Behavioral and Brain Functions最新文献

Background: Parkinson's disease (PD) is an incurable neurological disorder, and current pharmacological therapies primarily address symptoms without halting disease progression. Emerging evidence highlights PD as a neuroinflammatory disease, with chronic brain inflammation preceding the onset of motor dysfunction. This study investigates the role of C18:0 GM3, a long-chain fatty acids-containing ganglioside, in modulating inflammatory responses in PD, exploring its therapeutic potential in mitigating LPS-induced parkinsonism.

Methods: Male C57BL/6 mice were utilized in an LPS-induced PD model to evaluate the neuroprotective effects of C18:0 GM3 ganglioside. Pre-treatment with C18:0 GM3 was assessed through behavioral tests, including rotarod and beam-walking, to determine motor function improvements. Dopaminergic neurotoxicity was quantified using [¹⁸F]FE-PE2I positron emission tomography (PET) imaging and tyrosine hydroxylase (TH) staining. The anti-inflammatory and anti-gliosis effects of C18:0 GM3 were analyzed by measuring cytokine levels (IL-1β, TNF-α) and by assessing Iba1 and GFAP immunoreactivity as indicators of microglial and astrocytic changes, respectively.

Results: Pre-treatment with C18:0 GM3 ganglioside significantly enhanced motor coordination and balance, as evidenced by improved performance in rotarod and beam-walking tests. Furthermore, C18:0 GM3 ganglioside effectively attenuated LPS-induced dopaminergic neurotoxicity, evidenced by increased striatal dopamine transporter availability on [¹⁸F]FE-PE2I PET imaging and the preservation of TH-positive neurons in the striatum. In addition, C18:0 GM3 markedly suppressed the expression of pro-inflammatory cytokines, including IL-1β and TNF-α, along with cyclooxygenase-2 levels. C18:0 GM3 also reduced gliosis, as demonstrated by a decrease in Iba1-positive microglial cells and GFAP-positive astrocytes.

Conclusion: Our data indicate that C18:0 GM3 primarily attenuates the TLR4-driven inflammatory cascade initiated by intrastriatal LPS, thereby secondarily preserving striatal dopaminergic terminals and improving motor deficits. Although these results highlight anti-inflammatory neuroprotection, additional studies are required to determine whether GM3 also modulates downstream Parkinson-specific processes such as α-synuclein aggregation or progressive neurodegeneration.

Background: Mu-opioid receptors (MORs) are critical regulators mediating the modulation of several behavioral reactions, including analgesia, addiction, and sedation. Recent studies have reported that MORs are closely associated with mood disorders or anxiety behaviors; however, the underlying neural mechanisms remain unclear. The periaqueductal gray (PAG), a key brain area, participates in the modulation of aversive emotional behaviors. MORs show a high expression in the ventrolateral PAG (vlPAG) region. This study explored the preliminary role of MORs expressed in the vlPAG in modulating emotional behaviors.

Results: Bilateral administration of DAMGO, an MOR-specific agonist, into the vlPAG of male mice elicited anxiety-like behaviors in elevated plus maze tests. This phenotype was reversed by conditional knockdown of astrocytic MORs. In contrast, glutamatergic or GABAergic MORs were not involved in vlPAG MOR-dependent anxiety-like behaviors. By using in vitro calcium imaging of vlPAG astrocytes and chemical genetic technologies, we found that vlPAG astrocytic MORs can promote astrocytic calcium signaling, which can efficiently induce anxiety-like behaviors. Accordingly, the interference of astrocytic calcium signaling by viral infection reversed vlPAG-dependent anxiety-like behaviors.

Conclusion: Our findings demonstrated that vlPAG astrocytic, but not glutamatergic or GABAergic, MORs are involved in modulating emotional reactions, and these effects are accomplished by MOR-elicited astrocytic calcium signaling mechanisms. The present study provides a theoretical basis for treating emotional dysfunctions during MOR-targeted management.

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.

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.

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.

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.