Seizures & Amydala-Based Socioemotional Dysfunction

描述（由申请人提供）：很大比例的自闭症患者表现为癫痫发作障碍和癫痫。据报道，这种发病率在30-40%之间。在自闭症谱系中受损程度较高的个体中，癫痫和异常脑电图模式的发生率明显更高。自闭症人群的癫痫发作通常包括复杂的部分癫痫发作，涉及颞叶。支持这些癫痫发作的边缘网络由杏仁核、海马、丘脑中背侧、梨状皮质、鼻皮质和眶额皮质组成。反复发作和/或长时间的复杂部分性癫痫会改变该网络的功能连通性，从而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是相同的，因此这些癫痫发作可能对这一人群的不良精神结果构成最大的风险。在许多自闭症病例中，人们发现，与眶额叶皮层相连的杏仁核网络存在功能障碍（通常在没有结构异常的情况下）。这种功能障碍可能会因反复发作放电引起的异常可塑性而加剧。本应用程序的目的是确定反复发作活动的历史是否改变了该网络的反应性，以及它是否使该网络易受杏仁核介导的行为障碍的影响。我们最近的研究结果表明，局灶性脑内灌注GABAA受体激动剂或拮抗剂对基底外侧杏仁核（BLA）内GABAA受体的可逆操纵导致非人灵长类动物社会互动和奖励评价的深刻变化。特定目的将确定复杂部分性癫痫的历史，从一个半球的梨状皮质局灶性诱发，是否导致非人类灵长类动物对BLA解除抑制的脆弱性增加。这种敏感性的转变将通过评估对BLA中GABAA传播的焦点操纵的特定行为反应来探讨：社会互动（目的1），强化物贬值（目的2）和情绪条件反射（目的3）。这些研究将解决一种公认的共病，但尚未在临床前动物模型中进行研究，因此临床研究无法理清癫痫发作可能加剧自闭症症状的程度。联合研究人员在实验性癫痫模型、社会情感障碍的非人类灵长类动物模型以及人类情感障碍和精神病的神经基质方面提供了独特的专业知识。该团队非常适合分析癫痫发作和杏仁核诱发的自闭症样症状的合并症，并允许对动物数据进行有翻译意义的分析。

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.