Connecting Neural Plasticity to Learning and Memory

描述（由申请人提供）：现代神经科学的一个基本挑战是定义记忆如何在大脑中编码。 传统上，突触传递中的持久可塑性被认为是突触传递的细胞基质。 记忆，通过神经通路塑造信息流。 然而，到目前为止，被认为可以编码记忆痕迹的稀疏分布式神经网络还没有明确的描述。 因此，突触可塑性，感觉合奏和学习行为之间的联系仍然难以捉摸。在这里，我建议使用果蝇的嗅觉系统，果蝇，作为一个独特的范例，以弥合突触和行为之间的关键接口。 我提出了一种新的神经示踪技术，使用光转换荧光团和精确的电穿孔染料标记突触连接的神经元解剖和功能分析。 我建议应用这种创新的跟踪方法来映射苍蝇大脑中的关联嗅觉回路，并辨别如何通过突触连接和神经合奏编码气味协会。然后，我将使用体内功能成像和电生理记录在拴系苍蝇准备直接 将个体突触的可塑性与习得的嗅觉行为联系起来。 作为对这些高分辨率电路映射技术的补充，我提出了遗传策略，以目录选择性地诱导参与记忆痕迹的神经元中的转录变化，并提供深入了解介导神经回路功能的经验依赖性变化的分子机制。 总之，这些实验将提供对神经可塑性机制的综合理解，从分子和突触到电路和行为，并为开发合理的治疗方法奠定基础，以分子精度治疗痴呆症和其他记忆障碍。

DESCRIPTION (provided by applicant): A fundamental challenge of modern neuroscience is to define how memories are encoded within the brain. Classically, long-lasting plasticity in synaptic transmission has been proposed to be the cellular substrate for memory, shaping the flow of information through neural pathways. However, the sparse distributed neural networks thought to encode a memory trace have, until now, defied delineation. Consequently, the link between synaptic plasticity, sensory ensembles and learned behaviors remains elusive. Here I propose to use the olfactory system of the fruit fly, Drosophila melanogaster, as a unique paradigm to bridge the critical interface between synapses and behavior. I present a novel neural tracing technique that uses photoconvertible fluorophores and precise electroporation of dyes to label synaptically connected neurons for anatomic and functional analysis. I propose to apply this innovative tracing approach to map the associative olfactory circuits in the fly brain and discern how odor associations are encoded by synaptic connections and neural ensembles. I will then use in-vivo functional imaging and electrophysiolgical recordings in a tethered fly preparation to directly correlate the plasticity of individual synapses with learned olfactory behaviors. As a complement to these high-resolution circuit-mapping techniques, I propose genetic strategies to catalog the transcriptional changes selectively induced in neurons participating in a memory trace and provide insight into the molecular machinery that mediates experience-dependent changes in neural circuit function. Together, these experiments will offer an integrative understanding of neural plasticity mechanisms, from molecules and synapses to circuits and behavior, and lay the foundation for the development of rational therapeutic treatments to treat dementias and other memory disorders with molecular precision.