Neurobiological Investigation of BLA->NAc Circuit in Motivated Behavior

描述（由申请人提供）：预测奖励的环境刺激可以通过学习线索-结果关联获得生物学显著性。这些关联可以促进动机行为的表达，伏隔核（NAc）在这一过程中起着关键作用[1-5]。NAc通常被视为边缘-运动接口，整合来自皮层和皮层下结构的信息，这些结构与记忆、驱动和动机有关，并影响运动输出。基底外侧杏仁核（BLA）是一个重要的神经区域，它向NAc发送谷氨酸能投射，并似乎在响应奖励配对线索时促进目标寻求行为[7,8]。虽然大量研究表明，在动机行为的执行过程中，BLA宏回路之间和内部高度连接[14-19]，但利用现有技术，很难有选择地操纵BLA- nac通路。因此，对于孤立的BLA输入到NAc如何促进行为和NAc细胞放电，并最终驱动与动机行为相关的联想学习，我们知之甚少。重要的是，Stuber及其同事最近的一项研究使用光遗传学选择性地抑制BLA-NAc通路，并证明了在奖励预测提示呈现过程中目标导向行为的强大破坏。尽管信息量很大，但该研究并没有检验在单独的动物中，在获取和表达动机行为时BLA-NAc抑制的影响，或者在BLA-NAc失活期间对奖励配对和不配对（一般）线索的行为的影响。此外，尽管先前的研究表明，BLA的非特异性药物失活会在提示工具任务[21]中不同程度地破坏NAc细胞对线索的放电，但尚不清楚这种影响是由于BLA的普遍失活，还是抑制了对NAc的特异性BLA输入。因此，在此应用程序中提出了两个特定的目标来解决这些问题。目的1将使用光遗传学工具研究BLA-NAc途径在一阶条件反射（FOC）的获取和表达中的作用。目的2将使用光遗传学方法结合电生理记录程序来表征在FOC期间，BLA传入输入对NAc细胞放电的贡献。拟议研究的结果将为精确的

DESCRIPTION (provided by applicant): Environmental stimuli that predict reward can acquire biological salience through learned cue-outcome associations. These associations can promote the expression of motivated behaviors and the nucleus accumbens (NAc) plays a key role in this process [1-5]. The NAc is commonly viewed as the limbic-motor interface [6], integrating information from cortical and subcortical structures related to memory, drive and motivation and influencing motor output. The basolateral amygdala (BLA) is one important neural region that sends glutamatergic projections to the NAc and appears to promote goal-seeking behaviors in response to reward-paired cues [7, 8]. While a considerable body of research implicates the highly inter- and intra- connected BLA macrocircuit in the execution of motivated behaviors [14-19], it has been difficult to selectively manipulate the BLA-NAc pathway with available techniques. As such, little is known about how isolated BLA input to the NAc contributes to behavior and NAc cell firing and ultimately drives associative learning related to motivated behaviors. Importantly, a recent study by Stuber and colleagues [20] used optogenetics to selectively inhibit the BLA-NAc pathway and demonstrated a robust disruption of goal-directed actions during reward-predictive cue presentation. Although highly informative, that study did not examine the effects of BLA- NAc inhibition during acquisition versus expression of motivated behavior in separate animals, or behavior to reward-paired versus unpaired (general) cues during BLA-NAc inactivation. Further, although previous studies have shown that nonspecific pharmacological inactivation of the BLA differentially disrupts phasic NAc cell firing to cues during a cued-instrumental task [21], it is not known if this effect was the result of generalized BLA inactivation, or inhibition of specific BLA inputs to the NAc. As such, two specific Aims are proposed in this application to address these issues. Aim 1 will examine the role of the BLA-NAc pathway in the acquisition versus expression of first order conditioning (FOC) using optogenetic tools. Aim 2 will use optogenetic methods coupled with electrophysiological recording procedures to characterize the contribution of BLA afferent inputs to the NAc on NAc cell firing during FOC. The results of the proposed studies will provide critical information into the precise role of BLA inputs to the NAc in discrete aspects of FOC behavior, and in modulating the activity of NAc neurons that encode FOC. Importantly, completion of the proposed studies will also enable my continued training in electrophysiology and optogenetic methods in behaving animals.