Role of locus coeruleus and amygdala projections to ventral subiculum in stress regulation

Lipski, Witold Role of locus coeruleus and amygdala projections to ventral subiculum in stress regulation. Doctoral Dissertation, University of Pittsburgh.

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Abstract

The hippocampal formation, and the ventral subiculum (vSub), constitute a central node in mediating the forebrain’s stress response, particularly to psychogenic stressors. The vSub regulates midbrain dopamine neuron population activity via its output to the nucleus accumbens (NAc)-pallidal-ventral tegmental area circuit, providing a potential functional link between stress and dopaminergic system. However, it is not known how appropriate vSub activity is generated in response to stress. The vSub receives projections from two stress-related inputs, locus coeruleus (LC) and basolateral nucleus of the amygdala (BLA). In this study, direct LC innervation of the vSub and indirect input through the BLA was investigated as potential mediators of stress responses in the vSub. The effect of norepinephrine (NE) on single vSub neurons was examined using microiontophoresis combined with electrophysiological recording in anesthetized rats. The response to NE in the vSub was compared to the effect of electrical stimulation of the LC. Iontophoretic NE inhibited vSub neurons, while LC stimulation inhibited 16%, and activated 38% of neurons. Inhibition was mediated by alpha-2, whereas activation by beta-adrenergic receptors. Moreover, vSub neurons were activated by BLA stimulation, and LC pre-stimulation both potentiated and suppressed these responses in neuronal subpopulations. To examine the activation by stress, the effect of footshock on vSub neurons was tested. Footshock inhibited 13%, and activated 48% of neurons. Responses to footshock were correlated to LC stimulation-evoked responses in single neurons. Prazosin, an alpha-1 antagonist, reversed footshock-evoked inhibition, revealing an underlying activation. Inactivation of the BLA did not block LC stimulation- or footshock- evoked activation, while LC inactivation blocked both. To examine stress effects on vSub neurons involved in modulation of DA activity, a subpopulation of vSub neurons projecting to the NAc was identified using retrograde tracing. Restraint stress activated these neurons as measured by Fos expression. These results suggest that the LC NE system plays an important role in mediating responses to stress in the vSub. Stress-induced activation of the LC NE system evokes inhibition and activation in the vSub, both of which may contribute to stress adaptation. An imbalance of this system may lead to pathological stress responses in mental disorders.

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