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因子，因此是父母照料的中央调节的重要因素，即使仅通过其对催乳素的影响。VIP受体和纤维在所有已知对父母照顾有贡献的大脑区域以及整个社会行为回路中都以高密度存在。除了假设对父母行为的影响外，我们有很好的理由预计，VIP回路也会影响攻击性行为、社交、性行为和伴侣关系；还有更普遍的动机和焦虑方面的影响。雀科雌雀是检验这种不同假设的理想群体，因为1)斑雀(斑雀)表现出非常多样化的健壮、可量化的行为，以及2)几个雌雀物种在物种-典型的群体规模上表现出巨大的差异，同时在行为和生态的大多数其他方面仍然与斑纹雀非常接近。最近在雀类上的发现表明，群体大小的选择独立于简单的从属关系而被滴定，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障碍和心理问题一起被观察到，因此本提案将探索可能是健康社会行为的基础的神经行为机制，并找出可能使人们倾向于社交回避的变量。鸟类和哺乳动物的边缘-下丘脑回路是非常保守的，这使得雀类的行为健壮性为哺乳动物的相关研究提供了信息。具体目标1将利用VIP受体的中枢拮抗作用和使用反义寡核苷酸定点敲除VIP产生来检查对雄性和雌性斑马雀的社交、焦虑、筑巢和父母照顾的影响。焦点观察也将在群体环境中进行，允许量化20多种行为，包括配对结合。特殊目的2将使用类似的操作来测试高度地域性的紫耳蜡嘴(Uraegintus Granatina)的攻击性和焦虑样行为。《特定目标3》将采用原位杂交和免疫细胞化学相结合的方法来确定哪些VIP细胞群在1)雄性和雌性斑马雀的筑巢、2)雄性斑纹雀的求偶以及3)紫耳蜡鸟的攻击性互动和非社会防御反应中表现出更高的Fos活性。最后，特定目标4将1)检测在三个群居物种和两个区域物种中暴露于同性刺激后VIP细胞组的Fos激活，以及2)定量比较VIP mRNA在相同动物中的分布。在这些物种中，外侧隔膜中VIP结合位点的密度与社会性呈正相关，这表明VIP可能在区分群居和相对非社会性动物的行为和/或生理反应方面发挥重要作用。人们对这些过程知之甚少，但它们与心理健康有着明显的相关性。 与公共健康相关：拟议的实验将检查大脑中的血管活性肠多肽(VIP)回路，这些回路可能对整合与分组、结对、攻击性、焦虑和父母照顾相关的社会动机过程至关重要，并可能促进社会性的物种差异。这些实验的目的是：1)使用受体阻滞剂和靶向阻断VIP的产生，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)的脑组织，确定不同社交背景下VIP神经元的活动模式，以及在群居和相对非社交动物中的VIP活动模式。社交焦虑和接触行为缺陷通常与各种精神障碍和心理问题，特别是抑郁症和创伤后应激障碍一起被观察到，因此，这项提议将探索可能是正常、健康的社会取向的基础的神经行为机制，并找出可能使人倾向于社交退缩的变量。

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.