Abstract
One in five people in Aotearoa report experiencing long-term stress. Stress is a well-established risk factor for poor physical health, physical inactivity and weight gain. However, the mechanisms linking chronic stress and poor health outcomes remains unknown. During stress, the body engages the stress response by driving the activation of corticotropin-releasing hormone (CRH) neurons in the hypothalamus. The present research aimed to assess whether chronic activation of CRH neurons alone is sufficient to drive the pathophysiological disruptions observed during chronic stress.
To address this CRH-cre mice (n = 9 males, n = 6 females) underwent stereotaxic surgery and a viral vector was administered to transduce a designer receptor (hM3Dq), exclusively in CRH neurons. The hM3Dq receptor has no endogenous ligand but can be exclusively activated using the designer drug deschloroclozapine (DCZ), which was placed in mice’s drinking water (7.5 µL/mL). Control mice (n = 3 males, n = 3 females) did not receive the viral vector. Mice were housed in a novel custom-built smart housing unit which allowed the automated assessment of physiological parameters. Bodyweights were measured daily.
Following 2 weeks of DCZ treatment, mice exhibited a significant loss of physical activity (p = 0.004, RM one-way ANOVA). While a reduction in bodyweight was observed following the first 24 hours of DCZ treatment (-0.004762 ± 0.1405 g [control mice] vs -1.213 ± 0.2113 g [CRH-hM3Dq mice]; p=0.0006, paired Student’s t-test) the subsequent weeks of DCZ treatment led to a significant weight increase (-0.021 ± 0.169 g [control mice] vs 6.600 ± 0.766 g [CRH-hM3Dq mice]; p = <0.0001, two-way ANOVA).
Finally, using fluorescent imaging, the expression of hM3Dq in CRH neurons was validated. A significant correlation (p = <0.0001, Pearsons correlation) was found between the number of hM3Dq-expressing CRH neurons and reductions in physical activity.
Collectively these results indicate that chronic CRH neuron activation alone induced pathophysiological changes associated with chronic stress. This offers new insights into the mechanism underlying chronic stress related health disruptions.