College of Pharmacy, University of Texas at Austin, Austin, Texas 78712
College of Pharmacy, University of Texas at Austin, Austin, Texas 78712.
J Neurosci. 2019 Mar 27;39(13):2459-2469. doi: 10.1523/JNEUROSCI.3051-18.2019. Epub 2019 Jan 28.
A growing number of studies implicate alterations in glutamatergic signaling within the reward circuitry of the brain during alcohol abuse and dependence. A key integrator of glutamatergic signaling in the reward circuit is the nucleus accumbens, more specifically, the dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) within this region, which have been implicated in the formation of dependence to many drugs of abuse including alcohol. D1-MSNs receive glutamatergic input from several brain regions; however, it is not currently known how individual inputs onto D1-MSNs are altered by alcohol experience. Here, we investigate input-specific adaptations in glutamatergic transmission in response to varying levels of alcohol experience. Virally mediated expression of Channelrhodopsin in ventral hippocampal (vHipp) glutamate neurons of male mice allowed for selective activation of vHipp to D1-MSN synapses. Therefore, we were able to compare synaptic adaptations in response to low and high alcohol experience and Alcohol experience enhanced glutamatergic activity and abolished LTD at vHipp to D1-MSN synapses. Following chronic alcohol experience, GluA2-lacking AMPARs, which are Ca permeable, were inserted into vHipp to D1-MSN synapses. These findings support the reversal of alcohol-induced insertion of Ca-permeable AMPARs and the enhancement of glutamatergic activity at vHipp to D1-MSNs as potential targets for intervention during early exposure to alcohol. Given the roles of the nucleus accumbens (NAc) in integrating cortical and allocortical information and in reward learning, it is vital to understand how inputs to this region are altered by drugs of abuse such as alcohol. The strength of excitatory inputs from the ventral hippocampus (vHipp) to the NAc has been positively associated with reward-related behaviors, but it is unclear whether or how ethanol affects these inputs. Here we show that vHipp-NAc synapses indeed are altered by ethanol exposure, with vHipp glutamatergic input to the NAc being enhanced following chronic ethanol experience. This work provides insight into ethanol-induced alterations of vHipp-NAc synapses and suggests that, similarly to drugs such as cocaine, the strengthening of these synapses promotes reward behavior.
越来越多的研究表明，在酗酒和依赖期间，大脑奖励回路中的谷氨酸能信号发生改变。谷氨酸能信号在奖励回路中的关键整合器是伏隔核，更具体地说，是该区域中表达多巴胺 D1 受体的中型棘突神经元（D1-MSNs），它与包括酒精在内的许多滥用药物的依赖形成有关。D1-MSN 接收来自几个脑区的谷氨酸能输入；然而，目前尚不清楚酒精经历如何改变单个输入到 D1-MSN 的情况。在这里，我们研究了响应不同水平的酒精经验而产生的谷氨酸能传递的输入特异性适应。通过病毒介导的腹侧海马（vHipp）谷氨酸神经元中的 Channelrhodopsin 的表达，可以选择性地激活 vHipp 到 D1-MSN 突触。因此，我们能够比较低和高酒精经验下的突触适应，以及酒精经验增强了 vHipp 到 D1-MSN 突触的谷氨酸能活动并消除了 LTD。在慢性酒精经验之后，GluA2 缺失的 AMPAR，其是 Ca 可渗透的，被插入到 vHipp 到 D1-MSN 突触中。这些发现支持了酒精诱导的 Ca 可渗透 AMPAR 的逆转和 vHipp 到 D1-MSN 的谷氨酸能活动的增强，作为在早期接触酒精时进行干预的潜在目标。鉴于伏隔核（NAc）在整合皮质和皮质下信息以及奖励学习中的作用，了解滥用药物（如酒精）如何改变该区域的输入至关重要。腹侧海马（vHipp）到 NAc 的兴奋性输入的强度与奖励相关行为呈正相关，但尚不清楚乙醇是否会影响这些输入。在这里，我们表明，乙醇暴露确实改变了 vHipp-NAc 突触，并且在慢性乙醇经验之后，vHipp 谷氨酸能输入到 NAc 增强。这项工作提供了关于 vHipp-NAc 突触的乙醇诱导改变的见解，并表明，与可卡因等药物类似，这些突触的增强促进了奖励行为。
