Cholinergic modulation of olfactory bulb glomerular sensitivity

 描述(申请人提供)：这个项目的总体目标是直接测试来自Broca斜角带水平支核(HDB)的胆碱能输入如何改变嗅球(OB)肾小球回路，以及这种调制最终如何影响气味编码、感知和学习。我们将在小鼠体内和体外使用宽视野和双光子钙成像，表达特定OB细胞类型中神经元活动的遗传编码指标，以测试突触释放的乙酰胆碱作为主要气味强度的函数双向调节二尖瓣/簇状细胞气味反应的新的主导假设。我们进一步验证了这一假设，即这种调制是由于在球周抑制细胞上相反的毒碱和尼古丁受体作用，这两种作用对输入到肾小球的嗅觉感觉神经元突触前抑制的强度有不同的调节。 利用成像和良好的嗅觉调节行为，我们还将研究肾小球气味表达的胆碱能调节如何影响气味感知和学习。具体地说，我们测试了HDB在OB区释放乙酰胆碱的假设：(1)提高嗅觉敏感度，(2)使适应于外周嗅觉神经元水平的气味反应丧失习惯性，(3)对联想嗅觉学习至关重要。通过在群体和单细胞水平上研究在形态和生理上不同的神经元类型中受体类型特异性胆碱能调制，这一提议的实验将首次阐明胆碱能如何调节神经。 OB的气味反应影响嗅觉和学习行为。总体而言，这些发现将极大地促进我们对乙酰胆碱如何调节感觉表征、气味编码、感知和行为的理解。

 DESCRIPTION (provided by applicant): The overall goal of this project is to directly test how cholinergic input from the nucleus of the horizontal limb of the diagonal band of Broca (HDB) alters olfactory bulb (OB) glomerular circuits and how this modulation ultimately affects odor coding, perception, and learning. We will use of both wide-field and 2-photon in vivo and in vitro calcium imaging in mice expressing genetically encoded indicators of neuronal activity in defined OB cell types, to test the novel overarching hypothesis that synaptically-released acetylcholine bidirectionally modulates mitral/tufted cell odor responses as a function of the prevailing odor intensity. We further test the hypothesis that this modulation is due to opposing muscarinic and nicotinic receptor actions on inhibitory periglomerular cells that differentially regulate the strength of presynaptic inhibition of olfactory sensory neuron input to the glomeruli. Using imaging and well characterized olfactory-mediated behaviors, we will also investigate how this cholinergic modulation of the glomerular odor representation affects odor perception and learning. Specifically, we test the hypotheses that HDB-evoked acetylcholine release in the OB: (1) enhances olfactory sensitivity, (2) dishabituates odor responses adapted at the peripheral olfactory sensory neuron level and (3) is critical for associative olfactory learning. By investigating receptor type-specific cholinergic modulation in morphologically- and physiologically-distinct neuron types at both the population and single cell levels, the experiments of this proposal will for the first time elucidate how cholinergic modulation of neural odor responses in the OB impacts olfactory perception and learning behaviorally. The overall findings will dramatically advance our understanding of how acetylcholine modulates sensory representation, odor coding, perception and behavior.