Changes in adenosine A1 receptor-mediated regulation of hippocampal area CA2 following chronic high-dose caffeine treatment during adolescence in rats

记忆是一种高度复杂的认知功能，涉及许多大脑结构、蛋白质和信号分子之间的相互作用。的确，神经元间突触连接强度的经验依赖性变化被认为是大脑信息储存的基础。因此，理解突触的高度弹性或“可塑性”对于揭示大脑如何将我们的个人经历转化为持久记忆至关重要。为此，调节性神经递质系统在形成突触过程中起着核心作用，这些突触过程涉及神经回路中信息的编码和保留。然而，一个根本的问题仍然存在，即外在因素如何招募、模仿甚至劫持这些内源性调节信号，以影响对认知和记忆功能至关重要的大脑系统的发育。哺乳动物的神经系统在出生后的早期发育中经历了几个关键时期，在这个时期，认知和感觉功能对一系列环境因素的持续破坏很敏感。事实上，越来越多的证据表明，啮齿动物的海马嘌呤能系统也经历了一段与腺苷A1受体（A1R）表达模式相关的重要成熟期。腺苷是大脑中的一种神经调节剂，海马体中腺苷受体的信号已被证明通过调节突触可塑性来影响记忆的形成和行为。在大鼠中，A1R的表达模式在早期发育过程中不是静态的。特别是，在青春期，海马的一个特定部分，即所谓的coru amonis 2（或CA2）中，A1R的表面表达显著增加。然而，在动物模型中尚未探索在发育过程中破坏腺苷能信号传导的操作后，CA2区突触功能和神经元生理学的变化。与A1Rs在CA2中的高表达一致的观察结果是，咖啡因和其他A1R阻滞剂在浓度对海马其他部分的反应几乎没有影响的情况下优先增强CA2区域的兴奋性突触传递。这表明CA2中的A1Rs可能在调节咖啡因的认知增强作用中发挥核心作用。咖啡因是一种天然的认知增强剂，被广泛用于提高注意力和增强记忆力。它的主要作用机制被认为是通过阻断A1Rs，然而，对海马区CA2知之甚少，其中A1Rs高度表达，并且在青少年发育期间，A1R的表面表达发生了巨大变化。在过去的15年里，高咖啡因所谓的“能量”饮料的受欢迎程度急剧上升，最近的趋势表明，青少年经常饮用能量饮料，而且饮用量超过了建议的每日限量。然而，目前尚不清楚青少年时期习惯性饮用能量饮料是否与大脑功能的持久变化有关。考虑到A1Rs在青春期急剧增加，以及咖啡因在改变CA2突触功能方面的特异性，本提案的目的是评估慢性咖啡因给药对CA2生理和CA2依赖的认知形式的长期影响。为了实现这一目标，人类青少年能量饮料的消费模式将在大鼠实验中模拟，咖啡因诱导的突触功能、神经元形态和CA2蛋白表达的变化将在给药方案结束时进行评估。支持青少年可能容易因习惯性摄入咖啡因而产生持久神经功能障碍的发育窗口期的证据，可能为修改政策和规范向弱势群体销售高咖啡因产品提供了理由。

Memory is a highly complex cognitive function that involves interactions between numerous brain structures, proteins and signalling molecules. Indeed, experience-dependent changes in the strength of synaptic connections between neurons are though to underlie information storage in the brain. Thus, understanding the highly elastic nature, or the 'plasticity', of synapses is critical to uncovering how the brain converts our individual experiences into lasting memories. To this end, modulatory neurotransmitter systems play a central role in shaping synaptic processes involved in the encoding and retention of information within neural circuits. A fundamental problem remains, though, in understanding how extrinsic factors recruit, mimic or even hijack these endogenous regulatory signals to affect the development of brain systems critical to cognitive and mnemonic function.The mammalian nervous system undergoes several critical periods during early postnatal development in which cognitive and sensory functions are sensitive to lasting disruption by an array of environmental factors. Indeed, there is growing evidence to suggest that the hippocampal purinergic system in rodents also undergoes a period of significant maturation related to the expression pattern of the adenosine A1 receptor (A1R). Adenosine acts as a neuromodulator in the brain, and signalling at adenosine receptors in the hippocampus has been shown to influence memory formation and behaviour by regulating synaptic plasticity. In rats, the expression pattern of the A1R is not static during early development. In particular, the surface expression of the A1R increases significantly during adolescence in a specific part of the hippocampus, known as area Cornu Ammonis 2 (or CA2). However, changes in synaptic function and neuronal physiology in area CA2 following manipulations to disrupt adenosinergic signalling during development have yet to be explored in animal models.Consistent with the high expression of A1Rs in CA2 is the observation that caffeine and other A1R blockers preferentially enhance excitatory synaptic transmission in area CA2 at concentrations that have little effect on responses in other parts of the hippocampus. This suggests that A1Rs in CA2 may play a central role in mediating the cognitive enhancing effects of caffeine. Caffeine is a naturally-occurring cognitive enhancer that is widely-consumed to improve attention and augment memory. Its primary mechanism of action is thought to be through blockade of A1Rs, however, little is known about hippocampal area CA2 where A1Rs are highly expressed and where the surface expression of the A1R changes dramatically during adolescent development. The popularity of highly-caffeinated so-called 'energy' drinks has increased dramatically in the past 15 years, and recent trends highlight how teenagers consume energy drinks regularly and in quantities that exceed recommended daily limits. It is currently unknown, though, whether habitual consumption of energy drinks during adolescence is associated with lasting changes in brain function. Given that A1Rs increase dramatically during adolescence, together with the specificity that caffeine has in modifying synaptic function in CA2, the aim of this proposal is to evaluate the long-term effects of chronic caffeine administration on CA2 physiology and CA2-dependent forms of cognition. To achieve this, human adolescent energy drink consumption patterns will be modelled experimentally in rats and caffeine-induced changes in synaptic function, neuronal morphology and protein expression in CA2 will be assessed at the end of the dosing regimen. Evidence in support of a developmental window during which adolescents may be susceptible to lasting neurological dysfunction resulting from habitual caffeine consumption may provide justification to amend policy and regulate the sale of highly caffeinated products to vulnerable populations.