Abstract
Treatment-resistant depression (TRD) remains a pressing clinical problem. Optimizing treatment requires better definition of the specificity of the involved brain circuits. The rat strain bred for negative cognitive state (NC) represents a genetic animal model of TRD with high face, construct and predictive validity. Vice versa, the positive cognitive state (PC) strain represents a stress-resilient phenotype. Although NC rats show depressive-like behavior, some symptoms such as anhedonia require an external trigger, i.e. a stressful event, which is similar to humans when stressful event induces a depressive episode in genetically predisposed individuals (gene–environment interaction). We aimed to distinguish neurobiological predisposition from the depressogenic pathology at the level of brain-network reorganization. For this purpose, resting-state functional magnetic resonance imaging time series were acquired at 9.4 Tesla scanner in NC (N=11) and PC (N=7) rats before and after stressful event. We used a graph theory analytical approach to calculate the brain-network global and local properties. There was no difference in the global characteristics between the strains. At the local level, the response in the risk strain was characterized with an increased internodal role and reduced local clustering and efficiency of the anterior cingulate cortex (ACC) and prelimbic cortex compared to the stress-resilient strain. We suggest that the increased internodal role of these prefrontal regions could be due to the enhancement of some of their long-range connections, given their connectivity with the amygdala and other default-mode-like network hubs, which could create a bias to attend to negative information characteristic for depression.
Highlights
Treatment-resistant depression (TRD) remains a pressing clinical problem responsible for long-term disability and posing a therapeutic challenge
The response in the risk strain was characterized with an increased internodal role and reduced local clustering and efficiency of the anterior cingulate cortex (ACC) and prelimbic cortex compared to the stress-resilient strain
We suggest that the increased internodal role of these prefrontal regions could be due to the enhancement of some of their long-range connections, given their connectivity with the amygdala and other default-mode-like network hubs, which could create a bias to attend to negative information characteristic for depression
Summary
Treatment-resistant depression (TRD) remains a pressing clinical problem responsible for long-term disability and posing a therapeutic challenge. Two rat strains (congenital learned helpless (cLH) and congenital non-learned helpless (cNLH)) were bred based on a Seligman’s hypothesis that learned helplessness, a depression-like condition, is induced by uncontrollable stress in individuals with a predisposition.[1] The cLH strain represents a genetic animal model of TRD with high face, construct and predictive validity.[2,3,4] In contrast, the cNLH strain represents a stress-resilient phenotype This established genetic strain of cLH rats demonstrate congenital helpless behavior, as well as deficient reward perception,[5] depressive-like cognitive bias,[2,6] treatment resistance (to antidepressant and to electroconvulsive shock therapy)[7] and biochemical changes such as higher glutamate/GABA ratios in the hippocampus and prefrontal cortex.[7,8] Increased glutamate and reduced GABA levels are observed in depressive patients and could reflect depressionlike symptomatology.[9] Glutamate injection into the rat's frontal cortex is enough to induce learned helplessness.[10] In addition, the metabolism of the lateral habenula was found to be hyperactive in cLH rats,[11] and its pharmacological inhibition by GABA agonist muscimol reduces learned helplessness behavior in cLH rats[12] to the deep-brain stimulation of this region in TRD.[13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
