Inhibitory Microcircuits in the Piriform Cortex

梨状皮层的抑制微电路

• 批准号: 8112514
• 负责人: DIANA Leslie PETTIT
• 金额: $ 24.1万
• 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/8112514
• 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(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落在梨状皮质(PC)上。研究表明，气味识别被表示为PC中选定的、但空间上分散的神经元亚群。这些合奏是如何产生的，仍然是一个猜测的问题。阐明建立这些代码的机制的关键一步是了解PC是如何设置来读取和整合传入的嗅球(OB)信号的。这些计算能力在很大程度上是由PC神经元组件彼此之间的功能连接决定的。特别令人感兴趣的是由局部中间神经元与锥体细胞建立的突触连接，因为这些电路已被证明对调节锥体细胞对来自OB的气味相关输入非常重要。到目前为止，所有检查PC皮质内回路的研究都是纯粹的解剖学研究，因此还没有对功能性突触进行评估。为了测试功能抑制电路，我们将谷氨酸集中在PC中间神经元上，并记录了由此引起的锥体细胞的抑制性突触后电流(IPSCs)。然后，我们使用iPSC Charge作为连接强度的衡量标准。这种方法使我们能够对分布在广泛PC区域的单个和群体锥体细胞上的大量独特的抑制性连接进行采样。由于这一技术优势，我们第一次发现了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连接强度。位于锥体细胞尾部的中间神经元比位于吻部较多区域的中间神经元更有可能抑制其棘波输出。因此，主要激活尾部微电路的OB兴奋性输入比主要激活吻部微电路的输入更不可能在锥体细胞中引起尖峰。此外，我们还发现，位于尾侧PC区的锥体细胞受到的抑制是位于相对吻区的锥体细胞的3倍。因此，锥体细胞上抑制连接的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吻尾轴的位置。我们希望通过阐明PC间隙上这种差异抑制的细胞和电路基础，进一步了解这种吻尾不对称的意义。 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，还将为与神经退行性疾病相关的临床问题提供重要的见解。例如，成像研究显示，精神分裂症患者在处理嗅觉刺激的皮质区域表现出显著的功能障碍(Moberg等人，1999；Schneider等人，2007)。嗅觉辨别和识别的严重缺陷是帕金森氏症患者的早期预警症状(Mesholam等人，1998；Kranick和Duda，2008)。阿尔茨海默病、亨廷顿舞蹈症、酒精性Korsakoff综合征、皮克氏病，都有特有的嗅觉功能障碍和神经病理(Mesholam等人，1998)。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大有可为。