HABENULAR REGULATION OF FOREBRAIN DOPAMINE AND BEHAVIOR

缰核通过反曲束（FR）投射到 中脑被盖，形成一个解剖连接核团之间的 基底前脑-边缘端脑和中脑核团， 回到前脑有证据表明，缰发挥一个紧张 对1）中脑多巴胺能系统和2）血浆的抑制作用 与压力有关的荷尔蒙、儿茶酚胺和糖皮质激素的水平。 在大鼠中，FR的损伤产生行为（多动，刻板， 主动回避和学习任务的缺陷）提示 对新事物或压力的适应性反应能力受损 在某些情况下，这种缺陷也是某些类型的人类的特征。 精神病理学，包括精神分裂症，焦虑和抑郁。在这 研究中，我们将测试是否FR病变增加多巴胺能利用 和/或纹状体、丘脑核（NA）中的受体结合和/或 内侧前额叶皮质（mPFC）。基于功能性证据 肾上腺皮质和多巴胺能系统之间的相互作用，我们也将 检测FR损伤大鼠血浆皮质酮水平是否升高 与糖皮质激素受体（GR）介导的 通过测量基因表达水平进行反馈控制， 腹侧被盖区（VTA）、黑质和黑质中GR的免疫反应性 (SN)、纹状体、NAc和mPFC。我们将进一步探讨职能作用 在产生行为缺陷方面， 由多巴胺能激动剂实验诱导。我们假设 FR损伤的大鼠表现出注意力缺陷，这可能是一些 他们表现出的持之以恒的行为， 自发活动和学习任务的测试。我们将使用 一个行为范例评估潜在的抑制条件 非配对预暴露于条件刺激后的情绪反应。 FR损伤诱导的自发活动和刻板行为也将 在所有动物中进行评估。多巴胺能传递改变 是许多精神疾病的特征，包括精神分裂症， 图雷特综合征和注意缺陷多动障碍。与这些 研究，我们希望探索FR损伤大鼠的潜在效用 作为一个模型的精神障碍与多动症的 多巴胺能系统

The habenular nuclei project through the fasciculus retroflexus (FR) to the midbrain tegmentum, forming an anatomical link between nuclei in the basal forebrain-limbic telencephalon and midbrain nuclei which project back to forebrain. There is evidence that the habenulae exert a tonic inhibitory influence on 1) midbrain dopaminergic systems, and 2) plasma levels of stress- related hormones, catecholamines and glucocorticoids. Lesion of the FR in rats produces behaviors (hyperactivity, stereotypy, deficits in active avoidance and learning tasks) suggestive of an impairment in the ability to respond adaptively to novel or stressful situations, a deficit also characteristic of some types of human psychopathology, including schizophrenia, anxiety and depression. In this study, we will test whether FR lesions increase dopaminergic utilization and/or receptor binding in the striatum, nucleus accumbens (NA) and/or medial prefrontal cortex (mPFC). Based on evidence of functional interactions between adrenocortical and dopaminergic systems, we will also test whether the elevated plasma corticosterone levels of FR-lesioned rats are associated with decreased glucocorticoid receptor (GR)-mediated feedback control by measuring levels of gene expression and immunoreactivity for GRs in ventral tegmental area (VTA), substantia nigra (SN), striatum, NAc and mPFC. We will further explore the functional role of the habenular nuclei in generating a behavioral deficit which can also be experimentally induced by dopaminergic agonists. We hypothesize that FR-lesioned rats demonstrate attentional deficits which may underlie some of the perseverative behaviors which characterize their performance in tests of spontaneous activity and learning tasks. We will test this using a behavioral paradigm assessing latent inhibition of a conditioned emotional response after unpaired preexposure to the conditioned stimulus. FR-lesion-induced locomotor activity and stereotypic behaviors will also be evaluated in all animals. Altered dopaminergic transmission characterizes a number of psychiatric disorders, including schizophrenia, Tourette syndrome and attention deficit hyperactivity disorder. With these studies, we hope to explore the potential utility of the FR-lesioned rat as a model for psychiatric disorders associated with hyperactivity of dopaminergic systems.