The role of familiarity neurocircuitry in novelty seeking

项目总结/摘要 识别可能使个体易患成瘾的因素是预防成瘾的关键组成部分。 了解疾病的基础。与成瘾相关的最常见人格特征包括 增强的新奇寻求和偏好，这与增加的探索行为有关， 与熟悉的刺激相比，当给予一种刺激时， 选择，分别。遗传学研究将新奇与多巴胺（DA）神经递质联系起来 系统，以及参与血清素（5-羟色氨酸，5 HT）信号传导的基因。然而，互动 在大脑区域和涉及新奇寻求和偏好的神经元回路中， 不太了解。最近，我们已经表明，脚间核（IPN）是关键参与， 新奇和偏好。具体地，IPN GABA能神经元的激活充当减少神经元损伤的制动器。 探索新的刺激，因为他们变得熟悉。我们公布的和初步的数据表明，IPN 接受来自腹侧被盖区（VTA）和中缝（MR）的DA能和5 HTergic输入， 分别我们假设这两个IPN传入相互作用，影响新奇寻求和偏好 通过熟悉信号的调节。Aim 1将联合收割机与小鼠行为学相结合， VTA→IPN DA能回路激活阻止熟悉性信号传递以增加新奇性的假设 寻求和动机探索新的刺激。目标2将使用类似的方法来确定5 HT如何 通过从MR到IPN的多巴胺能输入的受体信号传导可能影响对 新奇和熟悉的刺激。最后，Aim 3将使用生物物理学和光遗传学方法来确定 5 HT和DA在IPN中相互作用，以及这如何控制新奇偏好。结果从拟议的 实验应该产生重要的洞察电路的关键新奇寻求和偏好， 阐明与成瘾相关的行为特征的新机制。

Project Summary/Abstract Identifying factors that may predispose individuals to developing addiction is a critical component in understanding the basis of the disease. The most common personality traits associated with addiction include heightened novelty seeking and preference, which are associated with increased exploratory behavior in response to novel stimuli and more interaction with novel stimuli compared to familiar stimuli when given a choice, respectively. Genetic studies have linked novelty seeking with the dopamine (DA) neurotransmitter system, as well as genes involved in serotonin (5-hydroxytryptophan, 5HT) signaling. However, the interaction between 5HT and DA in brain areas and neuronal circuits involved in novelty seeking and preference are poorly understood. Recently, we have shown that the interpeduncular nucleus (IPN) is critically involved in novelty seeking and preference. Specifically, activation of IPN GABAergic neurons acts as a brake to reduce exploration of novel stimuli as they become familiar. Our published and preliminary data indicate that the IPN receives DAergic and 5HTergic inputs from the ventral tegmental area (VTA) and median raphe (MR), respectively. We hypothesize that these two IPN afferents interact to affect novelty seeking and preference through modulation of familiarity signaling. Aim 1 will combine optogenetics and behavior in mice to test the hypothesis that activation of a VTA→IPN DAergic circuit prevents familiarity signaling to increase novelty seeking and motivation to explore novel stimuli. Aim 2 will use a similar approach to determine how 5HT receptor signaling through serotonergic input from the MR to the IPN may influence the behavioral response to novel and familiar stimuli. Finally, Aim 3 will use a biophysical and optogenetic approach to determine how 5HT and DA interact in the IPN and how this controls novelty preference. The results from the proposed experiments should yield significant insight into circuits critical for novelty seeking and preference and elucidate new mechanisms underlying behavioral traits associated with addiction.