Testing the Hemo-Neural Hypothesis: Tetrode, Two-photon & Computational Studies

描述(由申请人提供)：神经活动在时空上造成血液供应的局部增加，称为功能性充血，已知为神经成像信号的基础，如功能磁共振成像。发起人克里斯托弗·摩尔(Christopher Moore)博士最近提出的“血液-神经假说”预测，充血也可能调节神经兴奋性。血-神经的影响可通过神经胶质细胞间接或直接通过温度变化、血液传播的信使(如一氧化氮)或神经膜力门控离子通道的激活来调节。我将测试特定的假设，即充血增强锥体神经元的感觉反应，并削弱小鼠桶状皮质中快速放电的中间神经元的反应。我将使用两种方法来测试这些预测，这种方法将四极管记录和双光子成像的生理学实验技术与生物物理上真实的计算模型相结合。这些技术将被用来测试在基线和药物诱导的充血中快速尖峰中间神经元和锥体细胞的激活。使用老鼠将使我能够在我的研究的双光子部分识别被基因标记的特定细胞类型。我的结果将指导皮质神经和血管网络计算模型的发展，从中我们将研究血液诱导效应如何调节神经活动。根据该模型，我们将开发充血对网络活动的直接影响的定量预测，这将指导未来的实验。血管和神经系统之间的异常相互作用与许多神经系统疾病有关，包括阿尔茨海默氏症、偏头痛、中风和癫痫，尽管这些相互作用尚未成为治疗开发的主题。因此，这里提出的实验和计算工作可能为在这些条件下研究一类新的可能的治疗靶点奠定基础。PHS 416-1(9/08版)第2页在申请表第2页的底部连续编号。不要使用2a、2b等后缀。18.申请者姓名(姓氏、首字母、中间字母)维尔林-克拉森，L(由申请者填写-遵循PHS 416-1说明)18.

DESCRIPTION (provided by applicant): Neural activity creates a spatio-temporally localized increase in blood supply known as functional hyperemia, known to underlie neuroimaging signals such as functional magnetic resonance imaging. The 'Hemo-Neural hypothesis,' recently proposed by sponsor Dr. Christopher Moore, predicts that hyperemia may also modulate neural excitability. Hemo-Neural influence may be mediated indirectly via glial cells or directly by temperature change, blood borne diffusible messengers such as nitric oxide, or activation of force-gated ion channels in neural membranes. I will test the specific hypotheses that hyperemia enhances the sensory response of pyramidal neurons, and diminishes the response of fast-spiking interneurons in mouse barrel cortex. I will test these predictions using a two-fold approach that combines physiological experimental techniques of tetrode recording and two-photon imaging with biophysically realistic computational modeling. These techniques will be used to test the activation of fast spiking interneurons and pyramidal cells in baseline and pharmacalogically induced hyperemia. Use of mice will allow me to identify genetically labeled specific cell-types in the 2-photon portion of my research. My results will direct the development of a computational model of a cortical neural and vascular network, from which we will investigate how hemo-induced effects may modulate neural activity. From the model, we will develop quantitative predictions of the direct effects of hyperemia on network activity that will guide future experiments. Abnormal interactions between the vascular and neural systems are associated with many neurological illnesses, including Alzhelmers, migraine, stroke and epilepsy, though these interactions have not been a subject of therapeutic development. Thus, the experimental and computational work proposed here may lay the groundwork for study of a new class of possible therapeutic targets in these conditions. PHS 416-1 (Rev. 9/08) Page 2 Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. Kirschstein-NRSA Individual Fellowship Application NAME OF APPLICANT (Last, first, middle initial) Vierling-Claassen, Dorea L (To be completed by applicant- follow PHS 416-1 Instructions) 18.