Assessing dopaminergic modulation of an associative circuit within the dentate gyrus

项目摘要 这个建议的目的是评估多巴胺能调制的联合电路内的齿状回 海马回（DG）。作为海马的主要区域，DG充当传入的门 大脑皮层的信息，并在海马的学习和记忆中起着关键作用。因此，DG功能障碍 与癫痫、焦虑和抑郁等疾病有关。总干事的作用得到承认 在模式分离中，一种能够区分两个相似的上下文或记忆的过程。在这 在这一过程中，DG将相似的皮层输入模式转换为不同的输出模式， CA 3区。DG的两个主要的主细胞是颗粒细胞（GCs）和门苔藓细胞（MCs）。两 细胞类型是兴奋性的。GC接收皮质输入并将DG输出传送到CA 3区域。稀疏射击 GC被认为是模式分离的基础，MC被定位为通过一个特定的模式来塑造这种发射。 关联回路，或兴奋回路，与GC，称为GC-MC-GC回路。MC项目接近GC体细胞 沿着海马轴，也介导前馈抑制GC，影响 GC输入的兴奋/抑制平衡。卡斯蒂略实验室最近发现的证据支持， 该电路中的活性依赖性变化可能在DG信息处理中起关键作用。卡斯蒂略 实验室已经证明MC-GC突触经历一种新形式的LTP，其增强E/I平衡 上的GC以及GC点火，从而提高DG输出。人们对这一现象的影响知之甚少。 神经调节输入对这个回路的动态特性的影响，但正如整个大脑一样， 神经调节剂可以影响电路中的信息流，以以上下文依赖的方式塑造它们的功能。 多巴胺是一种神经调质，被认为在调节海马回路和海马神经元中起作用。 功能提示DG中存在多巴胺能输入和功能性受体的证据 支持多巴胺可能塑造GC-MC-GC回路的动态特性，并在以下方面发挥核心作用： DG依赖性学习为了研究内源性多巴胺在GC-MC-GC回路中的作用， 在急性小鼠海马切片中进行电生理学记录以监测兴奋性， 传递和多巴胺能输入的光遗传学刺激期间回路内的可塑性。测试 多巴胺在DG依赖性学习中的作用，多巴胺受体将从小鼠GC中敲除， MC使用病毒注射策略，这些小鼠将在新奇检测的行为测试中进行评估， 模式分离和情境恐惧学习这项工作可以帮助阐明细胞和分子 研究DG的作用机制，为DG的防治提供依据。 相关的病理。

PROJECT SUMMARY The goal of this proposal is to assess dopaminergic modulation of an associative circuit within the dentate gyrus (DG) of the hippocampus. As the principal region of the hippocampus, the DG acts as a gate of incoming cortical information and plays a critical role in hippocampal learning and memory. As a result, DG dysfunction has been implicated in diseases including epilepsy, anxiety, and depression. The DG is recognized for its role in pattern separation, a process that enables distinction between two similar contexts or memories. In this process, the DG transforms similar cortical input patterns into distinct output patterns that can be read by the CA3 region. The two main principal cells of the DG are granule cells (GCs) and hilar mossy cells (MCs). Both cell types are excitatory. GCs receive cortical input and convey DG output to the CA3 region. Sparse firing of GCs is thought to underlie pattern separation, and MCs are positioned to shape this firing through an associative circuit, or excitatory loop, with GCs, termed the GC-MC-GC circuit. MCs project close to GC somas along the hippocampal axis and also mediate feed-forward inhibition onto GCs, affecting the excitatory/inhibitory balance of input to GCs. The Castillo Lab has recently discovered evidence supporting that activity-dependent changes in this circuit likely play a critical role in DG information processing. The Castillo Lab has demonstrated that MC-GC synapses undergo a novel form of LTP which enhances the E/I balance onto GCs as well as GC firing, thus enhancing DG output. Very little is known about the effect of neuromodulatory inputs on the dynamic properties of this circuit, but as is true throughout the brain, neuromodulators can affect information flow in circuits to shape their function in a context-dependent manner. Dopamine is a neuromodulator recognized for its role in modulating hippocampal circuits and hippocampal function. Evidence suggesting the presence of dopaminergic inputs and functional receptors in the DG supports that dopamine may shape the dynamic properties of the GC-MC-GC circuit and play a central role in DG-dependent learning. To study the role of endogenous dopamine in the GC-MC-GC circuit, electrophysiology recordings will be performed in acute mouse hippocampal slices to monitor excitability, transmission, and plasticity within the circuit during optogenetic stimulation of dopaminergic inputs. To test the role of dopamine in DG-dependent learning, dopamine receptors will be knocked out from mouse GCs and MCs using a viral injection strategy and these mice will be assessed in behavioral tests of novelty detection, pattern separation, and contextual fear learning. This work can help elucidate the cellular and molecular mechanisms of DG function and thus can provide a foundation for the prevention and treatment of DG- associated pathologies.