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，因此是亲代抚育的重要调节因子，即使只是通过其对催乳素的影响。VIP受体和纤维在所有已知与亲代抚育有关的大脑区域以及更普遍的社会行为回路中都被高密度地发现。除了对父母行为的假设影响外，有充分的理由认为VIP回路也会影响攻击行为、社交、性行为和伴侣关系；以及动机和焦虑的更普遍的方面。雀科Estrildidae是测试这些不同假设的理想群体，因为1)斑胸草雀（Taeniopygia guttata）表现出非凡的多样性，表现出稳健的、可量化的行为；2)几种斑胸草雀在物种典型群体规模上表现出巨大差异，但在行为和生态学的大多数其他方面仍然与斑胸草雀密切匹配。最近对雀类的研究表明，群体大小的选择是独立于简单的隶属关系的，这表明存在着重要的、但在很大程度上尚未被探索的社会神经机制。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到，因此本提案将探索可能是健康社交行为基础的神经行为机制，并确定可能使人们倾向于社交回避的变异。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。特异性目的1将利用VIP受体的中枢拮抗作用和使用反义寡核苷酸对VIP产生的位点特异性抑制来研究雄性和雌性斑胸草雀的社会性、焦虑、筑巢和亲代抚育的影响。焦点观察也将在群体环境中进行，允许对20多种行为进行量化，包括成对结合。具体目标2将采用类似的操作来测试高度具有领土意识的紫耳蜡喙（Uraeginthus granatina）的攻击性和焦虑行为。特异性目标3将采用原位杂交和免疫细胞化学相结合的方案来确定哪些VIP细胞组在雄性和雌性斑胸草雀筑巢，雄性斑胸草雀求爱，以及紫罗兰耳蜡雀的攻击性相互作用和非社会性防御反应中表现出增加的Fos激活。最后，Specific Aim 4将1)在三种群居动物和两种领地动物中检测暴露于同性刺激后VIP细胞群的Fos激活，2)定量比较VIP mRNA在同一动物中的分布。这些物种侧隔中VIP结合位点的密度与社会性呈正相关，表明VIP可能在区分群居动物和相对非群居动物的行为和/或生理反应中发挥重要作用。人们对这些过程知之甚少，但它们与心理健康明显相关。

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.