Seizures & Amydala-Based Socioemotional Dysfunction

癫痫发作

• 批准号: 7154364
• 负责人: Ludise Malkova
• 金额: $ 17.46万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-18 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154364
• 关键词: Primates; amygdala; human; partial seizure

DESCRIPTION (provided by applicant): A large proportion of subjects with autism exhibit seizure disorders and epilepsy. This co morbidity has been reported to be in the range of 30-40%. Epilepsy and abnormal EEG patterns occur at a significantly higher rate in individuals in the more impaired range of the autism spectrum. Seizures in the autistic population often include complex partial seizures involving the temporal lobe. The limbic network supporting these seizures is composed of the amygdala, hippocampus, medio-dorsal thalamus, piriform, rhinal, and orbitofrontal cortices. Recurrent and/or prolonged complex partial seizures alter the functional connectivity of this network in a manner that can impact both cognitive function and socio-emotional regulation. Importantly, this is the same network implicated in autistic pathophysiology and therefore these seizures may pose the greatest risk for adverse psychiatric outcomes in this population. Dysfunction (often in the absence of structural abnormalities) in the network anchored in the amygdala, and interconnected with the orbital frontal cortex, has been found in many cases of autism. This dysfunction is likely to be exacerbated by the aberrant plasticity induced in response to repeated seizure discharge. The goal of this application is to determine if a history of repeated seizure activity changes the responsiveness of this network and whether it predisposes this network to amygdala-mediated behavioral disturbances. Our recent findings showed that reversible manipulations of the GABAA receptors within the basolateral amygdala (BLA) by focal intracerebral infusions of GABAA receptor agonists or antagonists resulted in profound changes in social interactions and reward evaluation in nonhuman primates. The Specific Aims will determine whether a history of complex partial seizures, focally-evoked from the piriform cortex in one hemisphere, result in an increased vulnerability to disinhibition within BLA in nonhuman primates. This shift in sensitivity will be probed by evaluating specific behavioral responses to focal manipulations of GABAA transmission within BLA: Social interactions (Aim 1), reinforcer devaluation (Aim 2), and emotional conditioning (Aim 3). The studies will address a recognized comorbidity, not yet studied in pre-clinical animal models, for which clinical studies cannot sort out the extent to which seizures may exacerbate the autistic symptomatology. The combination of co-investigators provides a unique blend of expertise in experimental epilepsy models, nonhuman primate models of socio-emotional disturbances, and neural substrates of human disorders of affect and psychopathy. The team is ideally suited to approach the analysis of comorbidity of seizures and autistic-like symptoms evoked from amygdala and to permit a translationally meaningful analysis of the animal data.

描述（由申请人提供）：大部分自闭症受试者表现出癫痫发作和癫痫。据报道，这种并发症的发病率在30- 40%的范围内。癫痫和异常脑电图模式在自闭症谱系中受损程度更高的个体中发生率明显更高。自闭症人群的癫痫发作通常包括涉及颞叶的复杂部分性癫痫发作。支持这些癫痫发作的边缘系统网络由杏仁核、海马、中背丘脑、梨状核、鼻和眶额皮质组成。反复发作和/或长时间复杂部分性癫痫发作改变了这个网络的功能连接，可以影响认知功能和社会情绪调节。重要的是，这与自闭症病理生理学中涉及的网络相同，因此这些癫痫发作可能对该人群的不良精神疾病结局构成最大风险。在许多自闭症病例中发现，杏仁核中锚定的网络功能障碍（通常在没有结构异常的情况下），并与眶额叶皮层相互联系。这种功能障碍可能会加剧异常可塑性诱导反复发作放电。本申请的目的是确定反复发作活动的历史是否会改变该网络的反应性，以及是否会使该网络易于发生杏仁核介导的行为障碍。我们最近的研究结果表明，可逆的操纵基底外侧杏仁核（BLA）内的GABAA受体的局部脑内灌注GABAA受体激动剂或拮抗剂导致深刻的变化，在社会交往和奖励评价在非人灵长类动物。特定目的将确定复杂部分性癫痫发作史（从一侧半球的梨状皮质局灶性诱发）是否会导致非人灵长类动物BLA内抑制解除的脆弱性增加。这种敏感性的转变将通过评估特定的行为反应BLA内的GABAA传输的焦点操纵：社会互动（目标1），货币贬值（目标2），和情绪调节（目标3）。这些研究将解决一种公认的合并症，尚未在临床前动物模型中进行研究，临床研究无法确定癫痫发作可能加剧自闭症的程度。共同研究者的组合提供了实验癫痫模型，社会情绪障碍的非人灵长类动物模型，以及人类情感障碍和精神病的神经基质的独特融合。该团队非常适合于分析杏仁核诱发的癫痫发作和自闭症样症状的共病，并允许对动物数据进行有意义的分析。