Limbic-Basal Ganglia Circuitry in PTSD

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情感和焦虑症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，用于社会病理学，导致不适当的攻击，社交焦虑/恐惧，社交退缩/分离，冲动或防御。对非人类灵长类动物社会行为的神经生物学研究尤其有前途，因为社会互动和情感处理的损伤产生了类似于在人类患者中观察到的精神病理学的行为学。拟议的研究旨在调查杏仁核为基础的网络，调节非人类灵长类动物的社会情绪反应的新组件，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，杏仁核内的特定部位的可逆药理学操作导致猕猴的社会互动和情感行为发生深刻变化。此外，我们已经发现，通过GABAA拮抗剂荷包牡丹碱的局灶性输注激活上级丘（DLSC;中脑结构）的中间层和深层对情绪反应性和防御反应具有深远的影响。在拟议的实验中，我们将使用的方法，脑内局灶性药物输注的GABA激动剂蝇蕈醇或GABA拮抗剂荷包牡丹碱的目的是在杏仁核或DLSC内的各个网站，以进一步测试这些结构在社会情绪行为的作用。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将检验DLSC的去抑制会引起攻击行为和情绪多动的假设。目的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PTSD患者中改变的条件反射范式。将以成对的方式评估社会互动，每只输注动物将与熟悉的非输注伴侣配对;由两名独立观察员使用标准化行为分类分析录像行为。将特别注意相互的社会互动，攻击性行为，以及任何异常行为的出现（例如，刻板印象、自我导向行为）。将通过向动物提供一组标准刺激（中性、阳性和阴性）来测试情绪反应。杏仁核衍生和丘衍生的社会互动和情绪调节之间的功能关系的理解，预计将揭示新的目标，为情感和焦虑症的病因和治疗干预。

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.