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，通常有益的社会交往可能会令人厌恶。赤字也可以是具体情况造成的。例如，一些患有自闭症的个体能够做出定向请求（例如，用于食品），其可以被额外增强（例如，通过接受食物）但在亲和性交流中表现出严重的缺陷（例如，非性的，闲聊），促进社会关系，是有益的，但不会导致一个直接的，明显的外部干扰。许多研究确定了多巴胺和阿片类药物在定向的、外在奖励的行为（例如，食物，配偶或药物导向）;然而，这些机制似乎不同于那些潜在的亲和沟通，留下了一个关键的差距，在基础知识的内在奖励机制的亲和社会行为。本提案的目的是确定阿片类药物在内侧视前核（mPOA）和核神经元（NAc）的作用机制，以启动，维持和奖励亲和通信使用独特的通信特性的鸣禽实验系统。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，其中阿片类药物在脊椎动物中没有明显的外在奖励的情况下启动，奖励和维持重要的社会行为。中心假设是阿片类药物作用于mPOA→VTA→NAc回路中的μ阿片受体（莫尔），以启动、促进和奖励亲和性社会行为。其基本原理是需要关于核心社会回路的基本机械信息，这些信息是精神疾病破坏行为的基础。基于初步数据，本研究提出了三个具体目标：1）分离mPOA和NAc中莫尔受体对亲和歌唱行为的功能作用; 2）确定mPOA和NAc中莫尔受体基因敲低对亲和歌唱相关奖赏的影响; 3）确定环境因素如何通过莫尔受体调节亲和歌唱。在目的1中，将莫尔激动剂和拮抗剂双套管微量输注到mPOA和NAc中，以鉴定莫尔在mPOA和NAc中启动和维持亲和性歌唱行为中所起的不同作用。在目标2中，靶向mPOA和NAc中的莫尔的siRNA将用于检查莫尔在使用条件性位置偏好测试测量的歌曲相关奖励中的作用。在目标3中，将使用环境和特定位点的药理学操作来检查环境应激对附属歌曲的莫尔调制的影响。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，目的是识别核心亲和回路。这项提议意义重大，因为它将阐明莫尔和奖励在非性、亲和性社会行为中的作用，并提供对可能被人类精神疾病破坏的核心神经回路的深入了解。

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.