Social and Motivational Properties of Vasoactive Intestinal Polypeptide Circuits

描述（由申请人提供）：血管活性肠多肽（VIP）是脊椎动物催乳素分泌的主要调节剂，因此即使仅通过其对催乳素的作用，也是父母护理的中枢调节的重要贡献者。VIP受体和纤维在所有已知有助于父母照顾的大脑区域中以高密度存在，并且更普遍地贯穿整个社会行为回路。除了对父母行为的假设影响外，还有很好的理由相信VIP回路也会影响攻击性行为、社交性、性行为和配对关系，以及更普遍的动机和焦虑方面。雀科雌雀科是一个理想的群体，以测试这种不同的假设，鉴于1）斑马雀（Taeniopygia guttata）表现出非常多样的强大，可量化的行为，2）几个雌雀物种是可用的，表现出巨大的差异，在物种典型的群体大小，而仍然是密切匹配的斑马雀在大多数其他方面的行为和生态。最近的研究结果表明，在雀类群体大小的选择滴定独立于简单的从属关系，这表明存在重要的，但在很大程度上未被探索的社会性神经机制。社交焦虑和退缩通常与各种精神疾病和心理问题一起观察，因此这项建议将探索可能对健康的社会行为至关重要的神经行为机制，并确定可能使人们倾向于社交回避的变化。鸟类和哺乳动物的边缘-下丘脑回路是高度保守的，这使得雀类的行为稳健性为哺乳动物的相关研究提供了信息。 具体目标1将采用VIP受体的中枢拮抗作用和使用反义寡核苷酸的VIP产生的位点特异性敲低来检查对雄性和雌性斑胸草雀的社会性、焦虑、筑巢和父母照顾的影响。还将在群体环境中进行重点观察，以量化20多种行为，包括配对。具体目标2将采用类似的操作来测试高度领土性的紫耳蜡嘴鸟（Uraeginthus granatina）的攻击性和焦虑样行为。具体目标3将采用原位杂交和免疫细胞化学的组合方案，以确定哪些VIP细胞组显示出增加的Fos激活，以响应1）雄性和雌性斑胸草雀的筑巢，2）雄性斑胸草雀的求爱，以及3）紫耳蜡鸟的攻击性相互作用和非社会防御。最后，Specific Aim 4将1）检查三种群居物种和两种领地物种暴露于同性刺激后VIP细胞群的Fos激活，以及2）定量比较相同动物中VIP mRNA的分布。VIP结合位点在侧隔的密度呈正相关，在这些物种的社会性，表明VIP可能发挥重要作用，在区分行为和/或生理反应的群居和相对asocial动物。人们对这些过程知之甚少，但它们与心理健康明显相关。 公共卫生相关性：拟议的实验将检查大脑中的血管活性肠多肽（VIP）回路，这些回路可能对与分组、配对、攻击、焦虑和父母照顾相关的社会动机过程的整合至关重要，并且可能促进社会性的物种差异。这些实验的目的是：1）使用受体阻断剂和VIP产生的靶向敲除，确定VIP对社会动机的重要性; 2）通过标记VIP和最近活动的蛋白质标记物（Fos）来确定VIP神经元在各种社会环境中的活动模式，以及在群居和相对不合群的动物中。社交焦虑和接触行为的缺陷通常与各种精神疾病和心理问题，特别是抑郁症和创伤后应激障碍一起观察，因此这项建议将探索可能对正常，健康的社会取向至关重要的神经行为机制，并确定可能使人们倾向于社交退缩的变化。

DESCRIPTION (provided by applicant): Vasoactive intestinal polypeptide (VIP) is a major regulator of prolactin secretion in vertebrates, and is thus an essential contributor to the central regulation of parental care, even if only via its effects on prolactin. VIP receptors and fibers are found at high density in all brain area that are known to contribute to parental care, and throughout social behavior circuits more generally. In addition to hypothesized effects on parental behavior, there are excellent reasons to expect that VIP circuits also influence aggressive behavior, sociality, sexual behavior and pair bonding; and more general aspects of motivation and anxiety. The finch family Estrildidae is an ideal group for testing such diverse hypotheses, given that 1) zebra finches (Taeniopygia guttata) exhibit an extraordinary diversity of robust, quantifiable behaviors, and 2) several estrildid species are available that exhibit massive differences in species-typical group size, while still being closely matched to the zebra finch in most other aspects of behavior and ecology. Recent findings in finches demonstrate that choice of group size is titrated independently from simple affiliation, suggesting the presence of important but largely unexplored neural mechanisms of sociality. Social anxiety and withdrawal are commonly observed in conjunction with a variety of psychiatric disorders and psychological problems, and thus this proposal will explore neurobehavioral mechanisms that are likely fundamental to a healthy social behavior, and identify variations that may predispose people to social avoidance. Limbic-hypothalamic circuits in birds and mammals are strongly conserved, allowing the behavioral robustness of finches to inform relevant studies in mammals. Specific Aim 1 will employ central antagonism of VIP receptors and site-specific knockdown of VIP production using antisense oligonucleotides to examine effects on sociality, anxiety, nesting, and parental care in male and female zebra finches. Focal observations will also be conducted in a colony environment, allowing for the quantification of more than 20 behaviors, including pair bonding. Specific Aim 2 will employ similar manipulations for tests of aggression and anxiety-like behavior in the highly territorial violet-eared waxbill (Uraeginthus granatina). Specific Aim 3 will employ a combined protocol for in situ hybridization and immunocytochemistry to determine which VIP cell groups show increased Fos activation in response to 1) nest-building in male and female zebra finches, 2) courtship in male zebra finches, and 3) aggressive interactions and non-social defense in violet-eared waxbills. Finally, Specific Aim 4 will 1) examine the Fos activation of VIP cell groups following exposure to same-sex stimuli in three gregarious and two territorial species, and 2) quantitatively compare the distribution of VIP mRNA in the same animals. The density of VIP binding sites in the lateral septum is positively related to sociality in these species, suggesting that VIP may play an important role in differentiating the behavioral and/or physiological responses of gregarious and relatively asocial animals. Such processes are poorly understood, but are of clear relevance to mental health. PUBLIC HEALTH RELEVANCE: The proposed experiments will examine vasoactive intestinal polypeptide (VIP) circuits in the brain that are likely essential for the integration of social motivational processes relevant to grouping, pair bonding, aggression, anxiety, and parental care, and that likely promote species differences in sociality. The goals of these experiments are to 1) establish the importance of VIP for social motivation, using receptor blockers and targeted knockdown of VIP production, and 2) determine patterns of activity in VIP neurons across various social contexts, and in gregarious and relatively asocial animals, by labeling brain tissue for both VIP and a protein marker of recent activity (Fos). Social anxiety and deficits in contact behaviors are commonly observed in conjunction with a variety of psychiatric disorders and psychological problems, particularly depression and post-traumatic stress disorder, thus this proposal will explore neurobehavioral mechanisms that are likely fundamental to a normal, healthy social orientation, and identify variations that may predispose people to social withdrawal.