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: 8871527
• 负责人: Ludise Malkova
• 金额: $ 47.18万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8871527
• 关键词: Accounting; Acute; Affective; Aggressive behavior; Amygdaloid structure; Animal Model; Animals; Anti-Anxiety Agents; 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; Exposure to; Family; Fright; Functional disorder; GABA Agonists; GABA Antagonists; Goals; Habits; Health; 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; anxious; attenuation; base; brain circuitry; combat; conditioned fear; conditioning; effective therapy; emotion dysregulation; emotional behavior; emotional stimulus; experience; gamma-Aminobutyric Acid; neural circuit; neuropsychiatry; nonhuman primate; novel; prevent; relating to nervous system; research study; response; social; social anxiety; superior colliculus Corpora quadrigemina; traumatic event

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）：该提案旨在识别灵长类动物大脑中导致异常社会情绪行为的神经基质。这种理解对于开发诊断和治疗方法来识别和治疗神经精神疾病（例如情感障碍和焦虑症）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社会病理学动物模型，这些模型会导致不当攻击、社交焦虑/恐惧症、社交退缩/疏离、冲动或防御。对非人类灵长类动物社会行为的神经生物学的研究特别有前途，因为社会互动和情绪处理的受损会产生类似于在人类患者中观察到的精神病理学的症状。拟议的研究旨在调查非人类灵长类动物中调节社会情绪反应的杏仁核网络的新组成部分，以解释在没有结构性病变的情况下可能引起精神病理学的不平衡。我们已经确定，对杏仁核内特定位点进行可逆的药理学操作会导致猕猴的社交互动和情绪行为发生深刻变化。此外，我们还发现，局部输注 GABAA 拮抗剂荷包牡丹碱可激活上丘（DLSC；一种中脑结构）的中间层和深层，对情绪反应和防御反应具有深远的影响。在拟议的实验中，我们将使用针对杏仁核或 DLSC 内不同部位的 GABA 激动剂蝇蕈醇或 GABA 拮抗剂荷包牡丹碱的脑内局部药物输注方法，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 将定义杏仁核内负责 GABA 介导的社会情绪反应调节的特定核。目标 2 将检验 DLSC 去抑制会引发攻击性行为和情绪过度活跃的假设。目标 3 将评估 DLSC 和杏仁核在恐惧增强惊吓中的作用，这是一种在患有 PTSD 的人类患者中发生改变的调节范式。社交互动将以二人一组的形式进行评估，每只接受输注的动物将与一个熟悉的未接受输注的伙伴配对；录像中的行为将由两名独立观察员使用标准化行为分类进行分析。我们将特别关注相互的社交互动、攻击性行为以及任何异常行为（例如刻板印象、自我导向行为）的出现。通过向动物提供一组标准刺激（中性、积极和消极）来测试情绪反应性。了解杏仁核衍生和丘丘衍生的社交互动和情绪基调调节之间的功能关系有望揭示情感和焦虑障碍的病因学和治疗干预的新目标。