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性障碍病因的贡献，包括海马腹侧下带（vSub）和杏仁核基底外侧（BLA）。伏隔核（NAc）接收来自BLA和vSub的谷氨酸能输入，以及来自腹侧被盖区的多巴胺能输入。我们假设，在情感性障碍中发生的信息处理受损，部分是由于NAc神经反应的正常调节受到传入事件的破坏。虽然前额叶皮层（PFC）、vSub和NAc之间的相互作用已经被研究过，但BLA在这种相互作用中的作用相对较少受到关注，尽管它在调节情感反应中起着重要作用。特别是vSub已经被证明在NAc信息流的控制中起着重要的作用，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的细胞外多巴胺释放。目前还没有证据表明，在暴露于重复应激源后，NAc中vSub和BLA的信息门控是如何变化的。同样不清楚的是，应激后多巴胺强直性水平的变化是否导致了NAc中信息门控的改变。本研究的目的1将研究急性和重复约束应激对伏隔核内BLA和vSub传入的长期可塑性的影响。目的2将测试多巴胺在调节反复抑制对BLA-NAc和vSub-NAc通路的影响中的作用。此外，BLA和vSub失活是否可以逆转反复应激后伏隔核多巴胺能对可塑性的调节。目的3将探讨选择性血清素再摄取抑制剂慢性治疗对应激诱导的NAc可塑性变化的影响。这些研究将为vSub和BLA在相反传入输入驱动NAc神经元的能力中的调节作用以及这种相互作用对重复应激的敏感性提供新的见解。此外，抗抑郁药物治疗对应激诱导的BLA和vSub输入NAc强度变化的治疗效果也可以得到验证。众所周知，压力会加速或加剧抑郁症等主要情感障碍的症状。拟议中的研究将检验这样一种假设，即反复发作的压力会通过破坏对情感行为的调节很重要的神经回路而导致类似抑郁的症状。此外，抗抑郁药物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.