Amygdala modulation of hippocampus-accumbes interaction: Relevance to depression

杏仁核对海马-伏藏相互作用的调节：与抑郁症的相关性

• 批准号: 7806691
• 负责人: KATHRYN M GILL
• 金额: $ 5.01万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806691
• 关键词: Acute; Affect; Affective; Amygdaloid structure; Anhedonia; Antidepressive Agents; Attention; Autopsy; Behavior; Behavioral; Brain region; Cells; Chronic; Chronic stress; Cognitive deficits; Data; Diagnosis; Dopamine; Dopamine Antagonists; Emotional; Etiology; Exposure to; Fluoxetine; Functional Magnetic Resonance Imaging; Functional disorder; Gills; Glutamates; Hippocampus (Brain); Individual; Learning; Long-Term Depression; Long-Term Potentiation; Major Depressive Disorder; Measures; Mediating; Microdialysis; Modeling; Mood Disorders; Motor output; Neurons; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Patients; Physiological; Play; Precipitation; Prefrontal Cortex; Regulation; Role; Selective Serotonin Reuptake Inhibitor; Short-Term Memory; Stress; Structure; Symptoms; Synaptic plasticity; System; Testing; Treatment Efficacy; Ventral Tegmental Area; acute stress; aversive conditioning; classical conditioning; depressed; depression; depressive symptoms; dopamine system; extracellular; improved functioning; information processing; insight; neural circuit; neuroimaging; noradrenergic; relating to nervous system; research study; response; restraint; restraint stress; stressor

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.

描述（由申请人提供）：大量证据支持多个神经系统对情感障碍病因的贡献，包括海马的腹侧亚丘脑（VSUB）和基底外侧杏仁核（BLA）。伏隔核（NAC）从BLA和VSUB接收谷氨酸能收敛的输入，以及腹侧段区域的多巴胺能输入。我们假设在情感障碍中发生的信息处理受损的部分原因是其传入对NAC神经反应的正常调节。尽管已经研究了前额叶皮层（PFC），VSUB和NAC之间的相互作用，但BLA在这种相互作用中的作用在介导情感反应中的重要作用却较少。特别是VSUB已被证明在NAC中信息流的门控中起着重要作用，尤其是与上下文有关。除了调节对压力的行为和生理反应外，这两个区域还均显示出在NAC中调节细胞外多巴胺的释放。尚未证明VSUB和BLA在暴露于重复应力源后NAC变化中的信息门控。在压力之后，多巴胺的补品水平的变化是否是NAC中信息门控的改变是尚不清楚的。拟议的研究的目标1将检查急性和重复约束应力对伏隔核内BLA和VSUB传入的长期可塑性的影响。 AIM 2将测试多巴胺在调节重复约束对BLA-NAC和VSUB-NAC途径的影响中的作用。此外，将测试重复应力后，BLA和VSUB失活是否可以逆转伏隔核的多巴胺能调节。 AIM 3将探索选择性5-羟色胺再摄取抑制剂对压力诱导的NAC可塑性变化的影响。这些研究将为VSUB和BLA在相对传入输入驱动NAC神经元的能力以及这种相互作用对重复应力的敏感性方面的调节作用提供新的见解。此外，可以验证抗抑郁药治疗对应力诱导的BLA和VSUB输入对NAC的强度变化的治疗功效。已知应力会沉淀或加剧主要情感障碍（如抑郁症）的症状。拟议的研究将检验以下假设，即反复出现应力爆发会导致抑郁症状，从而破坏对调节情感行为重要的神经回路。另外，将探索抗抑郁药治疗逆转这些神经变化的能力。