Basic mechanisms regulating neuronal excitability and cognitive functions

背景：与自然衰老相关的记忆衰退归因于记忆过程所必需的脑回路中神经元可塑性的缺乏。大脑回路中的信息传递是通过突触传递化学信号来实现的。然后，这种化学信号被转化为电信号（神经元放电），将信息传递给下一个神经元，这一过程受到神经元内在兴奋性的严格控制。虽然年龄对化学信号传递的影响已被广泛研究，但我们对时间如何改变神经元的内在兴奋性知之甚少。这是至关重要的，因为内在兴奋性的调节是控制神经元突触可塑性和记忆形成能力的关键机制。今天，我们知道调节神经元兴奋性的细胞机制不是静态的，而是不断受到不断变化的生理环境的影响，例如涉及记忆过程的关键蛋白质的年龄驱动变化。识别这些衰老的分子靶标及其相关的细胞功能，并研究它们如何促进学习和记忆，是我们理解时间影响认知功能构建模块的机制的关键。sigma-1受体（s1）是一种神秘的蛋白质，既参与调节内在兴奋性，即神经元产生电信号的能力，也参与学习和记忆。有趣的是，与年轻人相比，s1激活对记忆的有益影响在老年人中更为明显。一个有趣的潜在候选机制是s1随时间调节神经元内在兴奋性的差异能力。长期目标：确定和研究调节神经元内在兴奋性、突触可塑性的基本细胞机制，以及这些机制如何促进记忆的形成。为此，我们结合了从分子、细胞到行为分析的各种方法。短期和长期目标：研究s1的前可塑性和记忆特性，旨在深入了解s1在整个生命周期中这些过程中的作用。1. 确定s1活动对神经元内在兴奋性和突触可塑性的影响，作为年龄的函数。2. 确定s1活动与学习和记忆之间的关系，作为年龄的函数。3. 阐明s1调节神经元内在兴奋性的细胞机制。4. 在神经元放电、突触可塑性和学习记忆之间建立51驱动的变化之间的因果关系。结论：我们研究的力量最终在于它们能够提供多管齐下的方法来研究s1在调节神经元内在兴奋性中的作用，以及这种功能如何随着时间的推移影响突触可塑性和学习能力，这与专业和广泛的神经科学受众相关。

BACKGROUND: Memory decline associated with natural aging is attributed to deficient neuronal plasticity in brain circuits necessary for memory processes.             Transmission of information within brain circuits occurs via transmission of a chemical signal at synapses. This chemical signal is then translated into an electrical signal (neuronal firing) that will convey information to the next neuron, a process that is tightly controlled by neuronal intrinsic excitability. While the effects of age on the transmission of the chemical signal has been extensively studied, we know little on how time alters neuronal intrinsic excitability. This is critical as the modulation of intrinsic excitability is a key mechanism that controls the capability of neurons to undergo synaptic plasticity and thereby memory formation. Today, we know that cellular mechanisms that regulate neuronal excitability are not static, but are continuously subjected to an ever-changing physiological milieu, such as age-driven changes of key proteins involved in memory processes. Identifying such molecular targets of aging, their associated cellular functions, and examining how they contribute to learning and memory is key to our understanding of the mechanisms by which time affects the building blocks of cognitive functions. The sigma-1 receptor (s1) is an enigmatic protein involved in both the regulation of intrinsic excitability, i.e., the ability of a neuron to generate the electrical signal, and learning and memory. Interestingly, the beneficial effect of s1 activation on memory is more pronounced in aged individuals compared to young. An intriguing underlying candidate mechanism is the differential ability of s1 to regulate neuronal intrinsic excitability through time.  LONG-TERM GOAL: To identify and examine fundamental cellular mechanisms regulating neuronal intrinsic excitability, synaptic plasticity, and how these mechanisms contribute to memory formation. To this end, we combine approaches ranging from molecular, cellular, to behavioral analyses. SHORT- AND LONG-TERM objectives: To examine pro-plasticity and promnesic properties of s1, aiming to gain mechanistic insights into the role of s1 in these processes across the whole lifespan. 1. Determine the impact of s1 activity on neuronal intrinsic excitability and synaptic plasticity as a function of age. 2. Determine the relationships between s1 activity and learning and memory as a function of age. 3. Elucidate cellular mechanisms by which s1 regulates neuronal intrinsic excitability. 4. Establish causality between s1-driven changes in neuronal firing, synaptic plasticity, and learning and memory.  CONCLUSION: The power of our studies ultimately lies in their ability to provide a multipronged approach on the role of s1 in the regulation of neuronal intrinsic excitability, and how this function impacts synaptic plasticity and learning abilities through time, which is relevant to a specialized and broad neuroscience audience.