Local Circuits in the Olfactory Bulb

描述(申请人提供)：了解环境中的感觉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。嗅觉系统是研究这一问题的一个有吸引力的感觉系统，因为连接感受器神经元、嗅球中的二级二尖瓣细胞和嗅皮层中的三级神经元的主要解剖通路是直截了当和容易理解的。细胞内记录表明，二级神经元中气味的神经表征并不完全来自感受器细胞的前馈输入，而是兴奋和抑制电路之间复杂的相互作用的结果。对二尖瓣细胞产生抑制的神经回路知之甚少，二尖瓣细胞是最常见的二级嗅觉神经元。目前的建议使用啮齿类动物脑片记录方法来确定生理相关通路如何兴奋嗅球中间神经元和抑制二尖瓣细胞。使用全细胞内记录和实时双光子成像方法，我们将确定顺向(感觉驱动)和皮质反馈通路在刺激GABA能颗粒细胞中的相对有效性。我们还将检验这一假说，该假说源于我们在前一个资助期和初步研究中发表的文章，即一致的抑制性输入可以同步抑制性中间神经元的放电，在二尖瓣细胞中产生大规模的IPSP。Blanes细胞是我们最近描述的一种新的中间神经元亚型，它在颗粒细胞上突触，因此非常适合于介导这种中间神经元的同步功能。这项拟议的研究将确定正常激活Blanes细胞的兴奋途径，并将检验这样的假设，即这些中间神经元在皮质放电后对颗粒细胞提供前馈抑制。确定在嗅球产生感觉诱发抑制的细胞机制，这是这项提议的总体重点，对于理解如何 嗅觉信息在大脑中呈现。拟议的研究也具有重要意义，因为它们代表着朝着了解许多影响嗅觉功能的主要神经退行性疾病的具体缺陷迈出的重要一步。在许多这些疾病中，嗅觉障碍发生在疾病发病的早期。对这些疾病中影响的特定嗅觉机制的洞察可能会导致关于皮质区域中类似机制的直接可测试假说，这些机制导致通常与神经退行性疾病相关的认知缺陷。

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.