Striatal Plasticity in Habit Formation as a Platform to Deconstruct Adaptive Learning
习惯形成中的纹状体可塑性作为解构适应性学习的平台
基本信息
- 批准号:10451714
- 负责人:
- 金额:$ 101.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
ABSTRACT
A distinguishing feature of the brain is that its circuitry isn’t computationally static, it adapts to
experience. Understanding the circuit mechanisms for adaptive behavior carries two-fold potential benefits -
revealing the brain’s learning rules and identifying key behaviorally significant functional “nodes”. These nodes
suggest potent sites to target for therapy development and may also be instructive to suggest more basic
circuit principles underlying behavior.
Using striatal circuitry and habit learning as a model system, we recently uncovered a set of paradigm-
challenging findings in a striatum-dependent habit learning task. In particular, we discovered a new circuit-level
signature, termed dviLP (direct vs indirect Latency Plasticity), which distinguishes striatal slices prepared from
habitual vs goal-directed animals. The features of dviLP shift long-held attention on rate differences between
the two principle projection neuron types, those to the direct and indirect pathways, to consider that
behaviorally adaptive signals may be generated by plasticity of their relative timing to fire. Moreover, the origin
of this plasticity appears to involve striatal fast-spiking interneurons, a highly non-canonical site for the
expression of long-lasting plasticity. Beginning with this highly novel foundation, here we propose to generate a
robust predictive computational model for striatal-dependent learning mechanisms by joining multiple
disciplines and multiple levels of analysis through an iterative process of circuit modeling and experimentation.
In Aim 1, we will comprehensively map functional changes in synaptic and cellular activity that define the
behavioral transition from goal-directed to habitual in an operant lever press task. We will use a layered suite of
molecular genetic tools to assign coordinates that specify inputs, outputs, compartments (striosome/matrix)
and regions (medial, dorsal). In Aim 2, we will measure the activity of genetically specified components of the
striatum in behaving mice, identifying the dynamic changes that correlate with and cause the shift from goal-
directed to habitual behavior. Our team offers multidisciplinary strengths. Dr. Calakos and Yin have expertise in
habit behavior, plasticity mechanisms and in vivo circuit dynamics; ideal for spearheading this effort. The
success and impact of this effort will be amplified by tightly incorporating Dr. Brunel’s expertise in
computationally modeling brain learning mechanisms and Dr. Tadross’s novel pharmacogenetic reagents that
are ideally positioned to test causality of synaptic plasticity events, offering the unique opportunity to
manipulate a specific synaptic receptor in a genetically defined cell type. Ultimately, we expect that the
knowledge gained through this highly collaborative proposal will provide a foundational resource to accelerate
understanding of striatal learning rules for adaptive behavior.
抽象的
大脑的一个显着特征是其电路不是计算静态的,它适应
经验。了解自适应行为的电路机制具有两倍的潜在优势 -
揭示大脑的学习规则并确定关键在行为上重要的功能“节点”。这些节点
提出有效的地点以进行治疗开发,并且可能会有所帮助提出更多基础
电路原则的基本行为。
使用纹状体回路和习惯学习作为模型系统,我们最近发现了一组范式
依赖纹状体的习惯学习任务中的挑战性发现。特别是,我们发现了一个新的电路级
签名,称为DVILP(直接与间接延迟可塑性),将纹状体切片与制备的纹状体切片区分开
习惯性与目标的动物。 DVILP移动的特征长期以来关注速率差异
两种主要投射神经元类型,即直接和间接途径的类型,以考虑
行为自适应信号可能是通过其相对时间发射的可塑性来产生的。而且,起源
这种可塑性似乎涉及纹状体快速刺激性中间神经元,这是一个高度非规范的位点
持久可塑性的表达。从这个高度新颖的基础开始,我们在这里提议生成一个
通过加入多个纹状体依赖性学习机制的强大预测计算模型
通过电路建模和实验的迭代过程,学科和多个分析级别。
在AIM 1中,我们将全面绘制突触和细胞活动的功能变化,以定义
在操作杠杆新闻任务中,从目标定向到习惯的行为过渡。我们将使用一套分层的套件
分子遗传工具分配指定输入,输出,隔室(striosome/artrix)的坐标
和区域(内侧,背)。在AIM 2中,我们将测量一般指定组件的活动
行为小鼠的纹状体,确定与目标相关的动态变化并导致从目标转移
针对习惯行为。我们的团队提供多学科的优势。 Calakos博士和Yin具有专业知识
习惯行为,可塑性机制和体内电路动力学;率先进行这项工作的理想选择。这
这项工作的成功和影响将通过紧密编码Brunel博士的专业知识来扩展
计算对脑学习机制的建模和塔德罗斯博士的新型药物遗传试剂
理想的位置可以测试突触可塑性事件的因果关系,从而提供了独特的机会
在一般定义的细胞类型中操纵特定的突触受体。最终,我们期望
通过这项高度协作的建议获得的知识将提供基本的资源来加速
了解适应性行为的纹状体学习规则。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Non-monotonic effects of GABAergic synaptic inputs on neuronal firing.
- DOI:10.1371/journal.pcbi.1010226
- 发表时间:2022-06
- 期刊:
- 影响因子:4.3
- 作者:
- 通讯作者:
共 1 条
- 1
NICOLE CALAKOS的其他基金
Significance of Protein Synthesis by the Integrated Stress Response in Neuromodulatory Neurons for Adaptive Behavior and Synaptic Plasticity
神经调节神经元综合应激反应蛋白质合成对适应性行为和突触可塑性的意义
- 批准号:1071834510718345
- 财政年份:2023
- 资助金额:$ 101.85万$ 101.85万
- 项目类别:
Striatal Plasticity in Habit Formation as a Platform to Deconstruct Adaptive Learning
习惯形成中的纹状体可塑性作为解构适应性学习的平台
- 批准号:1020780310207803
- 财政年份:2018
- 资助金额:$ 101.85万$ 101.85万
- 项目类别:
Striatal Plasticity in Habit Formation as a Platform to Deconstruct Adaptive Learning
习惯形成中的纹状体可塑性作为解构适应性学习的平台
- 批准号:97890689789068
- 财政年份:2018
- 资助金额:$ 101.85万$ 101.85万
- 项目类别:
Novel high-throughput screening for modifiers of TorsinA pathology
TorsinA 病理修饰因子的新型高通量筛选
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- 财政年份:2013
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Novel high-throughput screening for modifiers of TorsinA pathology
TorsinA 病理修饰因子的新型高通量筛选
- 批准号:86341538634153
- 财政年份:2013
- 资助金额:$ 101.85万$ 101.85万
- 项目类别:
Development of a Novel Model for Tourettes Syndrome
抽动秽语综合症新模型的开发
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- 财政年份:2012
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- 财政年份:2012
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- 财政年份:2012
- 资助金额:$ 101.85万$ 101.85万
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研究 TorsinA 功能障碍后果的新型基因小鼠模型
- 批准号:81145318114531
- 财政年份:2011
- 资助金额:$ 101.85万$ 101.85万
- 项目类别:
Novel Genetic Mouse Model to Study the Consequences of TorsinA Dysfunction
研究 TorsinA 功能障碍后果的新型基因小鼠模型
- 批准号:82875478287547
- 财政年份:2011
- 资助金额:$ 101.85万$ 101.85万
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