Bi-Directional Effect of Cholecystokinin Receptor-2 Overexpression on Stress-Triggered Fear Memory and Anxiety in the Mouse

Abstract

Fear, an emotional response of animals to environmental stress/threats, plays an important role in initiating and driving adaptive response, by which the homeostasis in the body is maintained. Overwhelming/uncontrollable fear, however, represents a core symptom of anxiety disorders, and may disturb the homeostasis. Because to recall or imagine certain cue(s) of stress/threats is a compulsory inducer for the expression of anxiety, it is generally believed that the pathogenesis of anxiety is associated with higher attention (acquisition) selectively to stress or mal-enhanced fear memory, despite that the actual relationship between fear memory and anxiety is not yet really established. In this study, inducible forebrain-specific cholecystokinin receptor-2 transgenic (IF-CCKR-2 tg) mice, different stress paradigms, batteries of behavioral tests, and biochemical assays were used to evaluate how different CCKergic activities drive fear behavior and hormonal reaction in response to stresses with different intensities. We found that in IF-CCKR-2 tg mice, contextual fear was impaired following 1 trial of footshock, while overall fear behavior was enhanced following 36 trials of footshock, compared to their littermate controls. In contrast to a standard Yerkes-Dodson (inverted-U shaped) stress-fear relationship in control mice, a linearized stress-fear curve was observed in CCKR-2 tg mice following gradient stresses. Moreover, compared to 1 trial, 36 trials of footshock in these transgenic mice enhanced anxiety-like behavior in other behavioral tests, impaired spatial and recognition memories, and prolonged the activation of adrenocorticotropic hormone (ACTH) and glucocorticoids (CORT) following new acute stress. Taken together, these results indicate that stress may trigger two distinctive neurobehavioral systems, depending on both of the intensity of stress and the CCKergic tone in the brain. A “threshold theory” for this two-behavior system has been suggested.

Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice

“…Moreover, this treatment could not attenuate the deficit in spatial learning and memory, indicating that the mnemonic dysfunction is not directly related to PTSD itself, but it is a psychopathology or sequela of the interaction between the elevated CCKergic tone and AT. These results also support our recently established "two-behavior system" in the brain in response to environmental stress (39).…”

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

“…The CCK2 receptor is expressed highly in regions modulating pain and fear/emotional processing (Bowers et al, 2012;Chen et al, 2010;Kurrikoff et al, 2004;Li et al, 2013). In preclinical studies, deletion of the CCK2 receptor decreased hyperalgesia in a mouse neuropathic pain model (Kurrikoff et al, 2004), and ablation (CCK2 knockout mice) of the receptor increased μ-and δ-opioid receptors expression in the whole brain (Pommier et al, 2002).…”

Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y

“…An impairment of freezing began at 12 trials and decreased further with 24 and 36 footshocks. This “U” curve was not observed in mutant mice with CCK-B overexpression, who exhibited a linear increase in freezing behavior [71]. …”