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的一个基本问题。嗅觉系统是解决这个问题的一个有吸引力的感觉系统，因为连接受体神经元、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接而容易理解的。细胞内记录表明，二级神经元对气味的神经表征并不完全来自受体细胞的前馈输入，而是来自兴奋和抑制回路之间复杂的相互作用。对二尖瓣细胞（最常见的二级嗅觉神经元）产生抑制作用的神经回路知之甚少。本研究采用啮齿类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和抑制二尖瓣细胞。利用全细胞胞内记录和活双光子成像方法，我们将确定刺激gaba能颗粒细胞的正交（感觉驱动）和皮质反馈通路的相对有效性。我们还将验证先前资助期和初步研究的出版物中提出的假设，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振幅的ipsp。Blanes细胞是我们最近描述的一种新的中间神经元亚型，在颗粒细胞上突触，因此非常适合调解这种中间神经元同步功能。拟议的研究将定义通常激活Blanes细胞的兴奋通路，并将验证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。定义在嗅球中产生感觉诱发抑制的细胞机制，这一提议的总体焦点，对于理解如何产生抑制至关重要

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.