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的线索-结果关联获得生物学上的显著。这些联系可以促进动机行为的表达，而伏隔核(NAC)在这一过程中起着关键作用[1-5]。NAC通常被视为边缘-运动界面[6]，整合来自皮质和皮质下结构的与记忆、动力和动机相关的信息，并影响运动输出。杏仁基底外侧核(BLA)是一个重要的神经区域，它向NAC发送谷氨酸能投射，并似乎促进目标寻找行为对奖励配对线索的反应[7，8]。虽然大量的研究表明，高度相互和内部连接的BLA宏电路与执行动机行为有关[14-19]，但用现有技术选择性地操纵BLA-NAC通路一直是困难的。因此，关于孤立的BLA输入如何影响行为和NAC细胞的激活，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和他的同事最近的一项研究[20]利用光遗传学选择性地抑制了BLA-NAC通路，并证明了在奖赏预测线索呈现过程中目标定向动作的强烈干扰。虽然这项研究信息量很大，但并没有检验在获取过程中抑制BLA-NAC与单独动物的动机行为表达之间的影响，或者在BLA-NAC失活期间对奖励配对线索的行为与不配对(一般)线索的行为的影响。此外，尽管以前的研究表明，在线索-工具任务中，BLA的非特异性药物失活不同地扰乱了NAC细胞对线索的时相激活[21]，但尚不清楚这种影响是普遍的BLA失活还是抑制特定BLA输入到NAC的结果。因此，在本申请中提出了两个具体目标来解决这些问题。目的1将利用光遗传学工具研究BLA-NAC通路在一阶条件反射(FOC)获得和表达中的作用。AIM 2将使用光遗传学方法结合电生理记录程序来表征在FOC过程中NAC的BLA传入输入对NAC细胞放电的贡献。拟议研究的结果将提供关键的信息，使 BLA对NAC的输入在FOC行为的离散方面以及在调节编码FOC的NAC神经元的活动中所起的作用。重要的是，完成拟议的研究还将使我能够继续训练动物的电生理学和光遗传学方法。

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.