Peripherally administered amylin inhibits stress-like behaviors and enhances cognitive performance

Authors: Laugero, Kevin; TRYON, MATTHEW - Non ARS Employee; MACK, CHRISTINE - Non ARS Employee; CALDARONE, BARBARA - Harvard Medical School; HANANIA, TALEEN - Psychogenics, Inc; MCGONIGLE, PAUL - Drexel University; ROLAND, BARBARA - Non ARS Employee; PARKES, DAVE - Non ARS Employee

Submitted to: Physiology & Behavior
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/30/2021
Publication Date: 12/2/2021
Citation: Laugero, K.D., Tryon, M., Mack, C., Caldarone, B., Hanania, T., McGonigle, P., Roland, B., Parkes, D. 2021. Peripherally administered amylin inhibits stress-like behaviors and enhances cognitive performance. Physiology and Behavior. 244. Article 113668. https://doi.org/10.1016/j.physbeh.2021.113668.
DOI: https://doi.org/10.1016/j.physbeh.2021.113668

Interpretive Summary: Amylin is a peptide hormone secreted along with insulin from the pancreas. Amylin acts on the brain to inhibit motivation to eat, suppress gastric emptying, and to facilitate the body’s regulation of circulating glucose levels. Prior studies also suggest that amylin may have additional benefits, including stress reduction and preventing stress or emotional related eating and risk for stress-related neuropsychiatric conditions. This study in mouse and rat models tested whether peripheral administration of amylin can prevent behavioral indicators of anxiety, depression, and psychosis, as well as enhance memory. Memory degradation is frequently observed in individuals who present with increased stress and stress related conditions, including obesity, type 2 diabetes, and neuropsychiatric diseases. Therefore, prevention strategies that also promote memory are expected to improve long term and total effectiveness in reducing risk for these stress related diseases. Although further testing is needed, our novel findings suggest a potential for amylin to access and benefit brain systems that impact or regulate memory, emotion, and mood.

Technical Abstract: Amylin, a 37 amino acid peptide pancreatic hormone co-secreted with insulin, normalizes the altered eating patterns induced by chronic stress in the rat. Because these stress-induced changes are driven, in part, by brain corticotropin-releasing factor (CRF) and corticosterone, and because alterations in the activity of these molecules and the stress system are commonly associated with neuropsychiatric diseases like anxiety, depression, and schizophrenia, we hypothesized that amylin might mitigate behavioral states associated with stress. Therefore, we tested the effects of rat amylin in standard rodent models of anxiety (stress-induced hyperthermia (SIH); marble burying; elevated plus maze (EPM)), depression (forced swim test (FST)), and schizophrenia (prepulse inhibition; Phencyclidine (PCP)-Induced Locomotion). To assess the neural underpinnings of amylin’s anxiolytic-like effects, we examined the effect of amylin on stress-indcued hyperthermia after lesioning the area postrema (AP), which mediates amylin’s metabolic effects. Amylin injection (IP, 0.1, 1.0, & 10 mg/kg) significantly (P<0.05) decreased SIH (97% below vehicle) and this effect was blocked by lesioning the AP. In other tests, amylin reduced marble burying (72% below vehicle), but had no effect in the EPM. Amylin injection also enhanced cognitive performance in the novel object recognition test. When administered continuously by SC-implanted osmotic pumps, amylin (300 'g/kg/d) blocked SIH when tested at 1 and 4 weeks. Compared to vehicle, amylin infusion (1 and 3 mg/kg/d) reduced the time immobile in the FST (P<0.05; 30 % below vehicle), suggesting antidepressant-like activity. Although further testing is needed, our novel findings suggest a potential for peripherally administered amylin to access and benefit pathways that regulate memory, emotion, and mood.