HABENULAR REGULATION OF FOREBRAIN DOPAMINE AND BEHAVIOR

前脑多巴胺和行为的缰核调节

• 批准号: 2253829
• 负责人: CAROL A MURPHY
• 金额: $ 3.93万
• 依托单位: ALLEGHENY UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2253829
• 关键词: attention; behavior test; chordate locomotion; conditioning; corpus striatum; corticosteroid receptors; dopamine; ethology; experimental brain lesion; frontal lobe /cortex; glucocorticoids; hormone regulation /control mechanism; immunocytochemistry; in situ hybridization; laboratory rat; neural transmission; neuropsychology; neurotransmitter metabolism; nucleus accumbens; prosencephalon; receptor binding; receptor expression; substantia nigra; tegmentum; thalamus

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.

缰核通过反屈肌束投射到 中脑被盖，在大脑中的核团之间形成解剖联系。 投射的基底前脑-边缘端脑和中脑核团 回到前脑。有证据表明缰核起到补药作用。 对1)中脑多巴胺能系统和2)血浆的抑制作用 压力相关荷尔蒙、儿茶酚胺和糖皮质激素水平。 损毁大鼠的FR会产生行为(多动，刻板印象， 主动回避和学习任务方面的缺陷)提示 对新奇事物或压力做出适应性反应的能力受损 情况，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，我们将测试FR损伤是否增加多巴胺能利用 和/或纹状体、伏隔核(NA)和/或 内侧前额叶皮质(MPFC)。基于功能性的证据 肾上腺皮质和多巴胺能系统之间的相互作用，我们还将 检测FR损毁大鼠血浆皮质酮水平是否升高 与糖皮质激素受体(GR)介导的减少有关 通过测量基因表达和基因表达水平的反馈控制 黑质腹侧被盖区GRs的免疫反应 (SN)、纹状体、NAC和mPFC。我们将进一步探索其功能作用 缰核在产生行为缺陷中的作用也可以 是由多巴胺能激动剂实验诱导的。我们假设 受损的大鼠表现出注意力缺陷，这可能是一些 坚持不懈的行为，这些行为是他们在 自发活动和学习任务的测试。我们将使用以下工具对其进行测试 一种评估条件反射潜伏抑制的行为范式 在不配对的预先暴露于条件刺激后的情绪反应。 FR损伤诱导的运动活动和刻板印象行为也将 在所有动物身上进行评估。多巴胺能传递的改变 是一系列精神障碍的特征，包括精神分裂症 多发性抽动症和注意缺陷多动障碍。有了这些 研究中，我们希望探索FR损伤大鼠的潜在用途 作为与多动症相关的精神障碍的模型 多巴胺能系统。