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

点击翻译按钮获取中文摘要

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.