Local Circuits in the Olfactory Bulb

描述(由申请人提供)：在最基本的水平上，中枢神经系统参与处理由单个神经细胞的动作电位的时间模式所代表的信息。嗅觉系统是研究感觉信息如何编码的理想大脑区域。虽然嗅觉传导发生在专门的嗅觉感受器神经元中，但产生时间调制的气味特异性神经放电的实际工作始于嗅球。这里，来自感受器神经元的简单单调输入激活了空间上定义的输出神经元亚群(二尖瓣细胞)。然而，二尖瓣细胞并不是简单地将感觉信息传递到三级大脑区域。相反，受体神经元的输入与二尖瓣细胞和树突抑制性突触连接中不寻常的内在电流相互作用，树突抑制性突触连接介导了不同亚群的二尖瓣细胞之间的强烈横向相互作用。这项建议研究了嗅球神经元不同寻常的内在特性和树突抑制回路的细胞机制，树突抑制回路是反复抑制和侧向抑制的基础。我们使用细胞内记录和神经药理学工具相结合的方法来研究为什么嗅球的反复抑制似乎依赖于NMDA受体，以及它是如何被胆碱能受体调制的。我们还发现了嗅球中一类新的中间神经元，它们在短暂刺激后变得持续活跃。我们建议用实验来定义调节和调节持续活动的细胞内信号机制。最后，我们提出了一系列实验来确定二尖瓣细胞在产生生理放电模式时如何整合这些不同的突触和内在电流。理解感觉信息如何被表示为时空放电模式将具有广泛的意义，而不仅仅是理解嗅球的突触组织的直接目标。电刺激不同的中枢神经系统区域已被证明对神经系统疾病有治疗作用。目前，这些干预措施是基于经验发现的，通常使用非生理性的强直性刺激序列，而不是生理频率的模式刺激。本研究的一个(1)结果可能是更好地理解局部回路如何产生生理活动模式。我们的工作可能会带来新的治疗策略，用于治疗帕金森氏症和癫痫等神经疾病，这些疾病使用生物启发的模式刺激序列。

DESCRIPTION (provided by applicant): At the most elemental level, the central nervous system is involved in processing information represented by temporal patterns of action potentials in individual nerve cells. The olfactory system is an ideal brain region in which to study how sensory information is encoded. While olfactory transduction occurs in specialized olfactory receptor neurons, the actual work of generating temporally-modulated odorant-specific neural discharges begins in the olfactory bulb. Here the simple monotonic input from receptor neurons activates spatially-defined subpopulations of output neurons (mitral cells). However, mitral cells do not simply relay sensory information on to third-order brain areas. Instead, receptor neuron input interacts with unusual intrinsic currents in mitral cells and dendrodendritic inhibitory synaptic connections that mediate the strong lateral interactions between different subpopulations of mitral cells. This proposal examines the cellular mechanisms that underlie both the unusual intrinsic properties of olfactory bulb neurons and the dendrodendritic inhibitory circuits that underlie recurrent and lateral inhibition. We employ a combination of intracellular recording and neuropharmacological tools to investigate why recurrent inhibition in the olfactory bulb appears to be dependent upon NMDA receptors and how it is modulated by cholinergic receptors. We also have discovered a new class of interneurons in the olfactory bulb that become persistently active following transient stimuli. We propose experiments to define the intracellular signaling mechanisms that mediate and modulate persistent activity. Finally, we propose a series of experiments to determine how mitral cells integrate these different synaptic and intrinsic currents when generating physiological discharge patterns. Understanding how sensory information is represented as spatio-temporal discharge patterns will have wide ranging significance beyond the immediate goal of understanding the synaptic organization of the olfactory bulb. Electrical stimulation of different CNS regions has been shown to be therapeutic in neurological disease. Currently, these interventions are based on empirical findings, often employing non-physiological tetanic stimulus trains, rather than patterned stimuli at physiological frequencies. One (1) outcome from the present study is likely to be a better understanding of how physiological patterns of activity are generated by local circuits. Our work may lead to new therapeutic strategies for treating neurological diseases such as Parkinson's disease and epilepsy that employ biologically-inspired patterned stimulus trains.