Inhibitory Microcircuits in the Piriform Cortex

描述（由申请人提供）：组合感觉信号以形成连贯的嗅觉表征的任务主要福尔斯在梨状皮质（PC）上。研究表明，气味的身份表示为选择，但在PC空间分散的神经元亚群。这些集合是如何产生的仍然是一个猜想的问题。阐明建立这些代码的机制的一个关键步骤是了解PC是如何设置的，以读取和整合传入的嗅球（OB）信号。这些计算能力在很大程度上取决于PC神经元组件彼此之间的功能连接。特别令人感兴趣的是由局部中间神经元到锥体细胞上的突触连接，因为这些回路已经被证明对于调谐锥体细胞以从OB接收与气味相关的输入是重要的。到目前为止，所有研究PC皮质内回路已经纯粹解剖，因此没有评估功能性突触。为了分析功能性抑制回路，我们在PC中间神经元上局部释放谷氨酸，并记录锥体细胞中产生的诱发抑制性突触后电流（IPSC）。然后，我们使用IPSC电荷作为连接强度的测量。这种方法使我们能够将大量独特的抑制性连接采样到分布在广泛PC区域的单个锥体细胞和锥体细胞群上。由于这种技术优势，我们已经发现，第一次，一个计算上显着的空间组织PC电路。我们发现中间神经元与锥体细胞的相对位置决定了连接强度。位于尾锥体细胞的中间神经元更有可能抑制其尖峰输出比中间神经元在更喙区域。因此，OB兴奋性输入，激活主要是尾部微电路是不太可能引起尖峰在锥体细胞比输入激活主要是喙微电路。此外，我们还发现，锥体细胞在尾PC地区收到3倍以上的抑制比锥体细胞位于比较喙部地区。因此，对锥体细胞的抑制连接的强度不仅取决于中间神经元的位置，而且还取决于锥体细胞本身沿着PC喙尾轴的位置。我们希望通过阐明PC空间这种差异抑制的细胞和电路基础，进一步了解这种喙尾不对称的意义。 公共卫生相关性：这项提案的发现不仅将揭示皮质嗅觉编码的基本原理，而且还将为神经退行性疾病相关的临床问题提供重要的见解。例如，成像研究已经揭示，精神分裂症患者在涉及处理嗅觉刺激的皮层区域中显示出显著的功能障碍（Moberg et al.，1999; Schneider等人，2007年）。嗅觉辨别和识别的严重缺陷是帕金森病患者的早期预警症状（Mesholam等人，1998; Kranick和杜达，2008）。阿尔茨海默病、亨廷顿舞蹈病、酒精性科尔萨科夫综合征、皮克病都具有特征性嗅觉功能障碍和神经病理学（Mesholam等人，1998年）。因此，从公共卫生的角度来看，阐明嗅觉网络编码的基础在理解神经退行性疾病方面有很大的希望。

DESCRIPTION (provided by applicant): The task of combining sensory signals to form a coherent olfactory representation falls mainly on the piriform cortex (PC). Studies have shown that odor identity is represented as select but spatially dispersed neuronal subgroups in the PC. How these ensembles are generated is still a matter of conjecture. A key step to elucidate the mechanisms that establish these codes is to understand how the PC is set up to read and integrate incoming olfactory bulb (OB) signals. These computational capabilities are determined in large part by the functional connections PC neuronal components make with each other. Of particular interest are synaptic connections made by local interneurons onto pyramidal cells, as these circuits have been shown to be important for tuning pyramidal cells to odor-related inputs from the OB. To date, all studies that have examined PC intracortical circuitry have been purely anatomical and as such have not assessed functional synapses. To assay functional inhibitory circuitry, we focally uncaged glutamate over PC interneurons and recorded the resulting evoked inhibitory postsynaptic currents (IPSCs) in pyramidal cells. We then used IPSC charge as our measure for connective strength. This method allowed us to sample a large pool of unique inhibitory connections onto a single and population of pyramidal cells spread over a wide PC area. Because of this technical advantage, we have found, for the first time, a computationally significant spatial organization to PC circuitry. We found that the relative location of an interneuron to a pyramidal cell dictates connective strength. Interneurons located caudal to a pyramidal cell are more likely to inhibit its spike output than interneurons at more rostral regions. Consequently, OB excitatory inputs that activate mostly caudal microcircuits are less likely to elicit spiking in a pyramidal cell than inputs activating mostly rostral microcircuits. In addition, we have found that pyramidal cells in caudal PC regions receive 3-fold greater inhibition than pyramidal cells located in comparatively rostral areas. Thus, the strength of inhibitory connectivity onto a pyramidal cell is not only determined by interneuron location, but also by the location of the pyramidal cell itself along the PC rostro-caudal axis. We hope to further understand the significance of this rostro-caudal asymmetry by elucidating the cellular and circuit basis for such differential inhibition over PC space. PUBLIC HEALTH RELEVANCE: Findings from this proposal will not only reveal fundamental principles involved in cortical olfactory coding, but will also provide significant insight into clinical issues related to neurodegenerative disease. For instance, imaging studies have revealed that schizophrenic patients display significant dysfunctions in cortical regions involved in processing olfactory stimuli (Moberg et al., 1999; Schneider et al., 2007). Severe deficits in olfactory discrimination and recognition are early warning symptoms of patients with Parkinson's disease (Mesholam et al., 1998; Kranick and Duda, 2008). Alzheimer's disease, Huntington's chorea, alcoholic Korsakoff's syndrome, Pick's disease, all have characteristic olfactory dysfunctions and neuropathology (Mesholam et al., 1998). Thus, from a public health standpoint, elucidation of the underpinnings olfactory network coding holds much promise in understanding neurodegenerative disorders.