Modification of amygdala circuit function with inhibitory interneuron transplants

通过抑制性中间神经元移植改变杏仁核回路功能

• 批准号: 9057613
• 负责人: Shawn Sorrells
• 金额: $ 6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-04 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057613
• 关键词: Acute; Adolescent; Adult; Adverse effects; Affect; Amygdaloid structure; Animal Behavior; Animal Model; Animals; Anxiety; Behavior; Behavioral; Brain; Cell Transplants; Cells; Chronic stress; Cues; Data; Depressed mood; Development; Disease; Eating; Embryo; Equilibrium; Exhibits; Fright; Health; Heterogeneity; Hippocampus (Brain); Homeostasis; Inherited; Interneuron function; Interneurons; Learning; Maps; Medial; Memory; Mental Depression; Modeling; Modification; Morphology; Motor; Mus; Mutant Strains Mice; Neurons; Neurotransmitters; Nociception; Parvalbumins; Pattern; Pharmacotherapy; Phenotype; Play; Post-Traumatic Stress Disorders; Prosencephalon; Rodent; Role; Somatostatin; Synapses; Testing; Time; Transplantation; Work; conditioned fear; critical period; fear memory; functional restoration; gamma-Aminobutyric Acid; neural circuit; neuronal circuitry; neuropsychiatric disorder; novel therapeutic intervention; precursor cell; repaired; research study

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.

描述（由申请人提供）：前脑中的大多数局部回路神经元（中间神经元）产生抑制性神经递质GABA。中间神经元在皮层和海马回路的兴奋-抑制平衡中起关键作用 神经回路的可塑性和功能。在杏仁核中，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，这些细胞及其连接的变化可能是产生病理性恐惧，焦虑和抑郁行为的不平衡的基础，就像在创伤后应激障碍中看到的那样。产生抑制性中间神经元的胚胎前体细胞可以在出生后移植（进入幼年和成年啮齿动物），这些细胞迁移并整合到现有的功能回路中。移植的前体细胞还分化为特定的中间神经元亚型，其可以重建抑制平衡或重新开放关键期可塑性。这种形式的神经回路修饰在疾病治疗中具有巨大潜力，但尚未探索通过中间神经元移植修饰杏仁核回路的可能性。中间神经元移植可以帮助恢复突触网络的平衡，这种平衡在创伤后应激障碍和抑郁症中的杏仁核中被病理性破坏。在这篇论文中，我将检验杏仁核中间神经元功能的病理变化（无论是遗传的还是获得的）可以通过将新的中间神经元引入回路来逆转的假设。我有初步的数据显示，移植到成年杏仁核中的前体细胞会变成中间神经元，并在移植后至少7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， 伤害感受或食物摄入模式。此外，我还开发了一种动物模型，该模型在基底外侧杏仁核中缺乏小清蛋白+中间神经元，并且在恐惧条件反射期间无法获得线索或背景恐惧记忆。利用这些初步工作，我将 目的（1）测试抑制性中间神经元前体移植物整合入小清蛋白缺陷小鼠并恢复其行为功能的能力。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，在目的（3）中，我将测试仅移植细胞的药理学急性失活或急性激活是否可以进一步改变宿主动物的行为。