Limbic-Basal Ganglia Circuitry in PTSD

创伤后应激障碍 (PTSD) 中的边缘-基底节环路

• 批准号: 8584900
• 负责人: Karen N Gale
• 金额: $ 46.65万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584900
• 关键词: Accounting; Acute; Affective; Aggressive behavior; Amygdaloid structure; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Arousal; Attention; Attenuated; Auditory; Basal Ganglia; Behavior; Behavioral; Benzodiazepines; Bicuculline; Blood Pressure; Brain; Brain Stem; Cell Nucleus; Chronic; Cues; Diagnostic; Disinhibition; Dose; Emotional; Employee Strikes; Etiology; Event; Exposure to; Family; Fright; Functional disorder; GABA Agonists; GABA Antagonists; Goals; Habits; Heart Rate; Human; Hyperactive behavior; Impairment; Impulsivity; Infusion procedures; Lesion; Macaca; Measures; Mediating; Methods; Midbrain structure; Military Personnel; Monkeys; Mood Disorders; Muscimol; Nature; Network-based; Neurobiology; Output; Pathology; Patients; Pharmaceutical Preparations; Post-Traumatic Stress Disorders; Prefrontal Cortex; Primates; Process; Prosencephalon; Psychopathology; Reciprocal Social Interaction; Recurrence; Reflex action; Refractory; Regulation; Research; Resistance; Role; Site; Social Behavior; Social Interaction; Social Phobia; Source; Stimulus; Structure; Substantia nigra structure; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Time; Trauma; Videotape; Visual; Withdrawal; attenuation; base; combat; conditioned fear; conditioning; effective therapy; emotional stimulus; experience; gamma-Aminobutyric Acid; neural circuit; neuropsychiatry; nonhuman primate; novel; prevent; public health relevance; relating to nervous system; research study; response; social; superior colliculus Corpora quadrigemina

DESCRIPTION (provided by applicant): The proposal aims to identify the neural substrates in the primate brain that are responsible for abnormal socio-emotional behavior. This understanding is vital for developing both diagnostic and therapeutic approaches to identify and treat the abnormal brain circuitry in neuropsychiatric conditions such as affective and anxiety disorders. The field of social behavior research still lacks appropriate animal models for social pathology that leads to inappropriate aggression, social anxiety/phobias, social withdrawal/detachment, impulsivity, or defensiveness. The study of the neurobiology of social behavior in the nonhuman primate is especially promising since the impairment in social interactions and emotional processing generates symptomatology that resembles psychopathology observed in human patients. The proposed research seeks to investigate the novel components of the amygdala-based network that regulate socioemotional responses in nonhuman primates in order to account for imbalances that can give rise to psychopathology in the absence of structural lesions. We have determined that reversible pharmacological manipulations of specific sites within the amygdala result in profound changes in social interactions and emotional behavior in macaque monkeys. Further, we have discovered that the activation of the intermediate and deep layers of the superior colliculus (DLSC; a midbrain structure) by focal infusions of GABAA antagonist bicuculline, has a profound impact on emotional reactivity and defensive responses. In the proposed experiments, we will use the method of intracerebral focal drug infusions of either the GABA agonist muscimol or the GABA antagonist bicuculline aimed at various sites within either amygdala or DLSC to test further the role of these structures in socioemotional behavior. Specific Aim 1 will define specific nuclei within the amygdala responsible for GABA- mediated regulation of socioemotional responses. Aim 2 will test the hypothesis that disinhibition of DLSC will evoke aggressive behavior and emotional hyperactivity. Aim 3 will assess the role of DLSC and amygdala in fear-potentiated startle, a conditioning paradigm that is altered in human patients with PTSD. Social interactions will be assessed in dyads, each infused animal will be paired with a familiar non-infused partner; videotaped behaviors will be analyzed by two independent observers using a standardized behavioral categorization. Special attention will be paid to reciprocal social interactions, aggressive behavior, and emergence of any abnormal behaviors (e.g., stereotypies, self-directed behaviors). Emotional reactivity will be tested by presenting the animals with a standard set of stimuli (neutral, positive, and negative). An understanding of the functional relationship between the amygdala-derived and colliculus-derived regulation of social interactions and emotional tone is expected to reveal novel targets for both etiology and therapeutic intervention for affective and anxiety disorders.

描述（由申请人提供）：该提案旨在确定灵长类动物大脑中负责社会情感行为的神经底物。这种理解对于开发诊断和治疗方法以识别和治疗神经精神病患者（例如情感和焦虑症）中的脑电路异常至关重要。社会行为研究领域仍然缺乏适当的社会病理动物模型，从而导致不适当的侵略性，社交焦虑/恐惧症，社交戒断/超脱，冲动或防御能力。非人类灵长类动物中社会行为神经生物学的研究尤其有希望，因为社会互动和情感处理的障碍会产生类似于人类患者观察到的精神病理学的症状。拟议的研究旨在调查基于杏仁核的网络的新成分，该网络调节非人类灵长类动物的社会情感反应，以说明在没有结构性病变的情况下会导致精神病理学的失衡。我们已经确定，杏仁核内特定部位的可逆药理操作会导致猕猴的社交互动和情感行为的深刻变化。此外，我们发现，上丘丘（DLSC；中脑结构）的中间和深层激活GABAA拮抗剂双瓜氨酸，对情绪反应和防御反应产生了深远的影响。在拟议的实验中，我们将使用GABA激动剂肌酚或GABA拮抗剂双瓜氨酸的脑内局灶性药物输注的方法，该方法针对杏仁核或DLSC中的各个地点，以进一步测试这些结构在社会情绪行为中的作用。具体目标1将在负责GABA介导的社会情感反应调节的杏仁核中定义特定核。 AIM 2将检验以下假设：DLSC的抑制作用将引起侵略性行为和情绪多动症。 AIM 3将评估DLSC和Amygdala在恐惧激动的惊吓中的作用，这是PTSD患者改变的条件范式。社交互动将在二元组中进行评估，每只注入的动物将与熟悉的非融合伴侣配对；使用标准化的行为分类，将通过两个独立观察者对录像行为进行分析。将特别关注任何异常行为（例如，刻板印象，自我指导的行为）的相互社会互动，侵略性行为和出现。通过向动物展示一组标准的刺激（中性，积极和负面），将测试情绪反应性。人们对杏仁核衍生的和胶质衍生的社会互动和情感语调调节之间的功能关系有望揭示病因学和治疗性干预的新目标，以实现情感和焦虑症。