Synaptic Strength in a CPG: Animal-to-animal Variability and Stereotypy

描述（由申请人提供）：神经元的内在特性及其突触相互作用在形成网络输出中的重要性已通过先前的工作得到广泛证明。内在特性不仅塑造神经元的活动和反应特性，而且在同一可识别的细胞中，离子通道的表达可以在不同的制备中变化2-5倍，而网络继续产生刻板的行为输出。根据计算研究，也有人认为突触强度变化2-5倍。我的主要假设是，水蛭心跳CPG中的突触强度会在2-5倍的范围内变化。尽管这种强度的变化，连接到同一突触后目标的相对强度将保持不变。抑制化学突触和兴奋性电耦合之间必须存在重要的平衡，才能可靠地产生定型相位。在我的每个目标中，突触强度将用突触后单电极电压钳在标准保持电位下测量。具体目的1：测量水蛭心跳CPG定时电路中所有突触的强度及其向开关中间神经元的输出。具体目的2：测量计时电路和开关中间神经元到中间前运动中间神经元的突触强度。确定如何在兴奋性电连接和抑制性化学连接之间建立平衡。具体目标3：通过测量第15节和第16节内和节间的电耦合以及它们与其他CPG中间神经元的连接强度，确定新特征的第15节和第16节后心脏中间神经元如何连接到电路的其余部分。计算研究表明，增加神经网络的可变性将大大降低网络的同步性。这种减少的同步性可能是在高变异性网络中预防癫痫的一种机制。这也暗示了可能还有其他神经系统疾病与神经系统内的变异性水平有关，因此从简单的神经系统开始探索这种变异性是很重要的。公共卫生相关性：对神经元如何聚集在一起执行特定行为（如行走或呼吸）的基本理解，在治疗脊髓损伤（SCI）和疾病以努力恢复关键行为时将至关重要。我们有能力建立一个精确的计算模型来描述这些网络是如何运作的，这将使我们能够创造出假肢和植入式设备，在未来，这些假肢和植入式设备可能会恢复这些失去的功能。

DESCRIPTION (provided by applicant): The importance of both intrinsic properties of neurons and their synaptic interactions in shaping network output has been extensively shown through previous work. Intrinsic properties not only shape activity and response properties of neurons, but ion channel expression can vary 2-5 fold across preparations in the same identifiable cell, while the network continues to produce a stereotyped behavioral output. It has also been suggested that synaptic strength varies 2-5 fold, based on computational studies. My central hypothesis is that the synapses in the leech heartbeat CPG will vary in strength over a 2-5 fold range. Despite this variability in strength, the relative strength of connections onto the same postsynaptic target will be maintained. An important balance must exist between inhibitory chemical synapses and excitatory electrical coupling to reliably generate stereotyped phasing. In each of my aims synaptic strength will be measured with postsynaptic single electrode voltage clamp at a standard holding potential. Specific Aim 1: To measure the strength of all synapses within the timing circuit of the leech heartbeat CPG and their output onto the switch interneurons. Specific Aim 2: To measure the strength of the synapses from the timing circuit and the switch interneurons onto the middle premotor interneurons. Determine how a balance is created between excitatory electrical and inhibitory chemical connections. .Specific Aim 3: To determine how the newly characterized rear heart interneurons in ganglia fifteen and sixteen connect to the rest of the circuit by measuring their intra- and inter-ganglionic electrical coupling and the strength of their connection to the other CPG interneurons. Computational studies have shown that increasing variability in a neural network will substantially decrease the synchrony of the network. This decreased synchrony could be a preventative mechanism for epilepsy in networks with high levels of variability. This is also suggestive that there may be other neurological disorders related to the levels of variability within the nervous system, and therefore it will be important to explore this variability starting in a simple nervous system. PUBLIC HEALTH RELEVANCE: A basic understanding of how sets of neurons come together to perform a specific behavior, such as walking or breathing, will be crucial when working with spinal cord injury (SCI) and disease in an effort to restore critical behaviors. Our ability to construct an accurate computational model of how these networks function will allow us to create prosthetics and implantable devices that may, in the future, restore some of these lost functions.