NEURAL DEVELOPMENT IN THE ABSENCE OF NOREPINEPHRINE

肾上腺素能传递的改变发生在焦虑、抑郁障碍和阿尔茨海默病中。此外，6例人类自主神经衰竭患者被发现先天性缺乏多巴胺（β -羟化酶（DBH））。它们不能合成肾上腺激素肾上腺素(E)和肾上腺素能神经递质去甲肾上腺素（NE）。尽管这些患者的大脑中缺乏这些递质，但他们的情绪和心理功能都很正常。考虑到新神经网络在学习和记忆、觉醒和注意力以及恐惧和焦虑方面的假设作用，这是令人惊讶的。多巴胺（DA）， NE的前体，在这些患者的肾上腺素能末梢中储存和释放。一种可以解释这些患者正常中枢神经系统功能的假设是，他们的大脑通过激活多巴胺能或肾上腺素能受体，发展到利用DA作为肾上腺素能递质。我们建议研究人类dbh缺乏症的小鼠模型（dbh-/-），以研究出生后发育过程中可能出现的补偿NE缺失的机制。我们将通过几种组织化学技术确定dbh-/-和对照小鼠肾上腺素能细胞体和终末的数量和位置。我们将测试由于DA在发育过程中在新位置释放而导致的DA受体表达升高。由于NE缺失，我们也将量化肾上腺素能受体的表达。我们将描述小脑的形成，小脑的正常发育依赖于NE。重要的是，我们在dbh-/-小鼠中观察到的任何变化都可能是由于肾上腺素能囊泡中NE的缺失或DA的存在。我们将创建一个新的小鼠模型（th-/- /dat-th+/-）来区分这些病因，并在dbh-/-小鼠中识别由于NE缺失而被DA存在所掩盖的任何发育变化。最后，我们将通过使用氨基酸前体在突变小鼠中恢复NE来确定由于NE缺失而导致的表型的持久性。这些研究的结果将确定在出生后神经发育过程中肾上腺素能信号在体内的关键作用，以及DA是否可以替代中枢神经系统中的NE。

Alterations in adrenergic transmission occur in anxiety and depressive disorders, and in Alzheimer's disease. In addition, 6 human patients with autonomic failure have been found to be congenitally deficient in the enzyme dopamine (beta-hydroxylase (DBH). They are unable to synthesize the adrenal hormone epinephrine (E) and the adrenergic neurotransmitter norepinephrine (NE). Despite the absence of these transmitters in their brains, these patients have normal mood and mental function. This is surprising given the postulated roles for NE in learning and memory, arousal and attention, and fear and anxiety. Dopamine (DA), the precursor of NE, is stored in and released from the adrenergic terminals of these patients. A hypothesis that could account for normal CNS function in these patients is that their brains develop to utilized DA as the adrenergic transmitter, either by activating dopaminergic or adrenergic receptors. We propose to examine the mouse model (dbh-/-) of human DBH-deficiency to investigate mechanisms that may arise during postnatal development to compensate for the absence of NE. We will determine the number and location of adrenergic cell bodies and terminals in dbh-/- and control mice by several histochemical techniques. We will test for elevated DA receptor expression due to the release of DA in novel locations during development. Because NE is absent, we will also quantitate adrenergic receptor expression. We will characterize the formation of the cerebellum, which has been implicated as being dependent on NE for their proper development. Importantly, any changes we observe in the dbh-/- mice may be due to either the absence of NE or the presence of DA in the adrenergic vesicles. We will create a new mouse model (th-/- /dat-th+/-) to distinguish these etiologies, and to identify any developmental changes due to the loss of NE that are masked by the presence of DA in the dbh-/- mice. Finally we will determine the permanence of phenotypes due to the absence of NE by restoring NE in the mutant mice using amino acid precursors. Results from these studies will determine what are the critical roles of adrenergic signaling in vivo during postnatal neural development, and whether DA can substitute for NE in the CNS.