Synaptic and Circuit Interactions to Shape Multisensory Processing

在感觉处理过程中的一个关键步骤是从一个 大量令人分心的感官输入。产生显著的一种机制是将感觉信息 来自正在进行的体验，以及来自过去感官体验的记忆。在哪里以及如何实现这些 发生在大脑中的功能联系是神经科学的中心问题。这项提案旨在填补这一空白 通过探索电路相互作用和单神经元计算来帮助分配助记符 对感官信号的效价。在这项研究中，我们提出了海马体-学习和 记忆-在控制感觉信息流的过程中起着至关重要的作用，它通过与 内嗅皮层，一个处理多感官信息的中枢。为了检验这一假设，我们将使用 解剖学和功能连接图实验验证海马区如何与 内嗅皮层输出层(目标1)。我们将评估海马体的输入如何调节短期的 内嗅觉皮质兴奋性抑制性突触传递的可塑性动力学(目标2)。最后，我们 将测试海马体是否主动调节突触强度和感觉输入的获得 通过树突整合和长期可塑性机制的内嗅皮层(目标3a)以及如何沉默 对EC的CA1输入将影响情境学习行为(目标3b)。 尽管对记忆处理进行了60年的研究，但令人惊讶的是，我们对该组织知之甚少 海马区投射回路的功能和记忆调节持续进行的机制 内嗅觉皮质的感觉处理。我们的研究将结合体外和体内的最新技术 方法，包括电生理学、行为测试和光遗传学，以提供一个功能模型 未被探索的海马体-内嗅觉皮质相互回路。来自我们实验室的令人兴奋的试点实验 已经揭示了海马体和内嗅觉皮质之间的一条新通路，这意味着一种真正的互惠 反馈电路回路。这个回路将海马体直接连接到内嗅皮层的输出神经元 将感觉信息投射到海马体。我们的新电路模型具有潜在的变革性，因为 描述了一种海马体直接将记忆输入传输到内嗅觉皮质的途径， 最小的延迟和转换，根据相关性优化感觉输出，并快速适应 对不断变化的环境需求作出反应。这样的功能可以被大脑用来促进 强化学习，提炼旧记忆，形成新的记忆联想。通过识别神经回路 海马体和内嗅觉皮质之间的相互作用，我们的研究将极大地提高我们的理解 与记忆相关的感觉处理缺陷的机制有哪些 几种神经和神经精神疾病，包括阿尔茨海默病、精神分裂症和创伤后应激障碍。

A critical step during sensory processing is the extraction of relevant information about the outside world from a host of distracting sensory inputs. One mechanism for generating salience is to associate sensory information from ongoing experiences with memories derived from past sensory experiences. Where and how these functional associations occur in the brain are central questions in neuroscience. This proposal aims to fill this gap by exploring circuit interactions and single neuron computations that help assign mnemonic valence to sensory signals. In this study, we propose that the hippocampus—the center of learning and memory—plays a crucial role in gating sensory information flow through its reciprocal circuit interactions with the entorhinal cortex, a hub for processing multisensory information. To test this hypothesis, we will use anatomical and functional connectivity mapping experiments to validate how hippocampus communicates with entorhinal cortex output layers (Aim 1). We will assess how hippocampal inputs modulate the short-term plasticity dynamics of excitatory-inhibitory synaptic transmission in the entorhinal cortex (Aim 2). Finally, we will test whether the hippocampus actively modulates the synaptic strength and gain of sensory inputs to entorhinal cortex through dendritic integration and long-term plasticity mechanisms (Aim 3a) and how silencing the CA1 inputs to EC will affect contextual learning behavior (Aim 3b). Despite 60 years of research on memory processing, we know surprisingly little about the organization and function of hippocampal projection circuitry and the mechanisms by which memories modulate ongoing sensory processing in the entorhinal cortex. Our study will combine state-of-the-art in vitro and in vivo approaches, including electrophysiology, behavioral testing, and optogenetics, to provide a functional model of the unexplored hippocampal-entorhinal cortex reciprocal circuit. Exciting pilot experiments from our lab have already revealed a new pathway between the hippocampus and entorhinal cortex that implies a true reciprocal feedback circuit loop. This circuit connects the hippocampus directly to entorhinal cortex output neurons that project sensory information to the hippocampus. Our new circuit model is potentially transformative, for it describes a route by which the hippocampus directly transmits memory input to the entorhinal cortex, with minimal lag and transformation, to refine sensory output based on relevance and to quickly adapt behavior in response to changing environmental demands. Such a function could be used by the brain to facilitate reinforced learning, refine old memories, and form new memory associations. By identifying the neural circuit interactions between the hippocampus and entorhinal cortex, our study will greatly improve our understanding of the mechanisms that underlie the memory-related sensory processing deficits experienced by patients of several neurological and neuropsychiatric illnesses, including Alzheimer’s disease, schizophrenia and PTSD.