Assessing dopaminergic modulation of an associative circuit within the dentate gyrus

项目总结 这项建议的目的是评估齿状体内联合回路的多巴胺能调制。 海马回(DG)。作为海马体的主要区域，DG起着输入通道的作用 皮层信息，在海马区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。副总干事的角色是公认的 在模式分离中，一种能够区分两个相似的上下文或存储器的过程。在这 过程中，DG将相似的皮质输入模式转换为可由 CA3区。DG的两个主要细胞是颗粒细胞(GCs)和肺门苔藓细胞(MCs)。两者都有 细胞类型是兴奋性的。GCS接受皮质输入，并将DG输出传送到CA3区。稀疏的射击 GCS被认为是模式分离的基础，MC被定位为通过 与GC结合的回路或兴奋回路，称为GC-MC-GC回路。MCS项目接近GC SoMAS 也介导了对GCs的前馈抑制，影响了 对GC的兴奋性/抑制性输入平衡。卡斯蒂略实验室最近发现了支持这一观点的证据 该回路中依赖活动的变化可能在DG信息处理中起着关键作用。《卡斯蒂略》 实验室已经证明MC-GC突触经历了一种新的LTP形式，它增强了E/I平衡 添加到GC上，以及GC点火，从而提高DG产量。人们对其影响知之甚少 神经调节输入对这个电路的动态特性的影响，但整个大脑都是这样的， 神经调节剂可以影响电路中的信息流，以上下文相关的方式塑造其功能。 多巴胺是一种神经调节剂，因其在调节海马区和海马区的作用而被公认。 功能。证据表明DG内存在多巴胺能传入物质和功能性受体 支持多巴胺可以塑造GC-MC-GC回路的动态特性，并在 依赖DG的学习。为了研究内源性多巴胺在GC-MC-GC回路中的作用， 电生理记录将在急性小鼠海马片上进行，以监测兴奋性， 在多巴胺能输入的光遗传刺激过程中，回路内的传递和可塑性。要测试 多巴胺在DG依赖学习中的作用，多巴胺受体将从小鼠GCs和 使用病毒注射策略的MCS，这些小鼠将在新颖性检测的行为测试中进行评估， 模式分离和情境恐惧学习。这项工作有助于阐明细胞和分子 探讨DG的作用机制，为DG的防治提供依据。 相关的病理学。

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.