Understanding how social interactions influence reward-seeking behaviors: Developmental mechanisms

了解社交互动如何影响寻求奖励的行为：发展机制

基本信息

批准号：
10716898
负责人：
Shannon Leigh Gourley
金额：
$ 44.7万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716898
关键词：
Adolescence Adolescent Affinity Alzheimer&apos s disease risk Amygdaloid structure Behavior Behavioral Binding Biological Assay Biological Availability Brain Brain-Derived Neurotrophic Factor Cells Cognitive Complex Decision Making Dendritic Spines Development Developmental Process Dissociation Eating Empathy Food Future Goals Grant Human Incentives Investigation Learning Length Life Mammals Medial Mediating Mental Health Modality Mus National Institute of Mental Health National Institute of Neurological Disorders and Stroke Nature Neurobiology Neurons Nucleus Accumbens Operant Conditioning Organism Outcome PTK2B gene Phosphotransferases Population Prefrontal Cortex Process Protein Isoforms Proteins Restaurants Rewards Risk Factors Rodent Role Signal Transduction Site Social Behavior Social Controls Social Functioning Social Interaction Social Values Social isolation Socialization Spouses Strategic Planning Stress Testing Therapeutic Training Tropomyosin United States National Institutes of Health Up-Regulation Viral anterograde transport base career cell type cofactor cognitive function critical period early life adversity excitatory neuron experience experimental study information processing insight model organism neural circuit neurotrophic factor novel novel therapeutics overexpression postsynaptic premature receptor social social influence willingness young adult

项目摘要

SUMMARY Social interactions impact everyday decisions, even decisions lacking explicit social content. How mammals process social information is intensively investigated. Still, how prior social experiences influence later decision making is not well-understood, likely due in part to a dearth of assays for use in malleable model organisms. My team developed a task referred to as social incentivization of future choice (SIFC). Mice are trained to respond in operant conditioning chambers for two equally preferred foods, then one food is paired with the opportunity to interact with a novel conspecific. The other food is paired with a novel object. We find that mice will later respond more for the conspecific-associated food, even in the absence of that conspecific. Thus, prior social experience appears to confer value to familiar rewards and incentivize choosing that reward over another – akin to one repeatedly favoring a particular restaurant because it’s where one had a first date. The medial orbitofrontal cortex (MO) is necessary for generating reward-seeking actions when the motivating features of possible rewards are not available and must be envisioned – as in SIFC, when mice must recall social interactions. Brain-derived Neurotrophic Factor (BDNF) is integral to MO development, and we recently found that neuronal Bdnf depletion in the MO early in life obstructs SIFC. Many unanswered questions remain. We will: Aim 1: Determine whether BDNF in the developing MO impacts social value processing via MO-BLA connections. We will test the hypothesis that MO-BLA connections require neuronally-derived BDNF for maturation, such that Bdnf silencing in developing MO neurons, but not other cell types, will: 1) diminish MO terminal densities in the BLA and 2) occlude learning-dependent dendritic spine plasticity on excitatory BLA neurons. 3) We will test the hypothesis that dendritic spine plasticity in the BLA is necessary for SIFC to occur. Aim 2: Dissociate the roles of pre- vs. post-synaptic trkB in SIFC. BDNF is subject to anterograde transport; thus, where BDNF must bind to its ubiquitously expressed high-affinity receptor, tropomyosin receptor kinase B (trkB), to control SIFC remains unclear. We will test the hypothesis that BDNF-trkB in the MO and not BLA is necessary for mice to integrate social information into decision-making behavior. We will then replace trkB activity during specific developmental epochs to identify critical periods of action. In a sub-aim, we will compare any effects in the SIFC task to those in a traditional Pavlovian-to-instrumental transfer (PIT) task to reveal dissociable effects of neurotrophin signaling on social vs. non-social PIT behavior, if they exist. Aim 3: Recover SIFC following social isolation. Early-life adversity can profoundly impact cognitive and social function later in life. We find that adolescent social isolation causes the premature up-regulation of trkB full-length isoforms and stress-related co-factors and obstructs SIFC. We will test the hypothesis that select factors in the BLA causally influence SIFC, with overexpression obstructing SIFC and inhibition normalizing social decision-making.

概括社会互动会影响每天的决策，甚至缺乏明确的社会内容的决定。如何哺乳动物过程社会信息经过深入研究。不过，先前的社会经历如何影响以后的决定制作不是很好的理解，可能部分是由于用于锻造模型生物的测定法死亡。我的团队制定了一项被称为对未来选择的社会激励（SIFC）的任务。老鼠经过训练要以两种同样优选的食物进行操作调节室做出响应，然后将一种食物与与新颖概念互动的机会。另一种食物与新物体配对。我们发现老鼠后来，即使在没有特定的情况下，也将为特定相关的食物做出更多反应。那，先验社交经验似乎将价值与熟悉的奖励相关，并激励选择这种奖励而不是另一个奖励 - 类似于一再喜欢特定餐厅的人，因为这是一个约会的地方。媒体轨道额皮层（MO）对于激励时产生奖励行动是必要的可能的奖励的功能不可用，必须设想 - 就像在SIFC中一样，当老鼠必须回忆社交时互动。脑衍生的神经营养因子（BDNF）是MO发育不可或缺的一部分，我们最近发现生命早期MO中的神经元BDNF耗竭阻碍了SIFC。仍然存在许多未解决的问题。我们将：目标1：确定在发展中的BDNF是否通过Mo-Bla影响社会价值处理连接。我们将测试Mo-Bla连接需要神经衍生的BDNF的假设成熟，使得bDNF沉默在发育MO神经元中，但没有其他细胞类型，将：1）减少MO BLA中的末端密度和2）刺激性BLA上的闭塞依赖学习的树突状脊柱可塑性神经元。 3）我们将检验以下假设：SIFC发生BLA中的树突状脊柱可塑性。 AIM 2：解离SIFC中Pre-Pre-Synaptic TRKB的作用。 BDNF遭受顺序的约束运输;因此，如果BDNF必须与其普遍表达的高亲和力受体结合，那么Tropomyosin受体为了控制SIFC的激酶B（TRKB）尚不清楚。我们将测试MO中BDNF-TRKB的假设小鼠必须将社会信息整合到决策行为中，这不是BLA。然后我们将替换特定发育时期的TRKB活性以识别关键时期。在一个子aim中，我们将将SIFC任务中的任何效果与传统的Pavlovian到乐趣转移（PIT）任务中的任何效果进行比较揭示神经营养蛋白信号传导对社会与非社会坑行为的可分离作用，如果存在。目标3：在社会隔离之后恢复SIFC。早期的广告可以深远影响认知和以后的社会功能。我们发现青少年的社会隔离导致TRKB的过早上调全长同工型和与应力相关的辅助因子和阻塞SIFC。我们将测试选择的假设 BLA的因素随随便就会影响SIFC，过表达阻碍了SIFC并抑制标准化社会决策。