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.

概括社交互动影响日常决策，甚至影响缺乏明确社交内容的决策。尽管如此，先前的社会经历如何影响后来的决策仍然受到深入研究。人们对这一过程的了解还不够深入，部分原因可能是缺乏用于可塑性模型生物的分析方法。我的团队开发了一项称为未来选择社会激励（SIFC）的任务。为了在操作调节室中对两种同样喜欢的食物做出反应，然后将一种食物与另一种食物配对与新奇同种互动的机会我们发现，另一种食物与新奇物体配对。即使没有该同种，稍后也会对同种相关的食物做出更多反应。社交经验似乎赋予熟悉的奖励以价值，并激励人们选择该奖励而不是其他奖励 – 类似于一个人反复偏爱某家特定餐厅，因为这是他们第一次约会的地方。内侧眶额皮层 (MO) 对于在激励时产生寻求奖励的行为是必要的可能的奖励的特征是不存在的，并且必须被设想——就像在 SIFC 中一样，当老鼠必须回忆起社交时我们最近发现，脑源性神经营养因子 (BDNF) 是 MO 发育不可或缺的一部分。生命早期 MO 中的神经元 Bdnf 耗竭会阻碍 SIFC 我们将：目标 1：通过 MO-BLA 确定发展中 MO 中的 BDNF 是否影响社会价值处理我们将测试 MO-BLA 连接需要神经衍生的 BDNF 的假设。成熟，这样在发育中的 MO 神经元中 Bdnf 沉默，而不是其他细胞类型，将： 1) 减少 MO BLA 中的终末密度和 2) 遮挡兴奋性 BLA 上的学习依赖性树突棘可塑性 3) 我们将检验以下假设：BLA 中的树突棘可塑性对于 SIFC 的发生是必要的。目标 2：区分 SIFC 中 BDNF 顺行性的突触前 trkB 与突触后 trkB 的作用。因此，BDNF 必须与其普遍表达的高亲和力受体原肌球蛋白受体结合。激酶 B (trkB) 控制 SIFC 的作用仍不清楚，我们将检验 MO 和 BDNF-trkB 的假设。不是BLA对于小鼠将社会信息整合到决策行为中是必要的，然后我们将替换它。 trkB 在特定发育时期的活动，以确定行动的关键时期。将 SIFC 任务中的任何效果与传统巴甫洛夫到仪器转移 (PIT) 任务中的效果进行比较揭示神经营养素信号传导对社交与非社交 PIT 行为的分离效应（如果存在）。目标 3：在社会孤立之后恢复 SIFC。我们发现青少年的社会隔离会导致 trkB 过早上调。全长亚型和应激相关辅因子并阻碍 SIFC 我们将检验选择的假设。 BLA 中影响 SIFC 的因素，过度表达阻碍 SIFC 和抑制正常化社会决策。