Neurodevelopmental Basis of Anxiety and Depressive Behavior

描述(由申请人提供)：NIH独立之路奖(K99/R00)的建议旨在阐明情绪失调的神经发育基础，情绪失调可能在焦虑和情绪障碍的发病中发挥作用。性格和情感反应的先天差异强烈地塑造了个人对压力的反应方式，这种生物天赋加上早期的生活经验可以有力地影响神经和情感的发展。了解先天因素和环境因素相互作用导致发育中大脑情感功能障碍的神经生物学机制，对于改进预防性治疗至关重要。因此，这项拟议的研究将阐明焦虑和抑郁共病模型中神经回路的个体发育，以更好地理解发育过程中的连接改变如何在以后的生活中导致情绪障碍。该项目利用了在情绪反应方面表现出显著差异的大鼠？这些人要么表现出高度的求新行为，要么表现出自然受抑制的行为，表现出更少的新奇诱导活动以及夸张的焦虑和抑郁行为。这些高新颖性和低新颖性特征似乎是可遗传的，存在于早期生命中，可能与海马体回路的差异形成有关。目前的建议旨在描述低新奇寻求者和高新奇寻求者的海马神经元个体发育的特征，并确定早期生活因素如何改变他们的海马体发育轨迹。在特定的目标1中，我们将确定海马区基因表达、形态和连接性的潜在变化，以确定这些回路如何在发育过程中展开。由于低/高追求新颖性的母亲表现出不同的母性风格，目标2中的研究将利用交叉培养范式来确定母亲护理如何塑造低/高新颖性寻求者？行为和神经上的差异。最后，在目标3中，我们将通过给予神经营养因子成纤维细胞生长因子-2(FGF2)来操纵海马体的发育，以确定它是否可以重塑低新颖性寻求者的神经情感回路，并缓解他们焦虑/抑郁样表型的出现。这些研究将共同确定神经发育机制，这些机制可能是个体在情绪性和抑郁和焦虑易感性方面的关键方面的基础。这最终可能会影响我们对情绪障碍的神经生物学的理解，以及如何开发改进的治疗方法。 K99/R00申请的研究和教育部分旨在为申请者提供必要的培训，使其成为一名成功的独立研究员，能够整合动物研究的分子、神经解剖学和行为研究结果，并有效地转化这些结果，以提高我们对精神疾病病理生理学的理解。 公共卫生相关性：项目叙述性格和气质的先天差异强烈影响个人对压力的反应，并使一些人面临患上抑郁和焦虑等情绪障碍的风险。这项建议使用抑郁/焦虑的动物模型来研究大脑发育异常如何在以后的生活中导致情绪障碍。最终，这项工作希望提高我们对情绪障碍的神经生物学的理解，并帮助开发更好的治疗方法。

DESCRIPTION (provided by applicant): This proposal for a NIH Pathway to Independence Award (K99/R00) aims to elucidate neurodevelopmental underpinnings of emotional dysregulation which may play a role in the onset of anxiety and mood disorders. Innate differences in personality and emotional reactivity strongly shape how individuals respond to stress, and this biological endowment together with early-life experience can powerfully influence neural and emotional development. Understanding the neurobiological mechanisms whereby inborn and environmental factors interact to contribute to the onset of affective dysfunction in the developing brain is crucial for generating improved preventative treatments. Thus, the proposed studies will elucidate the ontogeny of neural circuits in a model of comorbid anxiety and depression to better understand how altered wiring during development may give rise to emotional dysfunction later in life. The project utilizes rats exhibiting dramatic differences in emotional reactivity ? those that either exhibit high levels of novelty-seeking behavior and those that are naturally inhibited, showing much less novelty-induced activity as well as exaggerated anxiety- and depressive- like behavior. These high versus low novelty-seeking traits appear to be heritable, present in early life, and likely linked to differential formation of hippocampal circuits. The current proposal aims to characterize the ontogeny of hippocampal circuits in low vs. high novelty-seekers and determine how early-life factors may alter the trajectory of their hippocampal development. In Specific Aim 1 we will determine potential alterations of hippocampal gene expression, morphology and connectivity to define how these circuits unfold across development. Since low/high novelty-seeking mothers exhibit distinct maternal styles, studies in Aim 2 will utilize a cross-fostering paradigm to determine how maternal care shapes low/high novelty-seekers? behavioral and neural differences. Finally, in Aim 3 we will manipulate hippocampal development via administration of the neurotrophic factor Fibroblast Growth Factor-2 (FGF2) to determine whether it can reshape low novelty-seekers' neural emotional circuits and assuage the emergence of their anxious/depressive-like phenotype. Together these studies will identify neurodevelopmental mechanisms that may underlie key aspects of individual differences in emotionality and susceptibility to depression and anxiety. This may ultimately impact our understanding of the neurobiology of emotional disorders and how to develop improved treatments. The research and educational components of this K99/R00 application aim to provide necessary training for the applicant to become a successful independent investigator who can integrate molecular, neuroanatomical, and behavioral findings from animal studies, and effectively translate these results to improve our understanding of the pathophysiology of psychiatric disease. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Inborn differences in personality and temperament strongly influence how individuals respond to stress and put some people at risk for developing emotional disorders such as depression and anxiety. This proposal uses an animal model of depression/anxiety to study how abnormal brain development may give rise to emotional dysfunction later in life. Ultimately this work hopes to improve our understanding of the neurobiology of emotional disorders and help to develop improved treatments.