Effect of chronic unpredictable stress on mice with developmental under-expression of the Ahi1 gene: behavioral manifestations and neurobiological correlates

Abstract

The Abelson helper integration site 1 (Ahi1) gene plays a pivotal role in brain development and is associated with genetic susceptibility to schizophrenia, and other neuropsychiatric disorders. Translational research in genetically modified mice may reveal the neurobiological mechanisms of such associations. Previous studies of mice heterozygous for Ahi1 knockout (Ahi1+/−) revealed an attenuated anxiety response on various relevant paradigms, in the context of a normal glucocorticoid response to caffeine and pentylenetetrazole. Resting-state fMRI showed decreased amygdalar connectivity with various limbic brain regions and altered network topology. However, it was not clear from previous studies whether stress-hyporesponsiveness reflected resilience or, conversely, a cognitive-emotional deficit. The present studies were designed to investigate the response of Ahi1+/− mice to chronic unpredictable stress (CUS) applied over 9 weeks. Wild type (Ahi1+/+) mice were significantly affected by CUS, manifesting decreased sucrose preference (p < 0.05); reduced anxiety on the elevated plus maze and light dark box and decreased thigmotaxis in the open field (p < 0.01 0.05); decreased hyperthermic response to acute stress (p < 0.05); attenuated contextual fear conditioning (p < 0.01) and increased neurogenesis (p < 0.05). In contrast, Ahi1+/− mice were indifferent to the effects of CUS assessed with the same parameters. Our findings suggest that Ahi1 under-expression during neurodevelopment, as manifested by Ahi1+/− mice, renders these mice stress hyporesponsive. Ahi1 deficiency during development may attenuate the perception and/or integration of environmental stressors as a result of impaired corticolimbic connectivity or aberrant functional wiring. These neural mechanisms may provide initial clues as to the role Ahi1 in schizophrenia and other neuropsychiatric disorders.

Behavioural characterisation of chronic unpredictable stress based on ethologically relevant paradigms in rats

“…Interestingly, a lighter, but considerably longer CUS protocol of 11 weeks was not able to produce anxiogenic effects on the EPM 81 . In mice, a reduction in the time spent on the open arms was observed after six weeks 69 , but not after nine weeks of CUS 82 . In this latter study, CUS mice stayed longer in the open arms of the EPM, spent more time in the centre of an OFT, and the bright side of the dark/light test 82 , suggesting a consistent anxiolytic profile induced by CUS, contrary to what can be expected.…”

“…In mice, a reduction in the time spent on the open arms was observed after six weeks 69 , but not after nine weeks of CUS 82 . In this latter study, CUS mice stayed longer in the open arms of the EPM, spent more time in the centre of an OFT, and the bright side of the dark/light test 82 , suggesting a consistent anxiolytic profile induced by CUS, contrary to what can be expected. Although all these discrepancies could be attributed to differences in CUS protocols, the EPM seems to be an unstable test that is more likely to yield false positives when treatments increase locomotion and exploratory activity, as may be the case for CUS.…”

Validation of a Psychosocial Chronic Stress Model in the Pig Using a Multidisciplinary Approach at the Gut-Brain and Behavior Levels

“…Further work investigating the number and organization of mature neurons might answer this question. Another study also reported an increase of DCX + cells in CMS (Wolf et al, 2018), but did not investigate the number and/or functionality of mature neurons.…”

From Obesity to Hippocampal Neurodegeneration: Pathogenesis and Non-Pharmacological Interventions

“…Obese and diabetic animals show depression-like behaviors [ 90 , 91 , 92 ], which could be partly contributed by impaired hippocampal adult neurogenesis [ 93 , 94 , 95 ]. Both rodent models of depression [ 96 , 97 , 98 , 99 ] and diabetes [ 100 , 101 , 102 ] have shown a hyper-activated hypothalamic-pituitary-adrenal (HPA) axis, resulting in elevated glucocorticoid levels in response to stressors. The hippocampus exerts inhibitory feedback control to the activation of the HPA axis through GABAergic innervation to the paraventricular nucleus (PVN) of the hypothalamus [ 103 , 104 , 105 ].…”