TEMPORAL LOBE PATHWAYS THROUGH THE DOPAMINE SYSTEM

描述(申请人提供)：杏仁核/海马体复合体的结构异常是精神分裂症患者一致的发现。在动物模型中，新生儿对杏仁核/海马体复合体的损伤会导致成人起病的多巴胺(DA)失调，这是这种疾病的另一个关键特征。因此，维持杏仁核/海马区回路的完整性似乎对后来的DA功能至关重要。我们之前已经证明，延伸的杏仁核是杏仁核和其他颞叶结构的主要输出区，具有广泛的多巴胺神经元输入。因此，这条通路是杏仁核-海马区异常最终可能导致DA调节失调的潜在途径。这项拟议的研究将研究杏仁核和海马体如何通过延伸的杏仁核影响中脑DA系统。颞叶损伤只在发育后期才导致DA的失调，这一事实表明可塑性变化最终会影响DA的输出。我们的初步结果表明，B淋巴细胞2蛋白(BCL-2)在成年灵长类动物颞叶的特定亚区高度集中，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，与精神分裂症相关的杏仁核、杏仁核和海马亚区中有高浓度的Bcl2阳性细胞。BCL-2在特定回路中的存在可能有助于识别成年动物中最容易受到可塑性变化和/或兴奋性毒性应激影响的兴奋通路。 这项拟议的研究将确定通过延伸的杏仁核影响DA的颞叶回路。具体地说，我们将：1)确定杏仁核和海马对扩展的杏仁核-DA通路的直接输入，2)确定通过杏仁核影响扩展的杏仁核的间接海马通路，3)确定特定的杏仁核和海马输入/输出路径是否包含Bcl-2免疫反应细胞，4)确定海马输入与投射到扩展的杏仁核的杏仁体亚区重叠的程度，以及该输入与抑制性中间神经元和含有bcl2的细胞重叠的程度。

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.