Afferent Regulation of VTA Dopamine Neuron Populations

VTA 多巴胺神经元群的传入调节

基本信息

批准号：
6830235
负责人：
Susan R. Sesack
金额：
$ 26.78万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2008-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Dopamine (DA) neurons in the midbrain ventral tegmental area (VTA) provide a critical modulation of limbic striatal and cortical targets that facilitates appropriate motor control, approach behaviors, motivation and cognition. Deficits in these forebrain dopamine systems are associated with mental health disorders such as schizophrenia, depression, attention deficit hyperactivity disorder and substance abuse. Hence, it is important to gain a clear understanding of how DA neuron activity is itself regulated. DA neurons fire tonically via pacemaker potentials, but important signals regarding future expectancy are generated by bursts and pauses in the activity pattern that are mediated by afferent drive. In our prior research, we examined excitatory afferents to VTA DA neurons from the prefrontal cortex. We discovered a surprising degree of specificity in these connections, in that prefrontal cortical afferents synapsed only onto DA neurons projecting back to the prefrontal cortex and not onto the more numerous DA cell population projecting to the nucleus accumbens. In the present proposal, we wish to address the likelihood of additional specificity in other synaptic inputs to these same DA neuron populations in the VTA that correlate with their activity levels and functions. This goal will be accomplished through the following five specific aims. We will examine both mesoprefrontal and mesoaccumbens DA neurons specifically for (1) their general excitatory and inhibitory drive as identified by glutamate and GABA in synaptic inputs, (2) specific excitatory afferents from the brainstem laterodorsal and pedunculopontine tegmentum, (3) extrinsically derived inhibitory afferents from the nucleus accumbens, (4) intrinsically derived inhibitory synapses from GABA neurons within the VTA, and (5) mixed/modulatory afferents from the lateral hypothalamus. Evidence consistent with selective afferent drive to different populations of DA neurons will provide valuable insight into the function of each cell group and the contributions they make to normal and abnormal behaviors. Evidence for selectivity in these afferents also has important implications for the development of specific pharmacological treatments for mental health disorders that involve these populations.

描述（由申请人提供）：中脑腹侧对盖区域（VTA）中的多巴胺（DA）神经元提供了对边缘纹状体和皮质靶标的关键调节，以促进适当的运动控制，进近的行为，动机和认知。这些前脑多巴胺系统中的缺陷与精神健康，抑郁症，注意力缺陷多动障碍和药物滥用等心理健康障碍有关。因此，重要的是要清楚地了解DA神经元本身的调节。 DA神经元通过起搏器电位进行调音，但有关未来预期的重要信号是由激发驱动器介导的活动模式中的爆发和停顿产生的。在先前的研究中，我们检查了前额叶皮层对VTA DA神经元的兴奋性传入。我们在这些连接中发现了令人惊讶的特异性，因为前额叶皮质传入仅突触到投射回前额叶皮层的DA神经元，而不是投影到伏隔核的更多DA细胞种群上。在本提案中，我们希望解决其他突触输入在VTA中与这些与其活性水平和功能相关的相同DA神经元种群的其他特异性的可能性。该目标将通过以下五个特定目标实现。我们将研究突触输入中谷氨酸和GABA所确定的，专门针对（1）针对（1）其一般兴奋性和抑制性驱动的神经元的神经元，（2）特定的兴奋性传入，来自脑茎后期和脊髓杆菌的脑词置和果皮的附加量，（3）插入式的（3）插入式（3）的分泌（3），（3）intirents intiments intiment intiment intiment intiment intiment intiment intiments intiment（3）intirents intiment intiment intiments intiment（3）来自VTA内GABA神经元的抑制性突触，以及（5）下丘脑外侧的混合/调节传入。与DA神经元不同种群选择性传入驱动器一致的证据将为每个细胞组的功能以及它们对正常和异常行为的贡献提供宝贵的见解。这些传入中选择性的证据也对涉及这些人群的精神疾病的特定药理治疗的发展具有重要意义。