Nesfatin-1 is a newly discovered peptide that was reported to reduce food intake when injected centrally. We recently described its wide distribution in rat brain autonomic nuclei which implies potential recruitment of nesfatin-1 by stress. We investigated whether restraint, a mixed psychological and physical stressor, activates nesfatin-1-immunoreactive (ir) neurons in the rat brain. Male Sprague-Dawley rats were either subjected to 30 min restraint or left undisturbed and 90 min later brains were processed for double immunohistochemical labeling of Fos and nesfatin-1. Restraint induced significant Fos expression in neurons of the supraoptic nucleus (SON), paraventricular nucleus (PVN), locus coeruleus (LC), rostral raphe pallidus (rRPa), nucleus of the solitary tract (NTS), and ventrolateral medulla (VLM). Double Fos/nesfatin-1 labeling revealed that Fos-ir neurons comprised 95% of nesfatin-1-ir cells in the SON, 90% in the VLM, 80% in the LC, 48% in the caudal NTS, 57% in the rRPa, 48% in the anterior parvicellular PVN, 27% in the medial magnocellular PVN, 18% in the lateral magnocellular PVN and 10% in the medial parvicellular PVN. These data demonstrate that nesfatin-1 neurons are part of the hypothalamic and hindbrain neuronal cell groups activated by restraint suggesting a possible role of nesfatin-1 in the response to stress.

The hippocampal formation is a highly plastic brain region that is sensitive to stress. It receives extensive noradrenergic projections, and noradrenaline is released in the hippocampus in response to stressor exposure. The hippocampus expresses particularly high levels of the alpha(1D) adrenergic receptor (ADR) and we have previously demonstrated that alpha(1d) ADR mRNA expression in the rat hippocampus is modulated by corticosterone. One of the defining features of a stress response is activation of the hypothalamic pituitary adrenal (HPA) axis, resulting in the release of corticosterone from the adrenal glands. However, the effect of stress on hippocampal expression of alpha(1d) ADR mRNA has not been determined. In this study, male rats were exposed to inescapable tail shock, loud noise or restraint, and the effect on alpha(1d) ADR mRNA expression in the hippocampus was determined by semi-quantitative in situ hybridization. All three stressors resulted in a rapid upregulation of alpha(1d) ADR mRNA in the dentate gyrus, with expression peaking at approximately 90min after the start of the stressor. Physical activity has previously been reported to counteract some of the effects of stress that occur within the dentate gyrus. However, 6weeks of voluntary wheel running in rats did not prevent the restraint stress-induced increase in alpha(1d) ADR mRNA expression in the dentate gyrus. Although the function of the alpha(1D) ADR in the dentate gyrus is not known, these data provide further evidence for a close interaction between stress and the noradrenergic system in the hippocampus.

Adolescent chronic stress has been shown to induce functional, biochemical and morphological modifications of the hippocampus, leading to stress-related disorders in adulthood. The present study investigated the effects of exercise, crocin and their combination on spatial learning and memory impairment and dendritic retraction of the CA3 pyramidal neurons induced by chronic adolescent stress in adult male rats. Rats were exposed to restraint stress 2 h/day for 10 days during postnatal days (PNDs) 30-40. Following this period, separate groups of animals were treated with crocin (25 and 50 mg/kg), exposed to running wheel, and or received the combined treatment during PNDs 41-55. Following the interventions, plasma levels of corticosterone, spatial learning and memory, apical dendritic length of CA3 pyramidal neurons and BDNF levels in the CA3 area were assessed. Findings showed that adolescent stress significantly increased corticosterone levels and caused a tendency to reduce CA3 BDNF levels. Adolescent stress also impaired spatial learning and memory, and retracted apical dendritic length of CA3 pyramidal neurons. Crocin, voluntary exercise, and their combination recovered stress-induced spatial learning and impairment and CA3 pyramidal neurons dendritic length retraction. All treatments also reduced significantly corticosterone levels and enhanced CA3 BDNF levels in the stress groups. Finally, these treatments even increased apical dendritic length of CA3 pyramidal neurons in the non-stress groups. These findings indicate that detrimental effects of adolescent stress on cognitive function and hippocampal morphology in adulthood could be restored by early interventions with physical activity and crocin treatment during adolescent period.