Mechanisms underlying intrinsically rewarded social behaviors

在抑郁、焦虑和自闭症谱系障碍的情况下，通常有益的社会互动可能是令人厌恶的。缺陷也可能与具体情况有关。例如，一些自闭症患者能够提出直接的请求（例如，食物），这种请求可以通过外部强化（例如，通过接受食物），但在附属沟通（例如，非性的，聊天）方面表现出严重的缺陷，这种联系可以促进社会联系，并且是有益的，但不会产生直接的，明显的外部强化。许多研究确定了多巴胺和阿片类药物在定向、外部奖励行为（例如，食物、伴侣或药物导向）中涉及的动机和奖励中的作用；然而，这些机制似乎与从属交际的内在机制不同，这使得对从属社会行为的内在奖励机制的基本认识存在重大空白。本提案的目的是确定阿片类药物在内侧视前核（mPOA）和伏隔核（NAc）中发挥作用的机制，利用鸣禽实验系统独特的通信特性启动、维持和奖励附属通信。重要行为背后的神经系统通常在物种间高度保守，因此对鸣禽的研究有望揭示一个核心的保守回路，在这个回路中，阿片类药物在没有明显外在奖励的情况下，在脊椎动物中启动、奖励和维持重要的社会行为。核心假设是，阿片样物质作用于mPOA→VTA→NAc回路中的mu阿片样受体（MOR），以启动、促进和奖励亲和社会行为。其基本原理是需要关于核心社会回路的基本的、机械的信息，这些信息是被精神疾病破坏的行为的基础。基于初步数据，本文提出了三个具体目标：1)分离mPOA中MOR和NAc对亲和歌唱行为的功能作用；2)确定mPOA和NAc中MOR基因敲低对亲和性歌曲相关奖励的影响；3)确定环境因素如何通过MOR调节亲和性歌曲。在Aim 1中，将MOR激动剂和拮抗剂双管微输注到mPOA和NAc中，以确定MOR在mPOA和NAc中启动和维持亲和歌唱行为中所起的不同作用。在Aim 2中，siRNA靶向mPOA和NAc中的MOR，将用于检查MOR在使用条件位置偏好测试测量的歌曲相关奖励中的作用。在目标3中，环境和特定部位的药理学操作将被用来研究环境应激源对MOR调节的影响。这种方法是创新的，因为它推进了对鸣禽内在奖励社会行为的理解，目标是识别核心从属回路。这一提议意义重大，因为它将阐明MOR和奖励在非性的、附属的社会行为中的作用，并为可能被人类精神疾病破坏的核心神经回路提供洞见。

In cases of depression, anxiety, and autism spectrum disorders, social interactions that are typically rewarding can be aversive. Deficits can also be context-specific. For example, some individuals with autism are able to make directed requests (e.g., for food) that can be extrinsically reinforced (e.g., by receipt of food) but exhibit profound deficits in affiliative communication (e.g., nonsexual, chitchat) that promotes social bonds and is rewarding but does not result in an immediate, obvious extrinsic reinforcer. Many studies identify roles for dopamine and opioids in motivation and reward involved in directed, extrinsically-rewarded behaviors (e.g., food-, mate- or drug-directed); however, these mechanisms appear to differ from those underlying affiliative communication, leaving a critical gap in basic knowledge about intrinsic reward mechanisms underlying affiliative social behaviors. The objectives of this proposal are to identify mechanisms by which opioids act in the medial preoptic nucleus (mPOA) and nucleus accumbens (NAc) to initiate, maintain, and reward affiliative communication using the unique communication properties of a songbird experimental system. Neural systems underlying important behaviors are usually highly conserved across species, thus studies in songbirds are expected to uncover a core, conserved circuit in which opioids act to initiate, reward, and maintain important social behaviors in contexts for which there is no obvious extrinsic reward, across vertebrates. The central hypothesis is that opioids act at mu opioid receptors (MOR) in the mPOA→VTA→NAc circuit to initiate, facilitate, and reward affiliative social behaviors. The rationale is the need for basic, mechanistic information on core social circuits that underlie behaviors disrupted by mental illness. Based on preliminary data, three specific aims are proposed: 1) Dissociate the functional roles of MOR in mPOA and NAc on affiliative singing behavior; 2) Determine effects of MOR gene knockdown in mPOA and NAc on affiliative song-associated reward; 3) Determine how environmental factors modulate affiliative song via MOR. In Aim 1 dual-cannula microinfusions of MOR agonists and antagonists into mPOA and NAc will be used to identify distinct roles played by MOR in mPOA and NAc in initiating and maintaining affiliative singing behavior. In Aim 2 siRNA targeting MOR in mPOA and NAc will be used to examine the role of MOR in song-associated reward measured using conditioned place preference tests. In Aim 3 environmental and site-specific pharmacological manipulations will be used to examine the impact of environmental stressors on MOR modulation of affiliative song. The approach is innovative because it advances the understanding of intrinsically-rewarded social behavior in songbirds with the goal of identifying core affiliative circuits. The proposal is significant because it will elucidate the role of MOR and reward in non-sexual, affiliative social behaviors and provide insight into core neural circuits that may be disrupted by mental illness in humans.