The Impact of Early Life Stress On Amygdala Circuitry And Chronic Excessive Aggression

早期生活压力是成年人攻击性的可靠预测因子。例如，38%的暴力犯罪分子 在童年时期受到身体虐待，28%的人在以后的生活中会因暴力犯罪而再次被捕， 美国纳税人每年数十亿美元。几乎没有治疗选择，而那些做的主要是 效果不佳，远不能预防。鉴于不受控制的暴力和侵略对 社会及其与儿童时期所经历的压力的关系，对儿童时期所经历的压力进行更彻底的审查， 潜在的神经机制将是开发新的和更好的治疗方法的关键。之前我们展示了 青少年早期的社会孤立，随后是青少年后期的急性创伤应激， 作为早期生活压力，通过诱导内侧杏仁核的可塑性变化促进长期的攻击性 (MeA)途径。削弱这些途径抑制侵略性的增加，而加强这些途径， 这些通路可以模拟早期生活压力对攻击性的影响。重要的是，无论是社会孤立还是急性 创伤压力本身就足以促进过度攻击的长期持续增加，这表明， 这些压力源通过不同但增强的可塑性机制驱动攻击性增加。的 这项计划的目标是确定社会孤立和急性创伤压力如何改变杏仁核 电路产生持久的攻击行为。核心假设是，社会孤立和急性 青春期的创伤性应激诱导了互补的内在、突触和结构可塑性变化 在MeA电路中驱动成年人的过度攻击。这将在两个具体目标中进行测试：1）评估 青少年期社会隔离对急性脑梗死后MeA回路可塑性和持久攻击性影响 创伤应激; 2）确定早期生活压力是否通过结构性的， MeA通路的可塑性。拟议的研究在概念和技术上都是创新的，因为它们 使用尖端的体内病毒追踪，成像，化学遗传学和光遗传学技术来解决社会如何 隔离和急性创伤应激共同作用，诱导内在、突触和结构可塑性变化 杏仁核回路中，导致过度的侵略性持续到成年。拟议的研究是 意义重大，因为它将确定控制早期生活压力如何塑造大脑回路的关键神经机制 来驱动长期的过度攻击拟议研究的长远目标是：1）促进我们的 了解早期生活压力如何诱导长期持续的攻击回路的可塑性变化 攻击行为，2）改进检测攻击小鼠模型中可塑性变化的方法，以及 3)有助于开发新的药物靶点，以改善过度和复发性攻击的治疗方法。 研究结果将产生重要的积极影响，因为它们将提供有关以下方面的基本知识： 儿童创伤对大脑功能的影响，最终导致新的诊断和治疗策略 用于控制病态愤怒和攻击性

Early life stress is a reliable predictor of aggression in the adult. For example, 38% of violent criminals are physically abused during childhood, and 28% will be rearrested for a violent crime later in life, costing the American taxpayers billions of dollars annually. Few treatment options exist, and those that do are largely ineffective and far from preventative. Given the immense danger of unchecked violence and aggression to society and its relationship to stress experienced during childhood, a more thorough examination of the underlying neural mechanisms will be essential in developing new and better therapies. Previously we showed that social isolation early in adolescence followed by acute traumatic stress late in adolescence, which we refer to as early life stress, promotes long-lasting aggression by inducing plasticity changes within medial amygdala (MeA) pathways. Weakening these pathways suppresses the aggression increase, while strengthening these pathways can simulate the effects of early life stress on aggression. Importantly, neither social isolation nor acute traumatic stress alone is sufficient to promote the long-lasting increase in excessive aggression, suggesting that these stressors drive the aggression increase through distinct but reinforcing plasticity mechanisms. The objective of this proposal will be to determine how social isolation and acute traumatic stress alter amygdala circuits to produce long-lasting attack behavior. The central hypothesis is that social isolation and acute traumatic stress during adolescence induce complementary intrinsic, synaptic, and structural plasticity changes in MeA circuits to drive excessive aggression in the adult. This will be tested in two specific aims: 1) assess the role of social isolation during adolescence on MeA circuit plasticity and long-lasting aggression after acute traumatic stress; 2) determine if early life stress promotes long-lasting increases in aggression through structural plasticity in MeA pathways. The proposed studies are conceptually and technically innovative because they use cutting-edge in vivo viral tracing, imaging, chemogenetic, and optogenetic techniques to address how social isolation and acute traumatic stress work in tandem to induce intrinsic, synaptic, and structural plasticity changes in amygdala circuits, leading to excessive aggression lasting into adulthood. The proposed research is significant because it will identify key neural mechanisms governing how early life stress shapes brain circuits to drive long-lasting excessive aggression. The long-term goal of the proposed studies is to 1) advance our understanding of how early life stress induces plasticity changes in aggression circuitry underlying long-lasting aggressive behavior, 2) improve methods for detecting changes in plasticity in mouse models of aggression, and 3) aid in the development of new drug targets for improved therapeutics for excessive and recurring aggression. The results will have an important positive impact because they will provide fundamental knowledge regarding the impact of childhood trauma on brain function, eventually leading to new diagnostic and therapeutic strategies for the management of pathological anger and aggression.