Maternal Transfer of Oxytocin and Thyroid-disrupting Indoor Flame Retardants Affecting Offspring Social Brain

社会认知是物种生存所必需的基本过程。社交过程中的干扰 被NIMH研究领域标准倡议确定为跨精神病学的一个主要领域 疾病包括神经发育障碍(NDDS)，如自闭症谱系障碍(ASD)。ASD 流行率继续以惊人的速度增长，每54名美国儿童中就有1名受到影响，其特点是 无法解释的性二态。虽然ASD有很强的遗传成分，但这种疾病在大多数情况下是， 多因素，由性别特有的遗传易感性与环境因素相互作用在 关键的发育期。因此，环境暴露，包括暴露于内分泌干扰 化学物质(EDCs)可能是ASD发病率上升的原因之一。然而，实验证据并没有 建立了与特定化学品的直接联系，机制仍然难以捉摸。多溴联苯醚是商业火焰 在人类母乳中发现的与儿童发育缺陷有关的阻滞剂。我们的实验室有 结果表明，商业多溴二苯醚混合物DE-71会产生与ASD相关的表型，包括缺乏 社会认知记忆，夸张的重复行为，以及改变社会认知的神经分子特征 神经肽、催产素和加压素及其受体。多溴联苯醚在结构上类似于甲状腺 荷尔蒙(TH)，对社会性大脑回路的神经发育至关重要，并调节OXT和AVP。 因此，我将测试这一新的假设，即发育中的多溴二苯醚会产生甲状腺功能低下状态，从而破坏 中枢氧化应激系统中的信号与社会神经回路畸形导致的缺陷 社会情绪行为。在目标1下的机理研究中，我将审查多溴二苯醚的TH目标和 TH干扰对暴露于多溴联苯醚的男性和 使用母体甲状腺补充的雌性后代。体内OXT释放的化学激活 PVN将被用来试图挽救PBDE诱导的异常表型。在电路级研究中使用 逆行追踪在目标2下，我将研究相互作用的边缘前皮质的PBDE重新编程 杏仁核基底外侧环路，这对社会识别能力至关重要。由于此电路依赖于0xT 受体(OXTR)信号，并声称接收来自PVN的OXTerable投射，我将确定是否 发育中的鼻腔OXT挽救了由多溴二苯醚产生的结构变化。这些研究将调查 多溴联苯醚跨生物组织母体移植对神经发育的影响 和发育年龄开始了解风险的机制和关键窗口。我的发现将提供 必要的关键机械信息，以突破关于可能的环境的知识空白 对NDDS的风险。他们还将告知后叶催产素在社交和情绪识别行为中的作用 以及在神经发育过程中改变电路水平功能的机制。最终，这些发现可能最终会 转化为开发治疗心理社会非传染性疾病的替代治疗方法。

Social cognition is a fundamental process essential for species survival. Disturbances in social processing have been identified by the NIMH Research Domain Criteria Initiative as a major domain disrupted across psychiatric disorders including neurodevelopmental disorders (NDDs) such as autism spectrum disorders (ASD). ASD prevalence continues to increase at an alarming rate, affecting 1 in 54 U.S. children, and characterized by an unexplained sexual dimorphism. While ASD has a strong genetic component, the disorder is in most cases, multifactorial, resulting from sex-specific genetic susceptibilities interacting with environmental factors during critical developmental periods. Thus environmental exposures, including exposures to endocrine disrupting chemicals (EDCs), may contribute to the rising prevalence of ASD. However, experimental evidence has not established a direct link with specific chemicals and mechanisms remain elusive. PBDEs are commercial flame retardants found in human breast milk that are associated with developmental deficits in children. Our lab has shown that the commercial PBDE mixture, DE-71, produces ASD-relevant phenotypes that include deficient social recognition memory, exaggerated repetitive behavior, and altered neuromolecular profiles for the social neuropeptides, oxytocin (OXT) and vasopressin, and their receptors. PBDEs structurally resemble thyroid hormones (TH), which are both critical for neurodevelopment of social brain circuits and regulate OXT and AVP. Therefore, I will test the novel hypothesis that developmental PBDEs produce a hypothyroid state, which disrupts signaling in the central OXTergic system and malformation of social neural circuits leading to deficient socioemotional behavior. In mechanistic studies under Aim 1, I will examine the TH targets of PBDEs and the contribution of TH disruption to altered behavior and neuropeptide phenotypes of PBDE-exposed male and female offspring using maternal thyroid supplementation. Chemogenetic activation of OXT release within the PVN will be employed in an attempt to rescue PBDE-induced abnormal phenotypes. In circuit-level studies using retrograde tract-tracing under Aim 2, I will examine PBDE reprogramming of the reciprocal preflimbic cortex to basolateral amygdala circuit, which is critical for social recognition ability. Since this circuit depends on OXT receptor (OXTR) signaling and is purported to receive OXTergic projections from PVN, I will determine if developmental intranasal OXT rescues structural changes produced by PBDEs. These studies will investigate the neurodevelopmental effects of maternal transfer of PBDEs across multiple levels of biological organization and developmental ages to begin to understand mechanisms and critical windows of risk. My findings will provide critical mechanistic information necessary to break through gaps in knowledge about the possible environmental risk to NDDs. They will also inform about the role of oxytocin underlying social and emotion recognition behavior and the mechanisms altering circuit-level function during neurodevelopment. Finally, the findings may eventually translate to the development of alternative therapeutic approaches to treat psychosocial NDDs.