Neural Circuit Mechanisms of Stress-Impaired Social Reward

压力受损社会奖赏的神经回路机制

• 批准号: 10711154
• 负责人: SCOTT JAMES RUSSO
• 金额: $ 42.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711154
• 关键词: Adolescent; Age; Age Months; Aggressive behavior; Agitation; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Anxiety; Attention; Award; Behavior Disorders; Behavioral; Behavioral Symptoms; Brain; Breeding; Caregivers; Cells; Chronic; Chronic stress; Cognitive deficits; Cues; Data; Dementia; Development; Diagnostic; Disinhibition; Emotions; Enterobacteria phage P1 Cre recombinase; Event; Exhibits; Female; Fiber Optics; Fluorescence; Functional disorder; Genetic; Genetic Diseases; Genotype; Gliosis; Heterozygote; Human; Image; Impaired cognition; Impairment; Implant; Infusion procedures; Knock-in; Lateral; Link; Mediating; Memory; Memory impairment; Mental Depression; Mus; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neurotensin; Operative Surgical Procedures; Outcome Study; Parents; Pathology; Patients; Photometry; Play; Predisposition; Problem behavior; Quality of life; Reporter; Reporting; Research; Rewards; Risk; Role; Same-sex; Senile Plaques; Signal Transduction; Slice; Social Behavior; Social Conditions; Social Controls; Social Interaction; Stress; Symptoms; Synapses; Testing; Therapeutic; Time; Viral; With laterality; Withdrawal; avoidance behavior; brain circuitry; brain dysfunction; comorbidity; conditioned place preference; extracellular; gamma-Aminobutyric Acid; in vivo; insight; male; mouse model; neural circuit; neuroinflammation; neuron loss; neuropathology; neuropsychiatric symptom; neuropsychiatry; new therapeutic target; optical fiber; pre-clinical; preference; psychological symptom; response; sex; social; social anxiety; social defeat; social stress; stress resilience

Abstract Alzheimer's disease (AD) is characterized by neurodegeneration of the brain that is associated with intraneuronal neurofibrillary tangles, extracellular neuritic plaques and neuroinflammation. Synaptic alteration or dysfunction is increasingly viewed as one of the earliest events in the initiation of AD-type cognitive decline preceding neuronal loss. Aside from cognitive and memory impairments, AD is also commonly associated with social behavioral abnormalities and psychological symptoms. It is estimated that approximately 80-90% of dementia patients suffer from behavioral disorders that include apathy, depression, irritability, agitation, anxiety, social withdrawal, social disinhibition, aggression and agitation. These behavior problems can have a huge impact on the quality of life of the patients and their caregivers. While the mechanisms of comorbid neuropsychiatric symptomswith AD are not well known, it is postulated that neurodegeneration in AD disrupts the brain circuitries involved in social behavior and emotion. Under the parent R01, my lab has been investigating the neural circuitries mediating chronic stress-induced social behavior alteration. We have shown that social stress induces occlusion of social reward and preference in stress susceptible mice and it is associated with aberrant activation of neurotensin (NT)-positive GABAergic neurons in the lateral septum (LS). We also found that chemogenetic activation of LSNT neurons promotes social avoidance behavior and reduced social reward in stress resilient mice, suggesting LSNT neurons plays an important role in determining responses to social rewards. In several genetic mouse models that recapitulate aspects of AD neuropathology, impairments in social behavior have also been observed. In a well-established 5xFAD mouse model of AD-related pathology, we confirm that these mice exhibit deficits in social reward. Thus, in this supplement, we propose to longitudinally examine the activity of LS circuit during social interaction in the 5xFAD mice to determine whether AD-associated reduced social preference is driven by LSNT neurons. Moreover, as it is well established that social stress exacerbates neuropsychiatric symptoms in AD, we will also test the effect of social defeat stress on LS circuit activity and social behavior in 5xFAD mice.

抽象的 阿尔茨海默氏病 (AD) 的特征是与神经元内相关的大脑神经变性 神经原纤维缠结、细胞外神经炎斑和神经炎症。突触改变或功能障碍 越来越多地被视为 AD 型认知衰退开始的最早事件之一 神经元损失。除了认知和记忆障碍之外，AD 通常还与社交相关。 行为异常和心理症状。据估计，大约 80-90% 的痴呆症患者 患者患有行为障碍，包括冷漠、抑郁、易怒、激动、焦虑、社交障碍 退缩、社会抑制解除、攻击性和激动。这些行为问题可能会产生巨大的影响 患者及其护理人员的生活质量。虽然共病神经精神疾病的机制 AD 的症状尚不清楚，据推测 AD 中的神经变性会扰乱大脑回路 参与社会行为和情感。在父 R01 下，我的实验室一直在研究神经 介导慢性压力引起的社会行为改变的电路。我们已经证明，社会压力会导致 应激易感小鼠的社会奖励和偏好被阻断，并且与异常激活有关 外侧隔膜 (LS) 中的神经降压素 (NT) 阳性 GABA 能神经元。我们还发现化学遗传学 LSNT神经元的激活促进社交回避行为并减少应激恢复中的社交奖励 小鼠，表明 LSNT 神经元在决定对社会奖励的反应中发挥着重要作用。在几个 基因小鼠模型概括了 AD 神经病理学的各个方面，也发现了社会行为障碍 被观察到。在一个完善的 AD 相关病理学 5xFAD 小鼠模型中，我们确认这些小鼠 表现出社会奖励的缺陷。因此，在本补充中，我们建议纵向研究 LS 的活性 5xFAD 小鼠社交互动期间的电路，以确定 AD 相关的社交活动是否减少 偏好是由 LSNT 神经元驱动的。此外，众所周知，社会压力会加剧 AD 的神经精神症状，我们还将测试社交失败压力对 LS 回路活动的影响和 5xFAD 小鼠的社交行为。