Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation

Abstract

Stressful events can generate emotional memories linked to the traumatic incident, but they also can impair the formation of nonemotional memories. Although the impact of stress on emotional memories is well studied, much less is known about the influence of the emotional state on the formation of nonemotional memories. We used the novel object-recognition task as a model of nonemotional memory in mice to investigate the underlying mechanism of the deleterious effect of stress on memory consolidation. Systemic, hippocampal, and peripheral blockade of cannabinoid type-1 (CB1) receptors abolished the stress-induced memory impairment. Genetic deletion and rescue of CB1 receptors in specific cell types revealed that the CB1 receptor population specifically in dopamine β-hydroxylase (DBH)-expressing cells is both necessary and sufficient for stressinduced impairment of memory consolidation, but CB1 receptors present in other neuronal populations are not involved. Strikingly, pharmacological manipulations in mice expressing CB1 receptors exclusively in DBH + cells revealed that both hippocampal and peripheral receptors mediate the impact of stress on memory consolidation. Thus, CB1 receptors on adrenergic and noradrenergic cells provide previously unrecognized cross-talk between central and peripheral mechanisms in the stress-dependent regulation of nonemotional memory consolidation, suggesting new potential avenues for the treatment of cognitive aspects on stress-related disorders. memory consolidation | stress response | cannabinoid receptor | endocannabinoid system | noradrenergic signaling M emory consolidation is sensitive to emotion-related manipulations after acquisition (1). However, the underlying neurobiological mechanisms are only partly understood. Emotions can contribute to memorizing important life events (1, 2); they can also impair memory consolidation (2). Specifically, emotional arousal caused by stress has been studied extensively in animal models and in humans, and it has been reported to produce both facilitation and impairment of memory (3-5). Most studies that investigated the neural mechanisms mediating the effects of stress have focused on emotional memories; the mechanisms underlying the effects of acute stress on nonemotional memories are less understood.Acute stressful stimuli activate the sympathetic-adrenal system and the hypothalamic-pituitary-adrenal (HPA) axis (6, 7). Increased activity in the sympathetic-adrenal system involves a rapid release of adrenaline and noradrenaline from adrenal chromaffin cells and sympathetic nerve terminals, respectively (7). Moreover, stress-induced activation of the HPA axis involves the synthesis and secretion of glucocorticoids (cortisol in humans and corticosterone in most rodents) from the adrenal cortex (8). Both animal and human studies have shown that these stress hormones have profound effects on cognition by acting on specific brain regions involved in the processing of emotional stimuli (1, 9-12).The endocannabinoid system is an endogenous neur...

CB1 Receptor Signaling in the Brain: Extracting Specificity from Ubiquity

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Current evidence of cannabinoid‐based analgesia obtained in preclinical and human experimental settings

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Cannabinoid type-1 receptor blockade restores neurological phenotypes in two models for Down syndrome

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