NEURAL DEVELOPMENT IN THE ABSENCE OF NOREPINEPHRINE

在焦虑和抑郁障碍以及阿尔茨海默病中，肾上腺素能传递会发生改变。此外，6名患有自主神经衰竭的人类患者被发现先天缺乏多巴胺酶(β-羟基酶)。他们无法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)。尽管他们的大脑中没有这些递质，但这些患者的情绪和心理功能正常。考虑到NE在学习和记忆、唤醒和注意力以及恐惧和焦虑方面的假定作用，这是令人惊讶的。多巴胺(DA)是去甲肾上腺素(NE)的前体，储存在这些患者的肾上腺素能终末，并从肾上腺素能终末释放。可以解释这些患者正常中枢神经系统功能的一个假设是，他们的大脑发育到利用DA作为肾上腺素能递质，要么激活多巴胺能受体，要么激活肾上腺素能受体。我们建议研究人类DBH缺乏的小鼠模型(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。我们将用几种组织化学技术来确定dBh-/-和对照组小鼠肾上腺素能胞体和终末的数量和位置。我们将测试在发育过程中由于DA在新位置的释放而引起的DA受体表达的升高。由于去甲肾上腺素缺乏，我们还将对肾上腺素能受体的表达进行定量。我们将描述小脑的形成，小脑被认为依赖于NE才能正常发育。重要的是，我们在dBh-/-小鼠身上观察到的任何变化都可能是由于肾上腺素能小泡中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，并识别由于去甲肾上腺素(NE)丢失而导致的任何发育变化，这些变化被DBH-/-小鼠中DA的存在所掩盖。最后，我们将通过使用氨基酸前体恢复突变小鼠的去甲肾上腺素来确定由于缺乏去甲肾上腺素而导致的表型的持久性。这些研究的结果将确定体内肾上腺素能信号在出生后神经发育过程中的关键作用，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.