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。虽然嗅觉转导发生在专门的嗅觉受体神经元中，但产生暂时调节的气味特异性神经放电的实际工作始于嗅球。这里，来自受体神经元的简单单调输入激活了具有空间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大脑的第三层区域。相反，受体神经元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，这些突触连接介导了二尖瓣细胞不同亚群之间强烈的横向相互作用。本研究探讨了嗅球神经元不寻常的内在特性和树突抑制回路背后的细胞机制，树突抑制回路是周期性和侧向抑制的基础。我们采用细胞内记录和神经药理学工具的组合来研究为什么嗅球中的复发抑制似乎依赖于NMDA受体，以及它是如何被胆碱能受体调节的。我们还在嗅球中发现了一类新的中间神经元，它们在短暂的刺激后变得持续活跃。我们建议通过实验来确定介导和调节持续活动的细胞内信号机制。最后，我们提出了一系列的实验，以确定二尖瓣细胞如何整合这些不同的突触电流和固有电流时，产生的生理放电模式。理解感觉信息是如何以时空放电模式呈现的，将具有广泛的意义，而不仅仅是理解嗅球的突触组织。电刺激不同的中枢神经系统区域已被证明是治疗神经系统疾病。目前，这些干预措施是基于经验发现，通常采用非生理性破伤风刺激序列，而不是生理频率的模式刺激。本研究的一个结果可能是更好地理解局部神经回路如何产生生理活动模式。我们的工作可能会导致新的治疗策略，以治疗神经系统疾病，如帕金森氏病和癫痫，采用生物启发模式刺激列车。

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.