Neural Circuit Mechanisms of Stress-Impaired Social Reward

摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种以脑神经元退行性变为特征的疾病， 神经纤维缠结、细胞外神经炎斑块和神经炎症。突触改变或功能障碍 越来越多地被认为是AD型认知功能减退的最早期事件之一， 神经元缺失除了认知和记忆障碍外，AD还通常与社交相关。 行为异常和心理症状据估计，大约80-90%的痴呆症 患者患有行为障碍，包括冷漠、抑郁、易怒、激动、焦虑、社交障碍、抑郁、焦虑、焦虑、抑郁、焦虑、焦虑 退缩、社交抑制解除、攻击和激动。这些行为问题会对 患者及其护理人员的生活质量。神经精神共病的机制 AD的发病机制尚不清楚，但据推测，AD的神经退行性病变破坏了大脑回路 参与社会行为和情感。在父R 01下，我的实验室一直在研究 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赏和偏好的阻断及其与异常激活的关系 神经降压素（NT）阳性GABA能神经元在外侧隔（LS）。我们还发现， LSNT神经元的激活促进社会回避行为和减少社会奖励的压力弹性 这表明LSNT神经元在决定对社会奖励的反应中起着重要作用。在几个 概括AD神经病理学方面的遗传小鼠模型，社会行为的损伤也 被观察到。在一个完善的AD相关病理学的5xFAD小鼠模型中，我们证实这些小鼠 表现出社会回报的不足。因此，在本补充中，我们建议纵向检查LS的活性 在5xFAD小鼠的社交互动过程中， 偏好由LSNT神经元驱动。此外，众所周知， 在AD的神经精神症状，我们还将测试社会失败压力对LS电路活动的影响， 5xFAD小鼠的社会行为。

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.