tracking-individual-running-metrics-mice-using-voluntary-wheel

Tracking Individual Running Metrics in Mice Using a Voluntary Wheel Running Protocol that Minimizes Social Isolation

Voluntary wheel running (VWR) in rodents is used to evaluate performance and endurance and to simulate exercise. In contrast to other exercise paradigms ...

Rowan University

Besides significant benefits to physical health, exercise promotes mental health, reduces symptoms of mental illness, and enhances psychological development. Exercise can offset the impact of chronic stress, which is a major precursor to the development of mental disorders. The effects of exercise on chronic stress-induced behaviors are contradictory in preclinical studies, primarily due to the lack of data and sex-specific investigations. We sought to evaluate the effects of exercise on chronic stress-induced behavioral changes in both male and female mice. Mice were subjected to an Unpredictable Chronic Mild Stress (UCMS) paradigm with accessibility to running wheels for 2 h daily. Physiological and behavioral evaluations were conducted throughout the stress paradigm to determine if exercise blunts the effects of UCMS. Chronic stress induced voluntary wheel running (VWR) and weight loss in male and female mice. Compared to males, increased VWR was reported in females who also regained their weight lost by the end of the UCMS protocol. Exercise promoted resilience to stress-induced hyponeophagia in the novelty-suppressed feeding test and increased sucrose consumption. Exercise induced a sex-specific reduction in immobility and avoidance behavior in the tail suspension and open field tests and increased exploratory behavior in the light-dark test. These results indicate that exercise can promote resilience to the behavioral effects of chronic stress in males and females, and can affect behavior independent of chronic stress.

Voluntary wheel running promotes resilience to the behavioral effects of unpredictable chronic mild stress in male and female mice.

The brain is the central organ of adaptation to stress because it perceives and determines threats that induce behavioral, physiological, and molecular responses. In humans, chronic stress manifests as an enduring consistent feeling of pressure and being overwhelmed for an extended duration. This can result in a persistent proinflammatory response in the peripheral and central nervous system (CNS), resulting in cellular, physiological, and behavioral effects. Compounding stressors may increase the risk of chronic-stress-induced inflammation, which can yield serious health consequences, including mental health disorders. This review summarizes the current knowledge surrounding the neuroinflammatory response in rodent models of chronic stress-a relationship that is continually being defined. Many studies investigating the effects of chronic stress on neuroinflammation in rodent models have identified significant changes in inflammatory modulators, including nuclear factor-κB (NF-κB) and toll-like receptors (TLRs), and cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6. This suggests that these are key inflammatory factors in the chronic stress response, which may contribute to the establishment of anxiety and depression-like symptoms. The behavioral and neurological effects of modulating inflammatory factors through gene knockdown (KD) and knockout (KO), and conventional and alternative medicine approaches, are discussed.

Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease.

Chronic stress is a major precursor to various neuropsychiatric disorders and is linked with increased inflammation in the brain. However, the bidirectional association between inflammation and chronic stress has yet to be fully understood. Astrocytes are one of the key inflammatory regulators in the brain, and the morphological change in reactive astrocytes serves as an important indicator of inflammation. In this study, we evaluated the sex-specific astrocyte response to chronic stress or systemic inflammation in key brain regions associated with mood disorders. We conducted the unpredictable chronic mild stress (UCMS) paradigm to model chronic stress, or lipopolysaccharide (LPS) injection to model systemic inflammation. To evaluate stress-induced morphological changes in astrocyte complexity, we measured GFAP fluorescent intensity for astrocyte expression, branch bifurcation by quantifying branch points and terminal points, branch arborization by conducting Sholl analysis, and calculated the ramification index. Our analysis indicated that chronic stress-induced morphological changes in astrocytes in all brain regions investigated. The effects of chronic stress were region and sex specific. Notably, females had greater stress or inflammation-induced astrocyte activation in the hypothalamus (HYPO), CA1, CA3, and amygdala (AMY) than males. These findings indicate that chronic stress induces astrocyte activation that may drive sex and region-specific effects in females, potentially contributing to sex-dependent mechanisms of disease.

Sex-dependent astrocyte reactivity: Unveiling chronic stress-induced morphological changes across multiple brain regions.

Opioid drugs have been long known to induce different responses in males compared to females, however, the molecular mechanisms underlying these effects are yet to be fully characterized. Recent studies have established a link between the gut microbiome and behavioral responses to opioids. Chronic opioid use is associated with gut dysbiosis, or microbiome disruptions, which is thought to contribute to altered opioid analgesia and reward processing. Gut microbiome composition and functioning have also been demonstrated to be influenced by sex hormones. Despite this, there is currently very little work investigating whether sex differences in the gut microbiome mediate sex-dependent responses to opioids, highlighting a critical gap in the literature. Here, we briefly review the supporting evidence implicating a potential role for the gut microbiome in regulating sexually dimorphic opioid response and identify areas for future research.

Article	Year
Voluntary wheel running promotes resilience to the behavioral effects of unpredictable chronic mild stress in male and female mice. Stress (Amsterdam, Netherlands)\| PubMed ID: 37125617	2023
Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease. International journal of molecular sciences\| PubMed ID: 38791125	2024
Sex-dependent astrocyte reactivity: Unveiling chronic stress-induced morphological changes across multiple brain regions. Neurobiology of disease\| PubMed ID: 39032799	2024
Sex differences in opioid response: a role for the gut microbiome? Frontiers in pharmacology\| PubMed ID: 39268474	2024

Melissa T. Manners

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