Amygdala modulation of hippocampus-accumbes interaction: Relevance to depression

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DESCRIPTION (provided by applicant): Substantial evidence supports the contribution of multiple neural systems to the etiology of affective disorders, including ventral subiculum (vSub) of the hippocampus and basolateral amygdala (BLA). The nucleus accumbens (NAc) receives converging glutamatergic input from BLA and vSub, along with dopaminergic input from the ventral tegmental area. We hypothesize that the impaired information processing that occurs in affective disorders arises in part from a disruption of the normal regulation of NAc neural responses by its afferents. Although the interactions among the prefrontal cortex (PFC), vSub and NAc have been investigated, the role of the BLA in this interaction has received comparatively less attention despite its important role in mediating affective responses. The vSub in particular has been shown to play a significant role in the gating of information flow in the NAc, particularly as it relates to context. In addition to regulating behavioral and physiological responses to stress, both regions have also been shown to modulate extracellular dopamine release in the NAc. It has not yet been demonstrated how information gating by vSub and BLA in the NAc changes following exposure to repeated stressors. It is also unknown whether changes in tonic levels of dopamine following stress underlie the alterations in information gating in the NAc. Aim 1 of the proposed studies will examine the effects of acute and repeated restraint stress on long-term plasticity of BLA and vSub afferents within the nucleus accumbens. Aim 2 will test the role of dopamine in modulating the effects of repeated restraint on the BLA-NAc and vSub-NAc pathways. In addition, whether BLA and vSub inactivation can reverse the dopaminergic regulation on plasticity in the nucleus accumbens following repeated stress will be tested. Aim 3 will explore the effects of chronic treatment with a selective serotonin reuptake inhibitor on stress-induced changes in NAc plasticity. These studies will provide new insight into the modulatory role of vSub and BLA in the ability of the opposing afferent input to drive NAc neurons and the sensitivity of this interaction to repeated stress. In addition, the therapeutic efficacy of antidepressant treatment on the stress-induced changes in the strength of BLA and vSub input to the NAc can be verified. Stress is known to precipitate or exacerbate the symptoms of major affective disorders, like depression. The proposed studies will test the hypothesis that repeated bouts of stress leads to depressive-like symptoms via disruption of the neural circuitry important for the regulation of affective behavior. In addition, the ability of antidepressant treatment to reverse these neural changes will be explored.