Project description:The goal of this study is to use bulk RNA-sequencing of to observe the effects of High Frequency Head Impacts contibuting to cognitive dysfunction in mice. Our results show HF-HI can alter brain function through synaptic adaptation. HF-HI mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling reveals that synapses are a primary target of this effect.
Project description:The goal of this study is to use bulk RNA-sequencing of to observe the effects of High Frequency Head Impacts contibuting to cognitive dysfunction in mice. Our results show HF-HI can alter brain function through synaptic adaptation. HF-HI mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling reveals that synapses are a primary target of this effect.
Project description:The goal of this study is to use bulk RNA-sequencing of to observe the effects of High Frequency Head Impacts contibuting to cognitive dysfunction in mice. Our results show HF-HI can alter brain function through synaptic adaptation. HF-HI mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling reveals that synapses are a primary target of this effect.
Project description:Repeated head impact exposure can cause memory and behavioral impairments. Here, we report that exposure to non-damaging, but high frequency, head impacts can alter brain function in mice through synaptic adaptation. High frequency head impact mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling of mouse and human chronic traumatic encephalopathy brain reveal that synapses are strongly affected by head impact. Electrophysiological analysis shows that high frequency head impacts cause chronic modification of the AMPA/NMDA ratio in neurons that underlie the changes to cognition. To demonstrate that synaptic adaptation is caused by head impact-induced glutamate release, we pretreated mice with memantine prior to head impact. Memantine prevents the development of the key transcriptomic and electrophysiological signatures of high frequency head impact, and averts cognitive dysfunction. These data reveal synapses as a target of high frequency head impact in human and mouse brain, and that this physiological adaptation in response to head impact is sufficient to induce chronic cognitive impairment in mice.
Project description:Neurotoxic damage resulting from lead pollution exposure constitutes a significant public health concern. The regulatory impact of lead (Pb) exposure on neuronal dendritic spine plasticity, a crucial mechanism for neuronal adaptation, warrants further investigation. To elucidate the role and mechanism of the Mitofilin-mtDNA axis in hippocampal synaptic plasticity and learning and memory impairment induced by lead exposure, in this study, both in vivo and in vitro models were subjected to chronic lead exposure. The results showed that the spatial learning and memory abilities of lead-exposed mice were significantly reduced. Furthermore, Western blotting and RT-PCR analyses demonstrated a significant down-regulation in the expression of the mitochondrial inner membrane protein Mitofilin. Extended exposure to lead has the potential to compromise the plasticity of dendritic spines within the CA1 region of hippocampal neurons and disrupt the structural integrity of neuronal mitochondria. Furthermore, lead exposure was associated with elevated levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in neurons. The study additionally demonstrated that the overexpression of Mitofilin ameliorated deficits in spatial learning and memory in mice subjected to chronic lead exposure. This overexpression also facilitated the normal formation of neuronal dendritic spines, preserved the structural integrity of the mitochondrial inner membrane, and mitigated mitochondrial damage. The study further revealed that the overexpression of Mitofilin markedly suppressed the release of mitochondrial DNA (mtDNA) in neurons subjected to chronic lead exposure, while concurrently reducing the expression levels of the inflammasome Nlrp3 and the inflammatory cytokine IL-1β. Additionally, there was a significant reduction in the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in lead-exposed neurons with Mitofilin overexpression. These findings suggest that the mitochondrial inner membrane protein Mitofilin may play a role in mediating synaptic plasticity impairment following chronic lead exposure through the regulation of mitochondrial function.
Project description:BackgroundPeople with multiple sclerosis (PwMS) experience various degrees of cognitive impairment (CI). Synaptic dysfunction may contribute to CI in PwMS but cerebrospinal fluid (CSF) synaptic biomarkers are unexplored in MS.ObjectiveTo assess the role of CSF synaptosomal-associated protein 25 (SNAP-25), β-synuclein, neurogranin and neurofilament light chain protein (NfL) in patients with early relapsing MS with and without CI.MethodsWe measured CSF SNAP-25, β-synuclein, and neurogranin in 48 untreated PwMS and 50 controls with other neurological diseases (ONDs) and tested their associations with neuropsychological and MRI data.ResultsCSF synaptic protein levels did not discriminate between MS subjects and patients with ONDs, with only SNAP-25 values being slightly increased in MS (p = 0.009). CSF synaptic markers were positively correlated with each other and with CSF NfL. Moreover, lower biomarker levels were found to be correlated with longer disease duration and lower brain volumes (especially of the thalamus). Moreover, we found significantly lower CSF SNAP-25 (p = 0.025), β-synuclein (p = 0.044), and neurogranin (p = 0.007) levels in PwMS with vs. without domain-specific cognitive impairment.ConclusionLower CSF synaptic biomarker levels were found in PwMS with longer disease duration and lower brain volumes and may identify PwMS at risk of CI.
