Local Circuits in the Olfactory Bulb

描述（由申请人提供）：了解环境中的感官刺激如何在我们的大脑中表现是神经科学中的一个基本问题。嗅觉系统是一个有吸引力的感觉系统来解决这个问题，因为连接受体神经元，嗅球中的二级僧帽细胞和嗅皮层中的三级神经元的主要解剖通路是简单的，并且很好地理解。细胞内记录表明，在二级神经元的气味的神经表征不完全从前馈输入从受体细胞，而是从兴奋性和抑制性电路之间的复杂的相互作用的结果。对最常见的二级嗅觉神经元二尖瓣细胞产生抑制的神经回路知之甚少。本提案使用啮齿动物脑切片记录方法来确定生理相关通路如何激发嗅球中间神经元并抑制二尖瓣细胞。使用全细胞细胞内记录和活双光子成像方法，我们将确定顺向（感觉驱动）和皮质反馈通路在兴奋GABA能颗粒细胞的相对有效性。我们还将测试的假设，从我们的出版物，从以前的资助期和初步研究，重合的抑制性输入可以同步放电的抑制性中间神经元，产生大幅度的IPSP在二尖瓣细胞。Blanes细胞是我们最近描述的一种新的中间神经元亚型，它与颗粒细胞形成突触，因此非常适合介导这种中间神经元同步化功能。拟议的研究将定义通常激活Blanes细胞的兴奋性通路，并将测试这些中间神经元在皮层放电后对颗粒细胞提供前馈抑制的假设。定义产生嗅球感觉诱发抑制的细胞机制，这一建议的整体重点，是理解如何关键 嗅觉信息在大脑中被代表。拟议的研究也很重要，因为它们代表了理解许多主要神经退行性疾病中嗅觉功能受到影响的特定缺陷的重要一步。在许多这些疾病中，嗅觉障碍发生在疾病发作的早期。深入了解这些疾病中受影响的特定嗅觉机制可能会导致直接可检验的假设，即负责通常与神经退行性疾病相关的认知缺陷的皮质区中的类似机制。

DESCRIPTION (provided by applicant): Understanding how sensory stimuli in the environment are represented in our brains is a fundamental question in neuroscience. The olfactory system is an attractive sensory system to approach this question since the major anatomical pathways connecting receptor neurons, second-order mitral cells in the olfactory bulb, and tertiary neurons in olfactory cortex are straightforward and well understood. Intracellular recordings demonstrate that neural representations of odors in second-order neurons do not result exclusively from feedforward input from receptor cells but, instead, result from complex interactions between excitatory and inhibitory circuits. Little is known about the neural circuits that generate inhibition onto mitral cells, the most common second-order olfactory neuron. The present proposal uses rodent brain slice recording methods to determine how physiologically-relevant pathways excite olfactory bulb interneurons and inhibit mitral cells. Using both whole-cell intracellular recording and live 2-photon imaging methods, we will determine the relative effectiveness of orthodromic (sensory-driven) and cortical feedback pathways in exciting GABAergic granule cells. We will also test the hypothesis, arising from our publications from the previous funding period and preliminary studies, that coincident inhibitory input can synchronize discharges in inhibitory interneurons, generating large-amplitude IPSPs in mitral cells. Blanes cells, a new interneuron subtype we described recently, synapse on granule cells and, therefore, are ideally suited to mediate this interneuron synchronizing function. The proposed studies will define the excitatory pathways that normally activate Blanes cells and will test the hypothesis that these interneurons provide feedforward inhibition onto granule cells following cortical discharges. Defining the cellular mechanisms that generate sensory-evoked inhibition in the olfactory bulb, the overall focus of this proposal, is critical to understand how olfactory information is represented in the brain. The proposed studies also are significant as they represent an important step toward understanding the specific deficits in many major neurodegenerative diseases in which olfactory function is affected. In many of these diseases, olfactory impairments occur early in the disease onset. Insights into the specific olfactory mechanisms affected in these diseases may lead to directly testable hypotheses regarding analogous mechanisms in the cortical areas responsible for the cognitive deficits commonly associated with neurodegenerative disorders.