Modification of amygdala circuit function with inhibitory interneuron transplants

描述(申请人提供)：前脑中的大多数局部环路神经元(中间神经元)产生抑制性神经递质GABA。中间神经元是大脑皮层和海马环路兴奋性-抑制性平衡所必需的，并发挥着关键作用。 在神经回路中的可塑性和功能。在杏仁核，多种类型的中间神经元对正常的电路功能和可塑性至关重要，这些细胞及其连接性的变化可能是导致病理性恐惧、焦虑和抑郁行为的失衡的基础，就像在创伤后应激障碍中看到的那样。产生抑制中间神经元的胚胎前体细胞可以在出生后移植到(幼年和成年啮齿动物体内)，在那里这些细胞迁移并整合到现有的功能回路中。移植的前体细胞ALS分化为特定的中间神经元亚型，可以重建抑制平衡或r-开放临界期可塑性。这种形式的神经回路修饰在疾病治疗中具有巨大的潜力，但通过神经元间移植改变杏仁核回路的可能性尚未被探索。神经元间移植可以帮助恢复创伤后应激障碍和抑郁症患者杏仁核中受到病理性破坏的突触网络的平衡。在这项提议中，我将测试这样一种假设，即杏仁核中间神经元功能的病理变化(无论是遗传的还是后天的)可以通过将新的中间神经元引入回路来逆转。我有初步数据显示，移植到成年杏仁核中的前体细胞会成为中间神经元，并在移植后至少七个月内保持健康的形态。此外，移植动物在运动功能、活动水平、非空间记忆学习和回忆方面没有任何行为副作用， 伤害感，或食物摄取模式。此外，我开发了一种动物模型，该模型缺乏杏仁基底外侧核中的小白蛋白中间神经元，并且在恐惧条件反射过程中无法获得线索或背景恐惧记忆。利用这项前期工作，我将 目的(1)检测抑制性神经元间前体细胞移植对小白蛋白缺陷小鼠行为功能的整合和恢复能力。在目标(2)中，我将确定移植的中间神经元与哪些细胞形成突触，并将其与中间神经元的内源性连接进行比较。最后，在Aim(3)中，我将测试药理上的急性失活或仅移植细胞的急性激活是否可以进一步改变宿主动物的行为。

DESCRIPTION (provided by applicant): The majority of the local-circuit neurons (interneurons) in the forebrain produce the inhibitory neurotransmitter GABA. Interneurons are essential for excitatory-inhibitory balance in cortical and hippocampal circuits and play key roles in neural circuit plasticity and function. In the amygdala, multiple types of interneurons are critical to normal circuit function and plasticity, and changes within these cells and their connectivity may underlie imbalances that produce pathological fear, anxiety, and depressed behaviors, like those seen in post-traumatic stress disorder. Embryonic precursor cells that give rise to inhibitory interneurons can be grafted postnatally (into juvenile and adult rodents) where these cell migrate and integrate into existing functional circuits. The grafted precursor cells als differentiate into specific subtypes of interneurons that can re- establish inhibitory balance or r-open critical period plasticity. This form of neural circuit modification has great potential in th treatment of disease, yet the possibility of modifying amygdala circuitry by interneuron transplantation has not been explored. Interneuron transplants could help to restore the balance of synaptic networks that is pathologically disrupted in the amygdala in post-traumatic stress disorder and depression. In this proposal I will test the hypothesis that pathological changes (either inherited or acquired) in amygdala interneuron function can be reversed by bringing new interneurons into the circuit. I have preliminary data showing that precursor cells transplanted into the adult amygdala become interneurons and can persist with healthy morphology for at least seven months post-transplant. Furthermore, transplanted animals do not suffer from any behavioral side-effects in motor function, activity levels, non-spatial memory learning and recall, nociception, or food intake patterns. In addition, I have developed an animal model that is lacking parvalbumin+ interneurons in the basolateral amygdala and has the inability to acquire either cued or contextual fear memory during fear conditioning. Using this preliminary work, I will test in Aim (1) the ability of inhibitory interneuron precursor transplants to integrate into and restore the behavioral function in the parvalbumin-deficient mice. In Aim (2) I will determine which cells the transplanted interneurons form synapses with and I will compare that to the endogenous connectivity of interneurons. Finally, in Aim (3) I will test whether pharmacological acute-inactivation or acute-activation of only the transplanted cells can further modify the behavior of the host animal.