Stress vulnerability conferred by CX3CR1-deficiency is sexually dimorphic and responds to physical exercise in mice
1 Institute of Physiology II
2 Department of Psychiatry and Psychotherapy/ Institute of Physiology II
Chronic stress is a major risk factor for depression and anxiety disorders, particularly in women. Stress leads to impaired neuroplasticity and neuroinflammation, but these effects can be ameliorated by physical activity. Mechanistically, neuroplasticity and neuroinflammation are linked through the fractalkine pathway, whose receptor CX3CR1 is exclusively expressed on microglia in the brain. We previously linked CX3CR1 deficiency to impaired neuroplasticity and microglial function in the motor cortex (M1) and showed that, depending on stress vulnerability, stress also leads to impaired motor learning and alters spine dynamics and microglia in the M1. Here, we investigate the impact of CX3CR1 deficiency on stress vulnerability and changes in M1 with a focus on sexual dimorphism and whether deficits can be prevented by physical exercise. To this end, male and female mice with intact, partial or complete CX3CR1 deficiency were subjected to active training on a treadmill/sedentary then chronic restraint stress/control conditions and characterized for affective and motor symptoms. Additional male mice with partial or complete CX3CR1 deficiency were examined for changes in microglial dynamics and microglia-neuron communication using 2-photon-in vivo-microscopy. We found a striking sexual dimorphism in stress symptoms in CX3CR1-deficient mice, with higher levels in females. Importantly, physical training prevented stress effects in all genotypes with a clear dosedependency on CX3CR1 expression. Microglial dynamics in vivo showed that the impaired motility in a partial absence of CX3CR1 could be rescued by exercise. Taken together, this further links altered neuron-microglia communication to neuropsychiatric conditions and highlights the relevance of sex differences.