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High Salt Intake Enhances Stress Coping Behaviors: Role for Vasopressin Signaling from PVN to Amygdala

Responsivity to an acute stressor can vary depending on prior or concurrent stress exposure. High dietary sodium chloride (salt) is an osmotic stressor that increases the risk and severity of multiple stress‐related disease modalities, notably hypertension. Given that Americans consume more than twice the recommended daily salt allowance, we explored the possibility that high salt intake could enhance responsivity to a psychogenic stress. Mice underwent chronic salt loading (SL) by drinking 4% saline for 1 week. SL increased serum osmolality (P<0.01) and corticosterone (P<0.01), suggesting osmotic dehydration activated the hypothalamic‐pituitary‐adrenal stress axis. To determine if osmotic stress enhances behavioral responsivity to a psychogenic stress, salt loaded mice underwent a forced swim test (FST) for five minutes. SL increased time swimming (P<0.01) and time grooming thereafter (P<0.01), indicating enhanced active stress coping or responsivity. Furthermore, SL enhanced FST induction of c‐Fos in the hypothalamic paraventricular nucleus (PVN) (P<0.05) and the central (P<0.05) and basolateral (P<0.01) nuclei of the amygdala, which are synaptically connected and which modulate cardiovascular and behavioral responsivity to stress. Immunostaining for the stress‐related neuropeptide arginine vasopressin (VP) showed SL and FST each increased VP positive neurons in the PVN (P<0.05, P<0.05) with the greatest increase in mice exposed to both SL and FST stress (P< 0.05). This observed neurochemical plasticity raises the intriguing possibility that future stressors could elicit exaggerated circuit activation and hence exaggerated behavioral and cardiovascular responses due to a greater available VP reservoir. Indeed, co‐labeling for c‐Fos/VP showed SL drove activation of PVN‐VP cells (P<0.01). VP type 1 receptors (V1R) in the amygdala are a major synaptic target of PVN inputs, and nanoinjections of a V1R antagonist bilaterally into the amygdala attenuated the enhancing effect of SL on active coping (time spent mobile) in the FST. Of note, V1R antagonist reduced time spent mobile during the FST both in salt loaded and control mice (P<0.05, P<0.05). Data indicate that neuronal and behavioral responses to an acute psychogenic stressor is potentiated by high salt intake. This enhancing effect appears to involve activation of a PVN‐amygdala VPergic neural pathway. Ongoing retrograde labeling experiments will determine if SL and/or swim stress recruit and activate PVN‐VP neurons that project to the amygdala and to sympathoexcitatory regions including the rostroventral lateral medulla and spinal cord that drive sympathetic outflow in support of blood pressure. Future studies will utilize in situ hybridization to determine if recruitment of VP positive neurons occurs due to stress‐induced production of VP‐mRNA from VP output neurons. These data would provide mechanistic insight into how stress exposure sensitizes behavioral and cardiovascular responses to future heterotypic stressors.