Synaptic Correlates of Vulnerability and Resilience to Alcohol Use Disorder

尽管焦虑症患者患酒精使用障碍(AUD)的可能性比 对于健康对照，导致这种高风险的神经底物还知之甚少。这些 双重诊断还与两种疾病的症状严重程度更高和治疗不当有关 结果。这个项目的中心目标是在啮齿动物身上应用神经生物学和行为方法。 识别神经回路适应在促进发展风险增加中起因果作用的模型 AUD和焦虑症。为此，我们建立了啮齿动物青少年社会隔离模型 (ASI)会产生许多与患AUD和焦虑症的风险更大相关的行为。 相对于在整个青春期成群饲养的大鼠(AGH)，ASI大鼠表现出类似焦虑的增加 成年后的行为、新奇反应、冲动和攻击性。ASI大鼠也表现出受损的恐惧 自愿饮酒的灭绝和长期增加。神经生物学研究显示ASI 促进杏仁基底外侧核(BLA)谷氨酸能投射神经元兴奋性的增加， 大脑区域是焦虑类和动机行为的组成部分，以及区域内突触活动的增加 接受来自BLA的密集神经支配。最近还发现，血乳酸投射 神经元并不是同质的。相反，这些细胞沿着前部分布成两个不同的簇- 后轴，并在大脑下游区域形成基本上不重叠的环路。前路激活术 BLA(ABLA)回路促进厌恶/焦虑产生，而后部BLA(PBLA)回路激活 引发奖励/缓解焦虑的行为。基于这些发现，该项目将检验ASI的假设 在这些相反的杏仁核回路之间改变兴奋性/抑制性平衡，导致过度 ABLA通路中的兴奋性，这些适应不良的变化在成瘾中起着因果作用 ASI促进的“脆弱”表型。需要研究的第二个假设是ASI促进 雄性和雌性大鼠的适应相似，但出现的行为表型是有性的 双态的。其他研究还将寻求确定恢复正常的新的药理学方法 ABLA/pBLA兴奋性。总而言之，该项目将提供对底层电路的关键新见解 易患AUD和焦虑症，并可能导致识别新的和急需的 对患有这些常见共生疾病的个人进行治疗。 相关性(请参阅说明)： 这些研究将利用促进“易上瘾”表型的啮齿动物模型来识别 负责这些行为的特定于电路的神经适应。研究还将寻求识别小说 旨在逆转这些不适应变化的干预措施。总的来说，这些研究将有助于确定具体的 与AUD和共病焦虑症相关的神经通路并可能识别新的 对患有这些疾病的个人的治疗。

Although individuals with anxiety disorders are more likely to develop alcohol use disorder (AUD) than healthy controls, the neural substrates responsible for this heightened risk are poorly understood. These dual diagnoses are also associated with greater symptom severity of both disorders and poor treatment outcomes. The central goal of this project is to employ neurobiological and behavioral approaches in rodent models to identify neural circuit adaptations that play a causal role in promoting increased risk of developing AUD and anxiety disorders. To that end, we have established a rodent adolescent social isolation model (aSI) that engenders many behaviors associated with greater risk of developing AUD and anxiety disorders. Relative to rats reared in groups throughout adolescence (aGH), aSI rats exhibit increases in anxiety-like behaviors, novelty responding, impulsivity, and aggression in adulthood. aSI rats also display impaired fear extinction and long-lasting increases in voluntary ethanol drinking. Neurobiological studies revealed that aSI promotes increases in the excitability of glutamatergic projection neurons in the basolateral amygdala (BLA), a brain region integral to anxiety-like and motivated behaviors, as well as increased synaptic activity in areas that receive dense innervation from the BLA. It has also recently been discovered that BLA projection neurons are not homogenous. Rather, these cells are distributed into two distinct clusters along the anterior- posterior axis and form largely non-overlapping circuits in downstream brain regions. Activation of anterior BLA (aBLA) circuits promotes aversion/anxiogenesis whereas activation of posterior BLA (pBLA) circuits elicits rewarding/anxiolytic behaviors. Based on these findings, this project will test the hypothesis that aSI shifts the excitatory/inhibitory balance between these opposing amygdala circuits, leading to excessive excitability within aBLA pathways, and that these maladaptive changes play a causal role in the “addiction vulnerable” phenotypes promoted by aSI. A secondary hypothesis to be investigated is that aSI promotes similar adaptations in male and female rats but that the behavioral phenotypes that emerge are sexually dimorphic. Additional studies will also seek to identify novel pharmacological approaches to restore normal aBLA/pBLA excitability. Collectively, this project will provide critical new insight into the circuitry underlying vulnerability to AUD and anxiety disorders and potentially lead to the identification of novel and much needed treatments for individuals suffering from these frequently co-occurring diseases. RELEVANCE (See instructions): These studies will employ a rodent model that promotes an “addiction vulnerable” phenotype to identify circuit-specific neural adaptations responsible for these behaviors. Studies will also seek to identify novel interventions to reverse these maladaptive changes. Collectively, these studies will help to identify specific neural pathways associated with AUD and comorbid anxiety disorders and potentially identify novel treatments for individuals afflicted with these diseases.