Inhibitory Microcircuits in the Piriform Cortex

梨状皮层的抑制微电路

• 批准号: 7991093
• 负责人: DIANA Leslie PETTIT
• 金额: $ 20.75万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991093
• 关键词: Accounting; Alcohol Amnestic Disorder; Alzheimer' s Disease; Anterior; Area; Attention; Axon; Biological Assay; Characteristics; Charge; Clinical; Code; Discrimination; Faculty; Functional disorder; Glutamates; Goals; Huntington Disease; Image; Interneurons; Location; Maps; Measures; Methods; Morphology; Nature; Neurodegenerative Disorders; Neurons; Odors; Olfactory Cortex; Output; Parkinson Disease; Patients; Pattern; Pick Disease of the Brain; Population; Principal Investigator; Process; Property; Public Health; Pyramidal Cells; Reading; Relative (related person); Sampling; Schizophrenia; Sensory; Signal Transduction; Specificity; Subgroup; Symptoms; Synapses; Testing; Time; base; density; falls; information processing; insight; interest; neurobiotin; neuropathology; olfactory bulb; olfactory stimulus; piriform cortex; postsynaptic; programs; public health relevance; receptor density; response

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.

描述（由申请人提供）：将感觉信号结合起来形成连贯的嗅觉表征的任务主要落在梨状皮质（PC）上。研究表明，气味识别在PC中表现为选择性但在空间上分散的神经元亚群。这些集合是如何产生的仍然是一个猜测问题。阐明建立这些代码的机制的关键步骤是了解PC如何设置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是由PC神经元组件之间的功能连接决定的。特别令人感兴趣的是局部中间神经元与锥体细胞之间的突触连接，因为这些电路已被证明对锥体细胞调节来自OB的气味相关输入很重要。迄今为止，所有检查PC皮质内电路的研究都是纯粹解剖的，因此没有评估功能性突触。为了检测功能性抑制电路，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抑制性突触后电流（IPSCs）。然后，我们使用IPSC电荷作为我们的连接强度测量。这种方法使我们能够将大量独特的抑制连接取样到广泛的PC区域内的单个锥体细胞和种群上。由于这种技术优势，我们首次发现了PC电路的计算意义重大的空间组织。我们发现中间神经元与锥体细胞的相对位置决定了结缔组织的强度。位于锥体细胞尾部的中间神经元比位于吻侧区域的中间神经元更有可能抑制其尖峰输出。因此，主要激活尾侧微回路的OB兴奋性输入比主要激活吻侧微回路的输入更不可能引起锥体细胞的尖峰。此外，我们发现尾部PC区的锥体细胞受到的抑制比位于相对吻侧区域的锥体细胞大3倍。因此，锥体细胞上的抑制性连接强度不仅取决于神经元间的位置，还取决于锥体细胞本身沿PC上尾轴的位置。我们希望通过阐明这种在PC空间上的差异抑制的细胞和电路基础，进一步了解这种背尾不对称的意义。