Abstract
As a nonspecific antagonist of the adenosine A2A receptor (A2AR), caffeine enhances learning and improves memory impairment. Simultaneously, the consumption of caffeine correlates with a feeling of anxiety. The hippocampus is functionally differentiated along its dorsal/ventral axis and plays a crucial role both in memory and anxiety. Whether caffeine exerts its regulation by inhibiting A2ARs in different subregions of the hippocampus is still unknown. In the present study, we found that after chronic intake of drinking water containing caffeine (1 g/L, 3 weeks), mice exhibited aggravated anxiety-like behavior and enhanced memory function. Tissue-specific, functional disruption of dorsal hippocampal A2ARs by the CRE-LoxP system prevented the memory-enhancing effect of caffeine, while selective disruption of ventral hippocampal A2ARs blocked the impact of caffeine on anxiety. These results, together with the enhanced memory of dorsal hippocampus A2AR knockout mice and greater anxiety-like behavior of ventral hippocampus A2AR knockout mice without caffeine, indicates a dissociation between the roles of ventral and dorsal hippocampal A2A receptors in caffeine’s effects on anxiety-like and memory-related behavioral measures, respectively. Furthermore, optogenetic activation of dorsal or ventral hippocampal A2ARs reversed the behavioral alterations caused by drinking caffeine, leading to impaired memory or decreased anxiety-like behaviors, respectively. Taken together, our findings suggest that the memory- and anxiety-enhancing effects of caffeine are related to the differential effects of inhibiting A2ARs in the dorsal and ventral hippocampus, respectively.
Highlights
As the most widely consumed psychotropic substance and a component of the most popular beverages, caffeine is used to counteract performance impairments associated with sleep loss (Irwin et al, 2020).The consumption of caffeine attenuates memory impairments associated with aging and Alzheimer’s disease (AD) (Solfrizzi et al, 2015; Jacobson et al, 2020; Londzin, et al, 2021)and enhances memory in healthy humans (Borota et al, 2014; Irwin et al, 2020)
We found that localized knockout of dorsal hippocampus (dHPC) A2A receptor (A2AR) reduced the regulation of caffeine on memory but did not affect anxiety, whereas localized knockout of ventral hippocampus (vHPC) A2ARs reduced the regulation of caffeine on anxiety without affecting memory
Global A2AR Knockout Blocked the Effect of Caffeine on Anxiety and Memory
Summary
As the most widely consumed psychotropic substance and a component of the most popular beverages, caffeine is used to counteract performance impairments associated with sleep loss (Irwin et al, 2020).The consumption of caffeine attenuates memory impairments associated with aging and Alzheimer’s disease (AD) (Solfrizzi et al, 2015; Jacobson et al, 2020; Londzin, et al, 2021)and enhances memory in healthy humans (Borota et al, 2014; Irwin et al, 2020). The hippocampus belongs to the limbic system and plays an important role in memory, spatial navigation and emotion. According to a current consensus, the role played by the most dorsally located hippocampal segment is on cognitive operations like spatial navigation, while internally monitoring functions related to emotionality are taken on by the ventral segment of the hippocampus (Trompoukis and Papatheodoropoulos, 2020). Some studies have found that caffeine reverts memory impairment in a depression-prone mouse strain with upregulation of adenosine A2A receptors in the hippocampus (Machado et al, 2017), while selective A2AR knockout in the forebrain region (striatum, hippocampus, and cortex) induces anxiety-like behavior (Wei et al, 2014). Whether the different effects of caffeine on overall function are derived from its action on adenosine A2A receptors in different subregions of the hippocampus is still unclear
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