Role of thalamic versus cortical inputs to nucleus accumbens in stress-related disorders

丘脑与皮质输入对伏核的作用在应激相关疾病中的作用

• 批准号: 9188575
• 负责人: SCOTT JAMES RUSSO
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-11-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188575
• 关键词: Anhedonia; Antidepressive Agents; Anxiety; Behavior; Behavioral; Brain region; Centromedian Thalamic Nucleus; Chronic; Chronic stress; Coupled; Data; Deep Brain Stimulation; Dopamine D1 Receptor; Electrophysiology (science); Emotions; Excitatory Synapse; Glutamates; Goals; Halorhodopsins; Human; Interneurons; Mediating; Mental Depression; Microscopy; Moods; Mus; Muscarinic Antagonists; Neurons; Nucleus Accumbens; Pathway interactions; Phenotype; Play; Predisposition; Prefrontal Cortex; Rewards; Rodent; Role; Scopolamine; Slice; Social Controls; Social Interaction; Stress; Structure; Sum; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Thalamic structure; Toxin; Trauma; Whole-Cell Recordings; Work; anxiety-like behavior; avoidance behavior; base; behavioral response; cholinergic; cholinergic neuron; depression model; functional plasticity; in vivo; insight; nerve supply; optogenetics; paraventricular nucleus; postsynaptic; presynaptic; public health relevance; resilience; social; social stress; stress related disorder; transmission process; two-photon; vesicular glutamate transporter 2; voltage

 DESCRIPTION (provided by applicant): Chronic social defeat stress (CSDS) is a trauma based paradigm used to model depression- and anxiety-like behavior in rodents. We found previously that CSDS increases glutamatergic synapses on nucleus accumbens (NAc) medium spiny neurons, however the detailed circuitry meditating these effects is unclear. Previous work shows that the NAc receives dense glutamatergic innervation from the intralaminar thalamus (ILT) and prefrontal cortex (PFC). Thus, we analyzed levels of vesicular glutamate transporter 2 (VGLUT2) and VGLUT1, which are predominately found in ILT-NAc or PFC-NAc synapses, respectively. We found increased levels of VGLUT2 in susceptible mice that negatively correlated with social interaction ratio, suggesting that changes in ILT-NAc circuitry may regulate depression- or anxiety-like behavioral phenotypes following CSDS. To establish the functional relevance of these circuits in CSDS-induced depression- or anxiety-like behavior, we utilized circuit specific optogenetic approaches to modulate activity of the ILT-NAc or PFC-NAc. Our results show that rapid activation of the ILT-NAc circuit is both necessary and sufficient for the expression of stress-induced behavior, while rapid stimulation of PFC-NAc circuit had no effect. Interestingly, we also find that the ILT-NAc circuit selectively regulates activity of cholinergic interneurons, which seem to be necessary for the pro-depressant effects of ILT stimulation. In sum, our results identify circuit specific effects of different glutamate inputs wihin the NAc that control depression- or anxiety-like behavioral phenotypes. This provides us with unique insight into how stress impacts NAc circuitry and may inform a greater understanding of the mechanisms by which NAc deep brain stimulation is antidepressant in humans.

 描述（由申请人提供）：慢性社会失败压力（CSDS）是一种基于创伤的范式，用于模拟啮齿动物的抑郁和焦虑样行为。我们以前发现，CSDS增加了丘脑核（NAc）中型多刺神经元上的多巴胺能突触，但具体的电路冥想这些影响尚不清楚。以前的研究表明，NAc接受来自板内丘脑（ILT）和前额叶皮层（PFC）的密集的丘脑能神经支配。因此，我们分析了囊泡谷氨酸转运蛋白2（VGLUT 2）和VGLUT 1的水平，这主要是在ILT-NAc或PFC-NAc突触，分别发现。我们发现易感小鼠中VGLUT 2水平的增加与社会互动率呈负相关，这表明ILT-NAc电路的变化可能会调节CSDS后的抑郁或焦虑样行为表型。为了确定这些回路在CSDS诱导的抑郁或焦虑样行为中的功能相关性，我们利用回路特异性光遗传学方法来调节ILT-NAc或PFC-NAc的活性。我们的研究结果表明，快速激活的ILT-NAc回路是必要的和充分的表达的压力诱导的行为，而快速刺激的PFC-NAc回路没有影响。有趣的是，我们还发现ILT-NAc回路选择性地调节胆碱能中间神经元的活性，这似乎是ILT刺激的促凋亡作用所必需的。总之，我们的研究结果确定了控制抑郁或焦虑样行为表型的NAc中不同谷氨酸输入的回路特异性效应。这为我们提供了关于压力如何影响NAc电路的独特见解，并可能有助于更好地理解NAc脑深部刺激在人类中具有抗抑郁作用的机制。