Genetic functional inactivation of neuronal nitric oxide synthase affects stress-related Fos expression in specific brain regions

To identify neuronal substrates involved in NO/stress interactions we used Fos expression as a marker and examined the pattern of neuronal activation in response to swim stress in nNOS knock-out (nNOS–/–) and wild-type (WT) mice. Forced swimming enhanced Fos expression in WT and nNOS–/– mice in several brain regions, including cortical, limbic and hypothalamic regions. Differences in the Fos response between the two groups were observed in a limited set (6 out of 42) of these brain areas only: nNOS–/– mice displayed increased stressor-induced Fos expression in the medial amygdala, periventricular hypothalamic nucleus, supraoptic nucleus, CA1 field of the hippocampus, dentate gyrus and infralimbic cortex. No differences were observed in regions including the septum, central amygdala, periaqueductal grey and locus coeruleus. During forced swimming, nNOS–/– mice displayed reduced immobility duration, while no differences in general locomotor activity were observed between the groups in the home cage and during the open field test. The findings indicate that deletion of nNOS alters stress-coping ability during forced swimming and leads to an altered pattern of neuronal activation in response to this stressor in specific parts of the limbic system, hypothalamus and the medial prefrontal cortex.