How social challenges prime the brain and body for social instability

描述（由申请人提供）：社会竞争在动物和人类生活中无处不在，来自竞争对手的威胁通常会引起类固醇激素睾酮的全身激增。虽然过去的研究表明社会挑战、睾丸激素以及一系列生理和行为影响之间存在明确的联系，但这些表型变化背后的分子机制却知之甚少。对社会挑战产生适当的有机反应需要行为和生理学的大规模协调（例如攻击性、疼痛耐受性和新陈代谢的变化），但大脑和身体共同作用以对社会挑战产生协调反应的转录组机制尚不清楚。拟议研究的长期目标是确定类固醇激素如何在对环境突发事件的基因组和行为反应中将大脑和外周联系起来。有效的假设是，社会挑战及其相关的睾丸激素激增是个人在未来竞争中取得成功的主要因素，有利于更大程度地调动能量储备，增强对伤害或炎症的反应，以及更强的空间和感觉能力，所有这些都是以牺牲自我维护为代价的。这一特定应用的目标是确定基因转录如何通过积极的社会互动而改变，并描述社会挑战的环境影响在大脑和外周中的差异，同时对社会不稳定产生协调的有机反应。该受试者是经过充分研究的鸣禽，其中社会挑战导致睾酮激素的系统性激增，并且睾酮激素对行为和生理学许多方面的影响（攻击性、免疫功能、压力、活动等）得到了很好的表征。通过采用新兴的基因组技术，包括基因集富集和网络共表达分析，拟议的研究将确定（1）严重的社会挑战和（2）持续的社会不稳定对基因转录的影响，相对于未受到挑战的对照动物。这些数据将揭示基因家族、基因网络内的连接中心以及特别容易受到社会诱导的可塑性影响的神经和外周组织。组织之间的共变模式将进一步揭示社会挑战促使大脑和身体对社会不稳定做出协调反应的精确分子机制。关于社会压力因素如何破坏正常健康的机体功能的知识可以应用于一系列激素和社会引起的人类健康问题（例如生殖健康、高度攻击性的行为障碍等），而通过对社会环境、大脑和外围设备的共同讨论来获得的见解尚未得到充分认识。 公共健康相关性：由于社会压力源在人类和动物生活中普遍存在，并且拟议的研究将确定特别容易受到急性或持续性社会压力源影响的基因、大脑区域和外周器官，因此这项研究填补了有关社会挑战经历产生生理和行为影响的分子机制方面尚未解决的知识空白。社会竞争和与社会挑战相一致的荷尔蒙变化与人类的各种公共卫生问题有关（例如欺凌、多动症、行为障碍、心脏和生殖健康等）。因此，拟议的研究确定了社会不稳定对全有机体基因表达的影响，将为开发治疗和预防影响各年龄段儿童和成人的许多行为和生理疾病的新靶标的进展奠定基础。

DESCRIPTION (provided by applicant): Social competition is ubiquitous in both animal and human life, and the threat from a competitor typically induces a systemic surge in the steroid hormone testosterone. While past research demonstrates clear connections among social challenges, testosterone and a suite of physiological and behavioral effects, the molecular mechanisms underlying these phenotypic changes are poorly understood. Generating an appropriate organismal response to social challenges requires large scale coordination of behavior and physiology (e.g. changes in aggression, pain tolerance, and metabolism), yet the transcriptomic mechanisms by which brain and body act together to produce a coordinated response to social challenges are unclear. The long-term goal of the proposed research is to determine how steroid hormones serve to link brain and periphery in genomic and behavioral responses to environmental contingencies. The working hypothesis is that social challenges, and their associated testosterone surges, prime individuals for success in future competition, favoring greater mobilization of energy reserves, heightened response to injury or inflammation, and greater spatial and sensory capabilities, all at the expense of self-maintenance. The objectives of this particular application are to identify how gene transcription is altered by aggressive social interactions, and to characterize how the environmental effects of a social challenge differ in brain and periphery, while engendering a coordinated organismal response to social instability. The subject is a well-studied songbird in which social challenges lead to a systemic surge in testosterone, and the effects of testosterone on many aspects of behavior and physiology are well characterized (aggression, immune function, stress, activity, etc.). By employing emerging genomic techniques, including gene set enrichment and network co-expression analyses, the proposed research will identify the effects of (1) acute social challenges and (2) persistent social instability on gene transcription, relative to unchallenged control animals. These data will reveal gene families, hubs of connectivity within gene networks, and neural and peripheral tissues that are particularly prone to socially induced plasticity. Patterns of co-variation among tissues will further reveal the precise molecular mechanisms by which social challenges prime the brain and body for a coordinated response to social instability. Knowledge of how social stressors derail normal healthy organismal function can be applied to a range of hormonally and socially induced human health issues (e.g. reproductive health, behavioral disorders of high aggression, etc.), where insights to be gained by co-discussion of social environment, brain, and periphery have yet to be fully realized. PUBLIC HEALTH RELEVANCE: Because social stressors are pervasive in human and animal life, and the proposed studies will identify the genes, brain regions and peripheral organs that are particularly susceptible to either acute or persistent socially stressors, this research fills unresolved knowledge gaps about the molecular mechanisms by which socially challenging experiences engender physiological and behavioral effects. Social competition and the hormonal changes that coincide with social challenges have been linked with a variety of public health issues in humans (e.g. bullying, ADHD, conduct disorder, cardiac and reproductive health, etc.). Thus, the proposed research, which identifies the effects of social instability on organism-wide gene expression, will lay the groundwork for advances in developing new targets for the treatment and prevention of a number of behavioral and physiological disorders affecting children and adults of all ages.