The role of familiarity neurocircuitry in novelty seeking

项目摘要/摘要 确定可能使个人容易上瘾的因素是 了解疾病的基础。与成瘾有关的最常见的人格特征包括 更高的新颖性寻求和偏好，这与更多的探索行为有关 当给予新刺激时，与熟悉的刺激相比，对新刺激的反应和与新刺激的互动更多 分别选择。基因研究已将寻求新奇与多巴胺(DA)神经递质联系起来 系统，以及参与5-羟色胺(5-羟色氨酸，5-羟色胺)信号传递的基因。然而，这种互动 参与新奇寻求和偏好的脑区和神经元回路中的5-羟色胺和多巴胺之间是 人们对此知之甚少。最近，我们发现脚间核(IPN)在大脑中起重要作用。 追求新奇和偏爱。具体地说，IPN GABA能神经元的激活起到刹车的作用，以减少 探索新的刺激，因为它们变得熟悉。我们公布的和初步的数据表明，IPN 接受来自腹侧被盖区(VTA)和中缝正中缝(MR)的DAR和5HT能输入， 分别进行了分析。我们假设，这两个IPN传入相互作用，影响新奇寻求和偏好 通过熟悉度信号的调制。目标1将结合光遗传学和小鼠的行为来测试 一种假说：激活Vta→IPN DA能回路阻止熟悉性信号传递以增加新颖性 寻求和激励去探索新的刺激。目标2将使用类似的方法来确定5HT如何 从MR到IPN的5-羟色胺能传入的受体信号可能影响对 新奇而熟悉的刺激。最后，目标3将使用生物物理和光遗传学方法来确定 5HT和DA在IPN中相互作用，以及这如何控制新颖性偏好。建议的结果 实验应该对对新颖性寻求和偏好至关重要的电路有重要的洞察力 阐明与成瘾相关的行为特征潜在的新机制。

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.