The role of familiarity neurocircuitry in novelty seeking

熟悉性神经回路在寻求新奇事物中的作用

基本信息

批准号：
9982286
负责人：
ANDREW R TAPPER
金额：
$ 48.79万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982286
关键词：
5-Hydroxytryptophan Acute Address Affect Animal Model Anxiety Area Behavior Behavioral Biological Assay Biophysics Brain Cause of Death Cessation of life Consumption Country Data Disease Dopamine Dopamine Receptor Dose Drug Addiction Electrophysiology (science)Exploratory Behavior Familiarity Foundations Gene Delivery Genes Genetic study Goals Health Human Immunohistochemistry In Situ Hybridization Individual Intake Knowledge Link Mediating Molecular Molecular Biology Motivation Mus Neurons Neurotransmitters Nicotine Nicotine Dependence Nicotine Withdrawal Overdose Personality Traits Pharmaceutical Preparations Pharmacology Pharmacotherapy Publishing Receptor Signaling Rewards Role Serotonin Shapes Signal Transduction Slice Social Conditions Societies Stimulus System Testing Therapeutic United States Ventral Tegmental Area Viral Withdrawal Symptom Work addiction behavior influence behavioral response cigarette smoking conditioned place preference cost experimental study insight interpeduncular nucleus neural circuit neuronal circuitry neuropsychiatric disorder nicotine cessation novel novel therapeutic intervention optogenetics patch clamp preference prevent preventable death receptor recombinase-mediated cassette exchange response selective expression social trait

项目摘要

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.

项目概要/摘要识别可能使个人容易上瘾的因素是一个关键组成部分了解与成瘾相关的最常见的人格特征包括丰富的新奇寻求和偏好，这与增加的探索行为有关与熟悉的刺激相比，对新刺激的反应以及与新刺激的更多互动遗传学研究已将寻求新奇事物与多巴胺（DA）神经递质联系起来。系统以及参与血清素（5-羟色氨酸，5HT）信号传导的基因。大脑区域中 5HT 和 DA 之间的关系以及涉及新奇寻求和偏好的神经回路最近，我们发现脚间核（IPN）在其中发挥着重要作用。具体来说，IPN GABA 能神经元的激活可以起到抑制的作用。当新的刺激变得熟悉时，我们会对其进行探索。我们公布的初步数据表明，IPN 接收来自腹侧被盖区 (VTA) 和中缝 (MR) 的 DAergic 和 5HTergic 输入，我们认为这两个 IPN 传入相互作用会影响新奇寻求和偏好。通过调节熟悉度信号传导，目标 1 将结合光遗传学和小鼠行为来测试假设 VTA→IPN DAergic 回路的激活会阻止熟悉信号传递以增加新颖性目标 2 将使用类似的方法来确定 5HT 的寻求和探索新刺激的动机。通过从 MR 到 IPN 的血清素输入的受体信号传导可能会影响行为反应最后，Aim 3 将使用生物物理和光遗传学方法来确定如何。 5HT 和 DA 在 IPN 中相互作用以及它如何控制新颖性偏好所提出的结果。实验应该对对寻求新奇和偏好至关重要的电路产生重要的洞察力阐明与成瘾相关的行为特征的新机制。