Mechanisms of striatal structural and functional plasticity.

树突棘是神经元上显著的、专门化的膜室，它容纳着 突触后，大脑中大多数兴奋性谷氨酸能突触的接收端。它们是高度可塑性的， 在发育、学习和疾病过程中的变化。这一提议依赖于多激光双光子成像和 产生和评估基因靶向纹状体上新连接的光刺激方法 神经元，解剖性别、年龄和神经调节状态的相互作用变量。这项提议是建立在 脊椎发生中的性别差异的初步观察，这可能与其他汇聚信号相互作用 级联以控制树突棘的形成和对治疗剂的敏感性。此外，最早的阶段 纹状体神经元中新生突触的数量将从功能和超微结构上定义，使用新开发的 帮助实现这一目标的分子工具和成像方法。拟议的工作将产生有价值的 对新的脊柱和突触发生、早期功能和稳定性的洞察，影响基础研究 与突触发育和指导可塑性的规则相关。由此产生的平台将有助于推动 允许研究人员设计治疗方法以增强神经元重建的技术创新 架构或解构会破坏异常的连接。

Dendritic spines are the remarkable, specialized membrane compartments on neurons that house the postsynaptic, receiving end of most excitatory, glutamatergic synapses in the brain. They are highly plastic and change during development, learning, and in disease. This proposal relies on multi-laser 2-photon imaging and photostimulation approaches to generate and evaluate new connections on genetically targeted striatal neurons, dissecting interacting variables of sex, age, and neuromodulatory state. The proposal builds on preliminary observations of sex differences in spinogenesis, which may interact with other convergent signaling cascades to control dendritic spine formation and sensitivity to therapeutic agents. Further, the earliest stages of nascent synapses in striatal neurons will be defined functionally and ultrastructurally, using newly developed molecular tools and imaging approaches to assist this objective. The proposed work would yield valuable insights into new spine and synapse genesis, early-stage function, and stability, impacting basic research relevant to synaptic development and rules that guide plasticity. The resulting platform will help to drive technical innovation that would allow researchers to design therapies to augment reconstruction of neuronal architecture or deconstruct aberrant connectivity.