Inhibitory Microcircuits in the Piriform Cortex

梨状皮层的抑制微电路

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：将感觉信号组合形成相干嗅觉表示的任务主要落在梨状皮层（PC）上。研究表明，气味身份表示为PC中的选择但空间分散的神经元亚组。这些集合的生成如何仍然是猜想的问题。阐明建立这些代码的机制的关键步骤是了解如何设置PC来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功能连接PC神经元组件相互构成的。特别令人感兴趣的是局部神经元在金字塔细胞上建立的突触连接，因为这些电路已被证明对于将金字塔细胞调整为来自OB的气味相关输入很重要。迄今为止，所有检查了PC内电路的研究纯粹是解剖学的，因此尚未评估功能突触。为了测定功能性抑制回路，我们在PC中间神经元上局部局部谷氨酸，并记录了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充电作为结缔分子的衡量标准。这种方法使我们能够在一个宽阔的PC区域中对单个和人群的锥体细胞进行采样。由于具有这种技术优势，我们首次发现了PC电路的计算意义上的空间组织。我们发现，间神经元与锥体细胞的相对位置决定了结缔分子。位于锥体细胞上的尾骨中的中间神经元比在更倾斜区域的中间神经元更容易抑制其峰值输出。因此，与主要激活大多数激活的小胸膜微电路的输入相比，大多激活尾微电路的OB兴奋性输入不太可能引起尖峰。此外，我们发现尾部PC区域的锥体细胞比位于相对尾部区域的锥体细胞大3倍。因此，抑制性连通性在锥体细胞上的强度不仅取决于中间神经元位置，而且还取决于沿PC rostro-caudal轴的金字塔细胞本身的位置。我们希望通过阐明PC空间的这种差异抑制作用的细胞和电路基础来进一步理解这种Rostro-caudal不对称的重要性。公共卫生相关性：该提案的发现不仅会揭示皮质嗅觉编码涉及的基本原理，而且还将为与神经退行性疾病有关的临床问题提供重大见解。例如，成像研究表明，精神分裂症患者在涉及处理嗅觉刺激的皮质区域表现出明显的功能障碍（Moberg等，1999; Schneider等，2007）。嗅觉歧视和识别的严重缺陷是帕金森氏病患者的预警症状（Mesholam等，1998； Kranick和Duda，2008）。阿尔茨海默氏病，亨廷顿的舞厅，酗酒的科萨科夫综合症，Pick的疾病，都有特征性的嗅觉功能障碍和神经病理学（Mesholam等，1998）。因此，从公共卫生的角度来看，阐明基础嗅觉网络编码具有很大的希望，可以理解神经退行性疾病。