Mechanisms underlying intrinsically rewarded social behaviors

在抑郁症、焦虑症和自闭症谱系障碍的情况下，通常有益的社交互动可能是令人厌恶的。赤字也可能是特定于具体情况的。例如，一些自闭症患者能够提出直接的请求(例如，要食物)，这些请求可以从外部加强(例如，通过接收食物)，但在附属沟通方面表现出严重的缺陷(例如，非性、闲聊)，这促进了社会纽带，是有回报的，但不会产生直接的、明显的外部强化。许多研究发现，多巴胺和阿片类药物在定向、外在奖励行为(如食物、配偶或药物导向)所涉及的动机和奖励中所起的作用；然而，这些机制似乎与潜在的从属沟通不同，导致对从属社会行为背后的内在奖励机制的基本知识存在严重差距。该提案的目的是利用鸣禽实验系统的独特通信特性，确定阿片类药物在内侧视前核(MPOA)和伏隔核(NAC)启动、维持和奖励联系通信的机制。重要行为背后的神经系统通常在不同物种之间高度保守，因此对鸣禽的研究有望揭示一个核心的、保守的回路，在没有明显外在奖励的情况下，阿片类药物在脊椎动物中启动、奖励和维持重要的社会行为。中心假说是，阿片类药物作用于mPOA→Vta→NAc环路中的u阿片受体(MOR)，以启动、促进和奖励附属的社会行为。其理论基础是需要关于核心社会回路的基本机械信息，这些信息是被精神疾病扰乱的行为的基础。基于初步数据，我们提出了三个具体目标：1)分离mPOA和NAC中MOR基因在关联歌唱行为中的作用；2)确定mPOA和NAC中MOR基因敲除对关联歌曲奖赏的影响；3)确定环境因素如何通过MOR调节关联歌唱。在目标1中，将MOR激动剂和拮抗剂双套管微量注入mPOA和NAC，以确定MOR在mPOA和NAC启动和维持联系歌唱行为中所扮演的不同角色。在AIM 2中，针对mPOA和NAC中MOR的siRNA将被用来研究MOR在通过条件位置偏好测试测量的歌曲相关奖励中的作用。在AIM 3中，将使用环境和特定部位的药理学操作来研究环境应激源对联系歌曲的MOR调节的影响。这种方法是创新的，因为它促进了对鸣禽内在奖励社会行为的理解，目的是识别核心联系回路。这项提议意义重大，因为它将阐明MOR和奖励在非性社交行为中的作用，并为人类可能被精神疾病扰乱的核心神经回路提供洞察。

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.