Perineuronal nets and cocaine-associated memories

 描述(由申请者提供)：治疗人类成瘾的一种策略是针对作为成瘾行为基础的记忆过程。反复吸毒会建立与毒品有关的记忆。当这些与药物有关的记忆被召回时，就像生物体再次暴露在与药物有关的线索、背景或药物本身中时，这些记忆被重新巩固以维持或加强它们。内侧前额叶皮质(MPFC)是人类寻求可卡因行为复发和啮齿动物恢复行为的关键因素。MPFC锥体神经元对伏隔核(NAC)兴奋性输出的增加被认为是复发的基础。在啮齿动物中，这种输出增加是在注射5次可卡因后和戒除可卡因自我给药45天后发现的，这意味着mPFC在维持与可卡因相关的记忆方面发挥了关键作用。然而，我们不知道mPFC促进这些记忆表达的机制。MPFC的输出受到小白蛋白(PV)快速放电的GABA能中间神经元的有效调节，其中大部分被形成神经周围网络(PNN)的特殊细胞外基质结构所包围。PNNS在发育过程中包裹着某些神经元，似乎可以稳定突触，降低成年期神经元的可塑性。然而，PNN可以在成年期被移除，以重建可塑性或通过其他强加的刺激来改变可塑性。我们发现，去掉大鼠初级mPFC(PL MPFC)内的PNN会减少条件性位置偏爱(CPP；以下称为“可卡因CPP记忆”)对可卡因相关记忆的再巩固。反复接触可卡因则有相反的作用：它增加了PNN的强度，并且这种强度与行为呈正相关，提示PL mPFC中的PNN强度可能可以作为可卡因诱导行为的预测因子。我们实验的总体布局如下：建立可卡因CPP记忆→重新激活可卡因CPP记忆±PNNS→重新巩固可卡因CPP记忆→随后测试可卡因CPP记忆的恢复，看看它是维持还是减少。我们认为，从PL mPFC中去除PNN可以通过减少记忆再巩固来阻止可卡因CPP记忆的维持。然而，我们不知道去掉PNN会降低记忆再巩固的机制。我们假设，在可卡因CPP记忆的重新巩固过程中，去除PL mPFC内的PNN可以改变可卡因诱导的可塑性。我们进一步假设，PNNS通过改变PL mPFC中抑制性中间神经元和锥体神经元的活动来调节再巩固。我们将训练大鼠在存在和不存在PNNS的情况下进行可卡因诱导的CPP，并确定PNN周围神经元在PL mPFC中的动态变化：1)记忆重新激活之前和之后；2)可卡因诱导恢复之前和之后。我们将使用行为学、电生理学、形态学、共聚焦和电子显微镜等方法来检验我们的假设。PNNS是一个非常新颖的靶点，用于解剖对可卡因诱导的可塑性和维持可卡因相关记忆至关重要的事件。我们的发现将对理解已经形成的可卡因记忆如何通过靶向mPFC内PNN周围的神经元来破坏具有潜在深远的影响。

 DESCRIPTION (provided by applicant): One strategy for treating human addiction is to target memory processes that underlie addictive behaviors. Repeated drug use establishes drug-related memories. When these drug-related memories are recalled, as occurs when the organism is re-exposed to drug-associated cues, context, or the drug itself, those memories are reconsolidated to maintain or strengthen them. The medial prefrontal cortex (mPFC) is a key contributor to relapse to cocaine-seeking behavior in humans and reinstatement behavior in rodents. Increased excitatory output from mPFC pyramidal neurons to the nucleus accumbens (NAc) is thought to underlie relapse. In rodents, this increased output is found after 5 cocaine injections and after 45 days of withdrawal from cocaine self-administration, implicating a key role for the mPFC in the maintenance of cocaine-associated memories. However, we do not know the mechanisms by which the mPFC contributes to the expression of these memories. Output from the mPFC is powerfully regulated by parvalbumin (PV)-fast-spiking GABAergic interneurons, the majority of which are surrounded by specialized extracellular matrix structures that form perineuronal nets (PNNs). PNNs envelope certain neurons during development and appear to stabilize synapses, reducing plasticity in neurons during adulthood. However, PNNs can be removed during adulthood to re-establish plasticity or to modify plasticity by other imposing stimuli. We have discovered that removal of PNNs within the rat prelimbic mPFC (PL mPFC) decreases the reconsolidation of cocaine-associated memories as tested with conditioned place preference (CPP; hereafter called "cocaine CPP memory"). Repeated cocaine exposure has the opposite effect: it increases PNN intensity, and this intensity is positively correlated with behavior, suggesting that PNN intensity in the PL mPFC may serve as a predictor of cocaine- induced behavior. A general layout of our experiments is as follows: Establish cocaine CPP memory→ reactivate cocaine CPP memory ± PNNs→ reconsolidate cocaine CPP memory→ subsequent test for reinstatement of cocaine CPP memory to see if it is maintained or diminished. We propose that removal of PNNs from the PL mPFC prevents the maintenance of cocaine CPP memory via diminished memory reconsolidation. However, we do not know the mechanisms by which PNN removal decreases memory reconsolidation. We hypothesize that removal of PNNs within the PL mPFC modifies cocaine-induced plasticity during the reconsolidation of a cocaine CPP memory. We further hypothesize that reconsolidation is mediated by PNNs through altered activity of inhibitory interneurons and pyramidal neurons in the PL mPFC. We will train rats for cocaine-induced CPP in the presence and absence of PNNs and define the dynamic changes in PNN-surrounded neurons in the PL mPFC 1) just prior to and after memory reactivation; and 2) just prior to and after cocaine-induced reinstatement. We will use behavioral, electrophysiological, morphological, and confocal and electron microscopic approaches to test our hypotheses. PNNs are a highly novel target for dissecting events critical for cocaine-induced plasticity and the maintenance of cocaine-associated memories. Our findings will have potentially far-reaching consequences for understanding how already-formed cocaine memories can be disrupted by targeting PNN-surrounded neurons within the mPFC.