We examined the effect of chronic restraint stress and the counteractive effects of daily exercise on the molecular basis of the brain-bone marrow (BM) interactions, by especially focusing on the paraventricular nucleus (PVN) of the hypothalamus. Male Wistar rats were assigned into control, restraint stress, and stress + daily spontaneous exercise (SE) groups. BM and hypothalamic gene expression profiles were examined through the undertaking of RT-PCR and microarrays, respectively. The inflammatory blood cell population was investigated through flow cytometry. Through the use of immunohistochemistry, we examined the presence of BM-derived C-C chemokine receptor type 2 (CCR2)-expressing microglial cells in the rat PVN. The gene expression levels of BM inflammatory factors such as those of interleukin 1 beta and CCR2, and the inflammatory blood cell population were found to be significantly higher in both restrained groups compared with control group. Interestingly, chronic restraint stress alone activated the recruitment of BM-derived CCR2-expressing microglial cells into the PVN, whereas daily spontaneous exercise prevented it. A notable finding was that restraint stress upregulated relative gene expression of hypothalamic matrix metalloproteinase 3 (MMP3), which increases the permeability of the blood-brain barrier (BBB), and that exercise managed to normalize it. Moreover, relative expression of some hypothalamic genes directly involved in the facilitation of cell migration was downregulated by daily exercise. Our findings suggest that daily spontaneous exercise can reduce the numbers of BM-derived CCR2-expressing microglial cells into the PVN through the prevention of stress-induced changes in the hypothalamic gene expression.NEW & NOTEWORTHY Chronic restraint stress can upregulate MMP3 gene expression in the rat hypothalamus, whereas daily spontaneous exercise can prevent this stress-induced effect. Stress-induced BM-derived inflammatory cell recruitment into the rat PVN can be prevented by daily spontaneous exercise. Stress-induced increase of hypothalamic MMP3 gene expression may be responsible for BBB injury, thereby allowing for BM-derived inflammatory cells to be recruited and to accumulate in the rat PVN, and to be subsequently involved in the onset of stress-induced hypertension.