TEMPORAL LOBE PATHWAYS THROUGH THE DOPAMINE SYSTEM

描述（由申请人提供）：杏仁核/海马复合体的结构异常是精神分裂症的一致发现。在动物模型中，新生儿对杏仁核/海马复合体的损伤导致成人发病的多巴胺（DA）失调，这是该疾病的另一个关键特征。因此，维持杏仁核/海马回路的完整性似乎对后期的DA功能至关重要。我们之前已经证明，作为杏仁核和其他颞叶结构的主要输出区域，延伸的杏仁核对多巴胺神经元有广泛的输入。因此，这一途径是杏仁核-海马异常最终导致DA失调的潜在途径。拟议的研究将研究杏仁核和海马如何通过扩展的杏仁核影响中脑DA系统。事实上，颞叶损伤仅在发育后期导致DA失调，这表明可塑性变化最终影响DA输出。我们的初步研究结果表明，B淋巴细胞2蛋白（bcl-2）高度集中在成年灵长类动物颞叶的特定亚区，它可以保护细胞免受兴奋性毒性损伤并具有神经营养作用。我们的初步结果显示，高浓度的Bcl-2阳性细胞存在于延伸的杏仁核，以及与精神分裂症相关的杏仁核和海马体亚区。bcl-2在特定回路中的存在可能有助于识别成年动物最易受可塑性变化和/或兴奋性毒性应激影响的兴奋性通路。

DESCRIPTION (provided by applicant): Structural abnormalities of the amygdala/hippocampal complex are a consistent finding in schizophrenia. In animal models, neonatal damage to the amygdala/hippocampal complex results in adult onset dopamine (DA) dysregulation, another key feature of this illness. Maintaining the integrity of amygdala/hippocampal circuits therefore appears critical to later DA function. We have previously shown that the extended amygdala, a major output region of the amygala and other temporal lobe structures, has broad inputs to the dopamine neurons. This pathway is thus a potential route by which amygdala-hippocampal abnormalities may eventually lead to DA dysregulation. The proposed studies will examine how the amygdala and hippocampus can influence the midbrain DA system through the extended amygdala. The fact that temporal lobe injury results in DA dysregulation only later in development suggests that plastic changes eventually influence DA output. Our preliminary results show that B lymphocyte 2 protein (bcl-2), which protects cells from excitotoxic damage and also has neurotrophic effects, is highly concentrated in specific subregions of the adult primate temporal lobe. Our preliminary results show high concentrations of Bcl-2 positive cells in the extended amygdala, and in subregions of the amygdala and hippocampus associated with schizophrenia. The presence of bcl-2 in specific circuits may help to identify excitatory pathways most susceptible to plastic changes and/or excitotoxic stress in adult animals. The proposed studies will identify temporal lobe circuits that influence DA through the extended amygdala. Specifically we will: 1) identify direct amygdaloid and hippocampal inputs to the extended amygdala-DA pathway, 2) identify indirect hippocampal pathways through the amygdala that influence the extended amygdala, 3) determine whether specific amygdaloid and hippocampal input/output paths contain Bcl-2 immunoreactive cells, 4) determine the extent to which hippocampal inputs overlap amygdala subregions that project to the extended amygdala, and the extent to which this input overlaps inhibitory interneurons and bcl-2-containing cells.