic agent for AD. Additionally, the results suggest that earlier administration of melatonin may significantly enhance its efficacy, highlighting the importance of timely intervention in neurodegenerative diseases.
Dopamine D1 receptor agonist alleviates post-weaning isolation-induced neuroinflammation and depression-like behaviors in female mice.
Zhao ZW, Wang YC, Chen PC … +3 more , Tzeng SF, Chen PS, Kuo YM
Behav Brain Funct · 2025 Mar · PMID 40065395 · Full text
BACKGROUND: Major depressive disorder is a significant global cause of disability, particularly among adolescents. The dopamine system and nearby neuroinflammation, crucial for regulating mood and processing rewards, are...
BACKGROUND: Major depressive disorder is a significant global cause of disability, particularly among adolescents. The dopamine system and nearby neuroinflammation, crucial for regulating mood and processing rewards, are central to the frontostriatal circuit, which is linked to depression. This study aimed to investigate the effect of post-weaning isolation (PWI) on depression in adolescent mice, with a focus on exploring the involvement of microglia and dopamine D1 receptor (D1R) in the frontostriatal circuit due to their known links with mood disorders. RESULTS: Adolescent mice underwent 8 weeks of PWI before evaluating their depression-like behaviors and the activation status of microglia in the frontostriatal regions. Selective D1-like dopamine receptor agonist SKF-81,297 was administered into the medial prefrontal cortex (mPFC) of PWI mice to assess its antidepressant and anti-microglial activation properties. The effects of SKF-81,297 on inflammatory signaling pathways were examined in BV2 microglial cells. After 8 weeks of PWI, female mice exhibited more severe depression-like behaviors than males, with greater microglial activation in the frontostriatal regions. Microglial activation in mPFC was the most prominent among the three frontostriatal regions examined, and it was positively correlated with the severity of depression-like behaviors. Female PWI mice exhibited increased expression of dopamine D2 receptors (D2R). SKF-81,297 treatment alleviated depression-like behaviors and local microglial activation induced by PWI; however, SKF-81,297 induced these alterations in naïve mice. In vitro, SKF-81,297 decreased pro-inflammatory cytokine release and phosphorylations of JNK and ERK induced by lipopolysaccharide, while in untreated BV2 cells, SKF-81,297 elicited inflammation. CONCLUSIONS: This study highlights a sex-specific susceptibility to PWI-induced neuroinflammation and depression. While targeting the D1R shows potential in alleviating PWI-induced changes, further investigation is required to evaluate potential adverse effects under normal conditions.
Investigating the role of the brain-derived neurotrophic factor Val66Met polymorphism in repetitive mild traumatic brain injury outcomes in rats.
Giesler LP, O'Brien WT, Bain J … +6 more , Spitz G, Jaehne EJ, van den Buuse M, Shultz SR, Mychasiuk R, McDonald SJ
Behav Brain Funct · 2025 Mar · PMID 40045366 · Full text
BACKGROUND: Mild traumatic brain injury (mTBI) poses a significant public health concern, particularly regarding repetitive injury, with outcomes ranging from acute neurobehavioral deficits to long-term impairments. Whil...
BACKGROUND: Mild traumatic brain injury (mTBI) poses a significant public health concern, particularly regarding repetitive injury, with outcomes ranging from acute neurobehavioral deficits to long-term impairments. While demographic factors like age and sex influence outcomes, the understanding of genetic contributions, particularly the role of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, remains limited. This study aimed to characterize acute effects of repetitive mTBI (rmTBI) in rats with the Val68Met SNP, the rodent equivalent of the human Val66Met, focusing on behavioral, fluid biomarker, and histological changes. METHODS: Using a closed-head injury model, rats underwent five mTBIs over consecutive days. Behavioral assessments included sensorimotor function, anxiety-like behavior, spatial learning and memory, and nociceptive response. Plasma neurofilament light (NfL) levels served as a biomarker of axonal injury and immunohistochemistry evaluated microglial activation. RESULTS: Sensorimotor deficits and increased anxiety-like behavior were found in rats with rmTBI, but these changes were not affected by sex or genotype. Plasma NfL levels were higher in rmTBI compared with sham rats, with levels greater in female rmTBI when compared with male rmTBI rats. Microglial activation was observed in the hypothalamus of injured rats, but was not influenced by genotype or sex. CONCLUSIONS: While the Val68Met SNP did not significantly influence acute responses to rmTBI in this study, further investigation into alternative functional and pathophysiological outcomes, as well as long-term effects, is required.
Effects of TrkB-related induced metaplasticity within the BLA on anxiety, extinction learning, and plasticity in BLA-modulated brain regions.
Hazra JD, Shrivastava K, Wüstner LS … +8 more , Anunu R, Chervinsky E, Hazra S, Beuter S, Kriebel M, Maroun M, Volkmer H, Richter-Levin G
Behav Brain Funct · 2025 Mar · PMID 40033342 · Full text
BACKGROUND: Neuronal plasticity within the basolateral amygdala (BLA) is fundamental for fear learning. Metaplasticity, the regulation of plasticity states, has emerged as a key mechanism mediating the subsequent impact...
BACKGROUND: Neuronal plasticity within the basolateral amygdala (BLA) is fundamental for fear learning. Metaplasticity, the regulation of plasticity states, has emerged as a key mechanism mediating the subsequent impact of emotional and stressful experiences. After mRNA knockdown of synaptic plasticity-related TrkB, we examined the impact of chronically altered activity in the rat BLA (induced metaplasticity) on anxiety-like behavior, fear memory-related behaviors, and neural plasticity in brain regions modulated by the BLA. These effects were investigated under both basal conditions and following exposure to acute trauma (UWT). RESULTS: Under basal conditions, TrkB knockdown increased anxiety-like behavior and impaired extinction learning. TrkBKD also reduced LTP in the vSub-mPFC pathway but not in the dentate gyrus. Compared with those of control animals, acute trauma exposure led to increased anxiety-like behavior and impaired extinction learning in both the trauma-exposed group (CTR-UWT) and the trauma-exposed group on the background of TrkB knockdown (TrkBKD-UWT). However, the deficit in extinction learning was more pronounced in the TrkBKD-UWT group than in the CTR-UWT group. Accordingly, TrkBKD-UWT, but not CTR-UWT, resulted in impaired LTP in the vSub- mPFC pathway. Since LTP in this pathway is independent of BLA involvement, this result suggests that lasting intra-BLA-induced metaplasticity may also lead to transregional metaplasticity within the mPFC, as suggested previously. CONCLUSIONS: Taken together, these findings reveal the dissociative involvement of BLA function, on the one hand, in anxiety, which is affected by the knockdown of TrkB, and, on the other hand, in extinction learning, which is more significantly affected by the combination of intra-BLA-induced metaplasticity and exposure to emotional trauma.
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