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Activation of cell-free mtDNA-TLR9 signaling mediates chronic stress-induced social behavior deficits.

ABSTRACT: Inflammation and social behavior deficits are associated with a number of neuropsychiatric disorders. Chronic stress, a major risk factor for depression and other mental health conditions is known to increase inflammatory responses and social behavior impairments. Disturbances in mitochondria function have been found in chronic stress conditions, however the mechanisms that link mitochondrial dysfunction to stress-induced social behavior deficits are not well understood. In this study, we found that chronic restraint stress (RS) induces significant increases in serum cell-free mitochondrial DNA (cf-mtDNA) levels in mice, and systemic Deoxyribonuclease I (DNase I) treatment attenuated RS-induced social behavioral deficits. Our findings revealed potential roles of mitophagy and Mitochondrial antiviral-signaling protein (MAVS) in mediating chronic stress-induced changes in cf-mtDNA levels and social behavior. Furthermore, we showed that inhibition of Toll-like receptor 9 (TLR9) attenuates mtDNA-induced social behavior deficits. Together, these findings show that cf-mtDNA-TLR9 signaling is critical in mediating stress-induced social behavior deficits.

SUBMITTER: Tripathi A

PROVIDER: S-EPMC10730412 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Activation of cell-free mtDNA-TLR9 signaling mediates chronic stress-induced social behavior deficits.

Tripathi Ashutosh A Bartosh Alona A Whitehead Carl C Pillai Anilkumar A

Molecular psychiatry 20230801 9

Inflammation and social behavior deficits are associated with a number of neuropsychiatric disorders. Chronic stress, a major risk factor for depression and other mental health conditions is known to increase inflammatory responses and social behavior impairments. Disturbances in mitochondria function have been found in chronic stress conditions, however the mechanisms that link mitochondrial dysfunction to stress-induced social behavior deficits are not well understood. In this study, we found ...[more]

PMID: 37528226

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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.

Dataset Information

Activation of cell-free mtDNA-TLR9 signaling mediates chronic stress-induced social behavior deficits.

Publications

Activation of cell-free mtDNA-TLR9 signaling mediates chronic stress-induced social behavior deficits.

Similar Datasets

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