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导致异常社会情绪行为的神经底物。这一认识对于开发诊断和治疗方法以识别和治疗情感性和焦虑性障碍等神经精神疾病中的异常脑回路至关重要。社会行为研究领域仍然缺乏适当的动物模型来研究导致不适当攻击、社交焦虑/恐惧症、社交退缩/冷漠、冲动或防御性的社会病理。非人灵长类动物社会行为的神经生物学研究特别有希望，因为社会互动和情绪处理的障碍会产生类似于在人类患者中观察到的精神病理学的症状。这项拟议的研究试图调查杏仁核为基础的网络的新组成部分，该网络调节非人类灵长类的社会情绪反应，以解释在没有结构性损伤的情况下可能导致精神病理的失衡。我们已经确定，杏仁核内特定部位的可逆药物操作会导致猕猴社会互动和情感行为的深刻变化。此外，我们还发现，GABAA拮抗剂荷包牡丹碱对上丘(DLSC；中脑结构)中深层的激活对情绪反应和防御反应有深远的影响。在拟议的实验中，我们将使用GABA激动剂Muscimol或GABA拮抗剂荷包牡丹碱针对杏仁核或DLSC内不同部位的脑内局部药物注射的方法，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将定义杏仁核内负责GABA介导的社会情绪反应调节的特定核团。目的2验证去抑制DLSC会引起攻击性行为和情绪多动的假说。目的3将评估DLSC和杏仁核在恐惧强化惊吓中的作用，惊吓是一种在人类创伤后应激障碍患者中改变的条件反射范式。社会互动将被分成两组进行评估，每一只输血的动物将与一名熟悉的未输血的伴侣配对；录像的行为将由两名独立的观察者使用标准化的行为分类进行分析。将特别注意互惠的社会互动、攻击性行为和任何异常行为的出现(例如，刻板印象、自我导向行为)。情绪反应将通过向动物提供一组标准的刺激(中性、积极和消极)来测试。对杏仁核和丘脑来源的社会互动和情绪调节之间的功能关系的理解有望揭示情感和焦虑障碍的病因学和治疗干预的新靶点。