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: 8847236
• 负责人: Shawn Sorrells
• 金额: $ 5.6万
• 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: 2014-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847236
• 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; 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; Pharmaceutical Preparations; 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; neuropsychiatry; novel therapeutics; precursor cell; public health relevance; 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）：前脑的大部分局部回路神经元（中间神经元）产生抑制性神经递质GABA。在皮层和海马回路中，中间神经元在兴奋-抑制平衡中起着至关重要的作用