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Emotion regulation in the prefrontal - basal forebrain-amygdala circuit

前额叶 - 基底前脑 - 杏仁核回路的情绪调节

基本信息

批准号：
10381622
负责人：
Ekaterina Likhtik
金额：
$ 39万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-20 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381622
关键词：
Address Affect American Amygdaloid structure Anatomy Anxiety Attention Automobile Driving Autonomic nervous system Basal Cell Behavior Behavioral Brain Cell Nucleus Cells Cognition Collection Communication Complex Cues Development Diagnosis Disease Emotional Emotions Equilibrium Extinction (Psychology)Failure Female Freezing Fright Functional disorder Globus Pallidus Glutamates Goals Hippocampus (Brain)Hyperactivity Immunohistochemistry Impairment Intercalated Cell Interneurons Knowledge Learning Limb structure Location Major Depressive Disorder Medial Mediating Memory Mental disorders Midbrain structure Modeling Mus Neurobiology Neurons Noise Output Pathway interactions Pattern Physiology Play Post-Traumatic Stress Disorders Prefrontal Cortex Process Pyramidal Cells Rodent Role Signal Transduction Site Specificity Stress Structure Substance abuse problem Substantia Innominata Therapeutic Intervention Tracer Training Trauma Treatment outcome Viral Woman Work avoidance behavior basal forebrain cell type cholinergic comorbidity conditioned fear design emotion regulation experimental study generalized anxiety hippocampal pyramidal neuron improved in vivo learning extinction male men nerve supply neurophysiology novel therapeutic intervention optogenetics prevent relating to nervous system response sex targeted treatment

项目摘要

Abstract Post-traumatic stress disorder (PTSD) is a stress- and trauma- induced condition that affects millions of Americans, with women facing PTSD diagnoses at almost twice the rate of men. PTSD is characterized by persistent anxiety, a dysregulated autonomic nervous system, avoidance behaviors, and is often co-morbid with major depressive disorder and substance abuse. Diminished engagement of the medial prefrontal cortex concomitant with a hyperactive basolateral amygdala (BLA) strongly contribute to the dysregulated emotional responses associated with PTSD. During extinction learning, the medial prefrontal cortex is thought to suppress BLA activity, thereby decreasing defensive responding to non-threatening cues, a process that is disrupted in PTSD. There is much evidence to support the idea that direct prefrontal input affects plasticity in the BLA, and shifts the excitatory-inhibitory balance in the amygdala towards inhibition. However, the mechanisms of this circuit-level interaction are not well understood. Notably, the medial prefrontal cortex is not a monolithic structure, and its contiguous subregions, in rodents designated as the prelimbic (PL) and infralimbic (IL), are associated with increased and decreased defensive responding, respectively. Although some ideas have been proposed, thus far no differences have been found in direct PL vs. IL interactions with the BLA that can account for their functional dichotomy. This gap in knowledge prevents the development of more targeted therapeutic treatments for PTSD. One possibility is that the PL and IL may have differential effects upon amygdala function via indirect pathways. Previous work shows that the PL and IL are differentially connected with the basal forebrain, a critical region for modulating fear and extinction learning in the amygdala. The basal forebrain provides strong cholinergic, glutamatergic, and GABAergic inputs to the amygdala, the cortical mantle, and the hippocampus, making it an intriguing centralized location for prefrontal modulation of extinction learning in downstream structures. The goal of the proposed experiments is to uncover the structure and function of PL and IL -basal forebrain -amygdala communication during extinction. To this end, in Specific Aim I will use viral tracing and immunohistochemistry to uncover the detailed circuitry of PL and IL connectivity with amygdala-projecting cells in the ventral pallidum/substantia innominata, and horizontal limb of the diagonal band of the basal forebrain. Then, in Specific Aims 2 and 3, I will use optogenetics to manipulate IL and PL inputs to the basal forebrain, and multi-site in-vivo recordings to record the neurophysiology across the IL/PL-basal forebrain-BLA circuit during fear conditioning, extinction training and recall. Additional immunohistochemical analyses of neural activity will indicate which cell types the PL and IL drive in the basal forebrain during extinction. All experiments will be performed in both sexes to assess whether this circuit contributes to increased rates of PTSD diagnosis in women. This approach is specifically designed to improve our understanding of the circuitry underlying extinction learning, and is geared toward finding novel therapeutic approaches for improving treatment outcomes in PTSD.

摘要