Auger A P, Perrot-Sinal T S, McCarthy M M
Department of Physiology, University of Maryland, School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201, USA.
Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):8059-64. doi: 10.1073/pnas.131016298. Epub 2001 Jun 26.
Whereas adult sex differences in brain morphology and behavior result from developmental exposure to steroid hormones, the mechanism by which steroids differentiate the brain is unknown. Studies to date have described subtle sex differences in levels of proteins and neurotransmitters during brain development, but these have lacked explanatory power for the profound sex differences induced by steroids. We report here a major divergence in the response to injection of the gamma-aminobutyric acid type A (GABA(A)) agonist, muscimol, in newborn male and female rats. In females, muscimol treatment primarily decreased the phosphorylation of cAMP response element binding protein (CREB) within the hypothalamus and the CA1 region of the hippocampus. In contrast, muscimol increased the phosphorylation of CREB in males within these same brain regions. Within the arcuate nucleus, muscimol treatment increased the phosphorylation of CREB in both females and males. Thus, the response to GABA can be excitatory or inhibitory on signal-transduction pathways that alter CREB phosphorylation depending on the sex and the region in developing brain. This divergence in response to GABA allows for a previously unknown form of steroid-mediated neuronal plasticity and may be an initial step in establishing sexually dimorphic signal-transduction pathways in developing brain.
虽然大脑形态和行为的成年性别差异源于发育过程中对类固醇激素的暴露，但类固醇使大脑产生差异的机制尚不清楚。迄今为止的研究描述了大脑发育过程中蛋白质和神经递质水平的细微性别差异，但这些差异对于类固醇诱导的显著性别差异缺乏解释力。我们在此报告新生雄性和雌性大鼠对注射γ-氨基丁酸A型（GABA(A)）激动剂蝇蕈醇的反应存在重大差异。在雌性大鼠中，蝇蕈醇处理主要降低了下丘脑和海马体CA1区域内cAMP反应元件结合蛋白（CREB）的磷酸化水平。相比之下，蝇蕈醇增加了雄性大鼠相同脑区内CREB的磷酸化水平。在弓状核内，蝇蕈醇处理增加了雌性和雄性大鼠CREB的磷酸化水平。因此，对GABA的反应在发育中的大脑中，根据性别和区域的不同，对改变CREB磷酸化的信号转导途径可以是兴奋性的或抑制性的。这种对GABA反应的差异允许一种以前未知的类固醇介导的神经元可塑性形式，并且可能是在发育中的大脑中建立性别二态性信号转导途径的初始步骤。
