Amygdala modulation of hippocampus-accumbes interaction: Relevance to depression

描述（由申请人提供）：大量证据支持多种神经系统对情感障碍病因学的贡献，包括海马体的腹侧下托（vSub）和基底外侧杏仁核（BLA）。延髓核（NAc）接受来自BLA和vSub的会聚性多巴胺能输入，沿着来自腹侧被盖区的多巴胺能输入。我们推测，在情感障碍中发生的受损的信息处理，部分原因是由于其传入神经的NAc神经反应的正常调节中断。虽然前额叶皮层（PFC），vSub和NAc之间的相互作用已被调查，BLA在这种相互作用中的作用得到了相对较少的关注，尽管它在调解情感反应的重要作用。特别是vSub已被证明在NAc中的信息流的门控中发挥重要作用，特别是当它与上下文相关时。除了调节对压力的行为和生理反应外，这两个区域也被证明可以调节NAc中的细胞外多巴胺释放。尚未证明在暴露于重复压力源后，NAc中vSub和BLA的信息门控如何变化。也不知道压力后多巴胺的紧张性水平的变化是否是NAc中信息门控改变的基础。目的1的拟议研究将检查急性和重复约束应激的影响，在延髓核内的BLA和vSub传入的长期可塑性。目的2将测试多巴胺在调节重复约束对BLA-NAc和vSub-NAc通路的影响中的作用。此外，BLA和vSub失活是否可以逆转多巴胺能调节可塑性的延髓核重复应力后将进行测试。目的3将探讨慢性治疗与选择性5-羟色胺再摄取抑制剂对应激诱导的NAc可塑性变化的影响。这些研究将提供新的见解vSub和BLA的调制作用，在相反的传入输入的能力，以驱动NAc神经元和这种相互作用的敏感性，以重复的压力。此外，可以验证抗抑郁剂治疗对应激诱导的BLA和向NAc输入的vSub强度变化的治疗功效。众所周知，压力会加速或加剧严重情感障碍的症状，如抑郁症。拟议中的研究将检验这样一个假设，即反复的压力会通过对情感行为调节重要的神经回路的破坏而导致抑郁样症状。此外，抗抑郁药治疗逆转这些神经变化的能力将被探索。

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.