奖赏相关记忆的细胞编码及分子基础

Natural and drug reward memories constitute the core of our personal history. Reward memory has powerful influences on learning, judging and decision that involve multiple brain reward and memory systems engaged at different stages of information processing. Recently it was reported that memory can be optogenetically manipulated and altered through memory engram, however the underlying neuronal basis and signal pathways are unknown. Based on our previous research findings, the natural and drug reward memory mouse models were adopted. Our system uses c-fos-tTA transgenic mice, in which the promoter of the c-fos gene drives the expression of the tetracycline transactivator (tTA) to induce expression of a gene of interest downstream of the tetracycline-responsive element (TRE). Combined with conditional knockout mice, Cre/Loxp AAV and lentivirus system and optogenetical manipulation, the scientific question of how the reward memory is stored will be investigated. The neuronal bases and molecular maps in the brain of reward memory encoding will be defined and the plasticity of memory encoding will be demonstrated in this research. The expected results will be helpful for the understanding of the neurocircuits and molecular mechanisms of memory, including reward memory, and developing novel strategy for the change or erasure of abnormal reward memories such as addiction.

以奖赏为驱动的行为对认知、记忆、情感等具有重要影响。以经历奖赏刺激形成的奖赏相关记忆是脑的高级认知功能，在记忆中占有核心地位，其功能异常导致成瘾等疾病。揭示奖赏相关记忆的细胞编码及其分子基础，对理解记忆的本质和机制具有重要的科学意义，同时也将为成瘾等记忆相关脑疾病的防治提供启示。对条件性恐惧记忆的最新研究提示，在记忆形成过程中可能只有相关脑区的少量神经元被激活，这些神经元参与了记忆的编码，并证明通过操控编码神经元的活性，已形成的记忆能够被提取和改变。本项目将在我们前期工作基础上，采用食物奖赏和精神类药物奖赏动物模型，在体标记奖赏记忆相关神经元，揭示其在奖赏记忆编码中的作用；研究奖赏相关记忆编码的细胞特性，分析奖赏相关记忆编码细胞的分子表达和结构功能特征；并通过对编码神经元的操纵，实现对奖赏相关记忆的调控或重编码。

奖赏相关记忆是脑的高级认知功能，其功能异常导致成瘾等疾病。揭示奖赏相关记忆的细胞编码及分子基础，对理解记忆的神经机制有重要意义，也将为成瘾等记忆相关脑疾病的防治提供启示。本项目采用自然奖赏和精神类药物奖赏动物模型，通过在体标记奖赏记忆相关神经元，揭示奖赏相关记忆编码的信号调控机制和细胞结构功能特征，并通过操纵编码神经元，实现对奖赏相关记忆的调控或重编码。我们的研究首次揭示vCA1至AcbC记忆痕迹神经元环路及其突触联系的增强介导了可卡因奖赏记忆的存储和提取（Zhou et al., Nat Neurosci 2019）；前边缘皮层SST以及PV中间神经元上不同的阿片受体，以直接和间接的方式，协同调控抑制性微环路，削弱对兴奋性神经元的抑制性输入，促进吗啡奖赏记忆的形成（Jiang et al., Mol Psychiatry 2019）；亲代药物成瘾可能通过表观遗传学机制对后代的神经系统发育进行重构，进而促进后代可卡因奖赏记忆的形成（Le et al., Nat Commun 2017）。在信号转导机制发面，我们发现中脑边缘系统lepR信号通路，前额叶皮质GRK5-mTOR信号通路调控了自然奖赏及药物奖赏的形成（Shen et al., Transl Psychiatry 2016; Niu et al., Cereb Cortex 2018）。前额叶皮层β-arrestin偏向的β-肾上腺素受体信号通路能加快奖赏记忆的消退、抑制环境线索诱导的可卡因复吸（Huang et al., Sci Signal 2018）。而背侧海马椎体神经元内的Tet3和NPTX2，则分别介导可卡因奖赏记忆的再巩固和消退（Liu et al., Int J Neuropsychopharmacol 2018; Wang et al., Biol Psychiatry 2019）。我们的研究结果揭示了奖赏相关记忆编码的细胞机制，以及奖赏记忆形成，表达和继代遗传的信号转导及转录调控机制。项目执行期间在Nat Neurosci、Nat Commun等SCI杂志上发表论文21篇，研究结果为干预成瘾性药物的复吸提供理论依据。