Neural steroidogenic enzymes and brain function

描述(申请人提供)：有大量关于外周类固醇合成和分泌的信息，但令人惊讶的是，关于活跃神经回路中类固醇实际浓度的信息很少。我们对大脑类固醇，特别是那些在大脑中合成的类固醇(神经类固醇)的认识上的这种差距，阻碍了寻找最佳治疗方法以改善人类心理健康和认知的努力。雌二醇(E2)可通过与海马谷氨酸和GABA能信号相互作用来增强人类和非人类动物模型的记忆功能，但其机制尚不清楚。由于海马体可能在突触终末重新合成E2，因此对外周E2浓度的测量几乎不能告诉我们有关局部生物活性水平的信息。对海马体内雌二醇水平的实时测量将是非常有价值的，特别是考虑到有证据表明类固醇合成酶的快速调节和雌二醇对记忆功能的快速作用。为了解决这一差距，我们开发了使用活体微透析来测量自由行为鸣禽的类固醇水平的能力。我们的发现表明，鸣禽大脑中的E2和睾酮(T)水平在社会互动过程中波动相对较快，与它们的外周水平或邻近脑区的水平无关；抑制这种E2通量具有明显的行为意义。此外，我们发现，E2自然地与谷氨酸成反比波动，而谷氨酸透析后迅速降低了E2浓度。这些波动是如何以及为什么发生的尚不清楚。我们建议对鸣鸟的海马区进行微透析，以测量类固醇、谷氨酸和GABA，因为鸣禽表现出基于海马区的自然空间和时间记忆密集型行为。我们将使用反透析来抑制神经类固醇的合成，并检查空间记忆能力。我们将结合微透析和脑提取程序来确定具有生物活性的神经雌激素浓度。我们将确定神经递质调节大脑海马片中类固醇生成酶的机制，以产生我们在体内看到的水平。这些研究的结果将有助于澄清类固醇作为神经调节剂/神经递质的重要概念，并将有助于解决有关雌激素在认知、海马体生理和记忆功能的特定方面所起作用的争论。影响海马区雌激素信号的治疗可能会缓解创伤后应激障碍等障碍，以及由抑郁症和精神病等精神障碍引起的认知障碍。

DESCRIPTION (provided by applicant): There is a wealth of information about peripheral steroid synthesis and secretion, but surprisingly little information about actual concentrations of steroids in active neural circuits. This gap in our knowledge of brain steroids, especially those synthesized in the brain (neurosteroids), hampers efforts to identify optimal treatments to improve human mental health and cognition. Estradiol (E2) can enhance memory function in humans and non-human animal models by interactions with hippocampal glutamatergic and GABAergic signaling, but the mechanisms are poorly understood. Because the hippocampus synthesizes E2 de novo, perhaps at synaptic terminals, measures of peripheral E2 concentrations tell us little about biologically active local levels. Real-time in vivo measures of hippocampal E2 levels would be of great value, especially given evidence for rapid regulation of steroid synthetic enzymes and for rapid actions of E2 on memory function. To address this gap we have developed the ability to measure steroid levels in freely-behaving songbirds using in vivo microdialysis. Our findings show that E2 and testosterone (T) levels in the songbird brain fluctuate relatively rapidly during social interactions independent of their peripheral levels or levels in adjacent brain regions; inhibition of this E2 flux has clear behavioral implications. Further, we find that E2 naturally fluctuates inversely relative to glutamate and retrodialysis of glutamate rapidly reduces E2 concentrations. How and why these fluctuations occur is unknown. We propose performing microdialysis on the songbird hippocampus to measure steroids, glutamate and GABA as the birds perform natural hippocampal-based spatial and temporal memory intensive behaviors. We will use retrodialysis to inhibit neurosteroid synthesis and examine spatial-memory performance. We will combine microdialysis with brain extraction procedures to determine the biologically active neuroestrogen concentrations. We will identify mechanisms whereby neurotransmitters regulate steroidogenic enzymes in hippocampal slices of brain to produce the levels we see in vivo. Results of these studies will help clarify important concepts about steroids as neuromodulators/neurotransmitters and will help resolve debate over the role of estrogens on specific aspects of cognition, hippocampal physiology and memory function. Therapies that impact hippocampal estrogen signaling may provide relief from disorders such as post-traumatic stress and cognitive impairment arising from psychiatric disorders such as depression and psychosis.