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Neural Circuit Mechanisms of Stress-Impaired Social Reward

压力受损社会奖赏的神经回路机制

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

摘要阿尔茨海默病(AD)的特征是与神经元内相关的脑神经退行性变神经原纤维缠结，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引发AD类型认知衰退的最早事件之一神经元丢失。除了认知和记忆障碍外，阿尔茨海默病还通常与社交有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、烦躁、焦虑、社交退缩、社交去抑制、攻击性和激动感。这些行为问题可能会对患者及其照顾者的生活质量。而共病的神经精神障碍的机制阿尔茨海默病的症状尚不清楚，据推测，阿尔茨海默病的神经退行性变扰乱了大脑电路涉及社会行为和情感的。在父母R01下，我的实验室一直在研究神经调节慢性应激引起的社会行为改变的回路。我们已经证明，社会压力会导致应激敏感小鼠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，化学发生 LSNT神经元的激活在应激恢复中促进社交回避行为和减少社会奖赏这表明LSNT神经元在决定对社会奖励的反应方面发挥着重要作用。在几个月内概括了AD神经病理、社会行为障碍等方面的遗传小鼠模型也被观察到了。在AD相关病理的5xFAD小鼠模型中，我们证实这些小鼠在社会回报方面表现出不足。因此，在这份补充材料中，我们建议纵向研究LS的活性在5xFAD小鼠的社交互动过程中确定与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，社会压力加剧了 AD的神经精神症状，我们还将测试社会失败应激对LS回路活动和 5xFAD小鼠的社会行为。