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

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

The physiology of learning and memory: Role of peptides and stress

The neuropeptides, as well as their respective receptors, are widely distributed throughout the mammalian central nervous system. During learning and memory processes, besides structural synaptic remodeling, changes are observed at molecular and metabolic levels with the alterations in neurotransmitter and neuropeptide synthesis and release. While there is consensus that brain cholinergic neurotransmission plays a critical role in the processes related to learning and memory, it is also well known that these functions are influenced by a tremendous number of neuropeptides and non-peptide molecules. Arginine vasopressin (AVP), oxytocin, angiotensin II, insulin, growth factors, serotonin (5-HT), melanin concentrating hormone, histamine, bombesin and gastrin-re leasing peptide (GRP), glucagon-like peptide-1 (GLP-1). cholecystokinin (CCK), dopamine, corticotropin releasing factor (CRT) have modulatory effects on learning and memory. Among these peptides CCK, 5-HT and CRF play strategic roles in the modulation of memory processes under stressful conditions. CRF is accepted as the main neuropeptide involved in both physical and emotional stress.. with a protective role during stress, possibly through the activation of the hypothalamo-pitiuitary (HPA) axis. The peptide CCK has been proposed to facilitate memory processing and CCK-like immunoreactivity in the hypothalamus was observed upon stress exposure, suggesting that CCK may participate in the central control of stress response and stress-induced memory dysfunction. On the other hand, 5-HT appears to play a role in behaviors that involve a high cognitive demand and stress exposure activates serotonergic systems in a variety of brain regions. The physiological role and therapeutic efficacy of various neuropeptides and the impact of stress exposure in the acquisition and consolidation of memory will be reviewed thoroughly

Interactive lecturing for meaningful learning in large groups

In order to enhance the quality of integration of physiological basic concepts with clinical sciences and to facilitate problem solving skills, a 'structured integrated interactive' two-hour block lecture on growth hormone physiology was implemented. A template showing the central regulation of growth hormone release and its peripheral effects was developed as an advanced organizer. Based on this template, new information was presented. Student feedback demonstrated that the lecture, based on the expository teaching model and enhanced by different forms of question and problem solving activities, was successful and interactive. It was also more motivating and was able to keep the attention of the students in relatively higher levels throughout the lecture. Furthermore, students felt that they had made important gains in transferable problem solving skills and this opinion was supported by their performance in clinical cases. These findings reinforced the idea that systematic incorporation of active learning strategies into lectures may minimize many of the weaknesses of traditional lectures