Gender differences in aortic baroreceptor function and neural integration

描述（由申请人提供）：心血管功能的性别差异众所周知。激素和相关受体是至关重要的因素，但临床研究揭示了传入介导的自主神经系统（ANS）功能的潜在性别差异。一些ANS评估心迷走神经反射已被证明是性二态性的。在这项研究中，我们调查的假设有关的可能的神经解剖，神经生理和生物物理差异的主动脉压力感受器（BR）在男性和女性大鼠。主动脉BR纤维类型、压力编码和神经激素调节中的性别相关偏倚可能揭示与综合心迷走神经控制中的性别差异相关的尚未认识到的机制。这个建议建立在我们以前的研究量化的有髓和无髓BR传入的离子通道的差分组合物和方式，这定义了这些神经解剖学上不同的传入通路引起的心率和血压的显着不同的反射控制。第一个目的是研究大鼠主动脉BR传入的性别相关差异。主动脉BR纤维的形态学分析和荧光鉴定的主动脉BR神经元（ABN）的研究提供了初步证据，雌性大鼠的有髓BR多约50%，首次揭示了在年龄匹配的雄性中很少存在（约2%）功能不同的低阈值有髓ABN亚型。第二个目标量化的神经调节能力的雌二醇（E2）后，这种独特的亚型BR传入。神经记录显示，E2可增加雌性大鼠主动脉单个有髓BR纤维的压力依赖性放电。生理水平的E2（0.1 - 1 nM）至少部分通过膜结合雌激素受体起作用，可以选择性地增加雌性大鼠中ABN亚型的兴奋性。有趣的是，E2对两种性别的无髓鞘ABN均无影响。第三个目标是确定E2是否可以改变K+离子通道功能，其方式与观察到的兴奋性增加一致。我们的初步数据表明，与男性中所有有髓鞘ABN和女性中有髓鞘ABN的平衡不同，这个独特的子集表达BKCa通道，提供约25%的全细胞钾电流。我们进一步表明，E2选择性抑制BKCa电流，提供了一个潜在的机制E2致敏的有髓鞘BR兴奋性在雌性大鼠。最后，在目标四，我们确定是否E2可以改变单突触传递的BR传入到第二阶BR神经元的NTS。在雄性大鼠，单突触传递的有髓传入的NTS不涉及BKCa通道。与此形成鲜明对比的是，雌性大鼠中的E2可以增加有髓鞘传入通路的单突触传递，相关研究表明BKCa通道发挥了作用。BR感觉信息从传入末梢到NTS中的第二阶BR神经元的神经整合中的性别相关差异可能会导致女性人群心血管健康和疾病管理的新进展。 公共卫生相关性：心血管功能的性别差异是众所周知的，虽然性激素是重要的影响因素，但越来越多的证据表明存在替代机制。本项目旨在确定男性和女性之间的压力感受器传入通路是否存在基本的神经解剖学和神经生理学差异。压力感受器的性别相关差异的证据可能会导致女性人群心血管健康和疾病的有效管理的新进展。

DESCRIPTION (provided by applicant): Gender differences in cardiovascular function are well known. Hormones and related receptors are critically important factors, but clinical studies are revealing potential gender differences in afferent mediated autonomic nervous system (ANS) function. Some ANS assessments of cardiovagal reflexes have proven to be sexually dimorphic. In this study we investigate hypotheses related to possible neuroanatomical, neuophysiological and biophysical differences between aortic baroreceptors (BR) in male and female rats. A gender-related bias in aortic BR fiber type, pressure encoding and neurohormonal regulation may reveal as yet unrecognized mechanisms associated with noted gender differences in integrated cardiovagal control. This proposal builds upon our previous studies quantifying the differential composition of ionic channels in myelinated and unmyelinated BR afferents and the manner in which this defines the strikingly different reflex control of heart rate and blood pressure evoked by these neuroanatomically distinct afferent pathways. The first aim examines gender-related differences in rat aortic BR afferents. Morphometric analysis of aortic BR fibers and study of fluorescently identified aortic BR neurons (ABN) gives preliminary evidence that female rats have ~50% more myelinated BR, revealing, for the first time, a functionally distinct subtype of low threshold myelinated ABN rarely present (~2%) in age-matched males. The second aim quantifies the neuromodulatory capacity of estradiol (E2) upon this unique subtype of BR afferents. Nerve recordings show that E2 can increase the pressure-dependent discharge of single myelinated aortic BR fibers from female rats. Physiological levels of E2 (0.1 - 1 nM) acting, at least in part, via membrane bound estrogen receptors can selectively increase the excitability of this ABN subtype in female rats. Interestingly, E2 had no effect upon unmyelinated ABN from either gender. The third aim determines if E2 can alter K+ ion channel function in a manner consistent with the observed increased excitability. Our preliminary data show that, unlike all myelinated ABN in males and the balance of myelinated ABN from females, this unique subset expresses BKCa channels that provide ~25% of the whole cell potassium current. We further show that E2 selectively inhibits this BKCa current, offering one potential mechanism for the E2 sensitization of myelinated BR excitability in female rats. Finally, in aim four we determine if E2 can alter monosynaptic transmission of BR afferents onto 2nd-order BR neurons in the NTS. In male rats, monosynaptic transmission of myelinated afferents to the NTS does not involve BKCa channels. In stark contrast, E2 in female rats can increase monosynaptic transmission of myelinated afferent pathways with companion studies implicating a role for BKCa channels. Gender-related differences in the neural integration of BR sensory information from the afferent terminal through to 2nd-order BR neurons in the NTS could potentially lead to novel advances in the management of cardiovascular health and disease in the female population. PUBLIC HEALTH RELEVANCE: Gender differences in cardiovascular function are well known and while sex hormones are important contributing factors, there is growing evidence for alternative mechanisms. This project aims to determine if there are fundamental neuroanatomical and neurophysiological differences in the baroreceptor afferent pathway between men and women. Evidence for a gender-related difference in baroreceptors could potentially lead to novel advances in the effective management of cardiovascular health and disease in the female population.