Inherited behaviors, BDNF expression and response to treatment in a novel multifactorial rat model for depression

Abstract

Major depressive disorder (MDD) is a common and devastating mental illness behaviorally characterized by various symptoms, including reduced motivation, anhedonia and psychomotor retardation. Although the etiology of MDD is still obscure, a genetic predisposition appears to play an important role. Here we used, for the first time, a multifactorial selective breeding procedure to generate a distinct 'depressed' rat line (DRL); our selection was based upon mobility in the forced swim test, sucrose preference and home-cage locomotion, three widely used tests associated with core characteristics of MDD. Other behavioral effects of the selection process, as well as changes in brain-derived neurotrophic factor (BDNF) and the response to three antidepressant treatments, were also examined. We show that decreased mobility in the forced swim test and decreased sucrose preference (two directly selected traits), as well as decreased exploration in the open field test (an indirectly selected trait), are hereditary components in DRL rats. In addition, lower BDNF levels are observed in the dorsal hippocampus of DRL rats, complying with the neurotrophic hypothesis of depression. Finally, electroconvulsive shocks (ECS) but not pharmacological treatment normalizes both the depressive-like behavioral impairments and the BDNF-related molecular alterations in DRL rats, highlighting the need for robust treatment when the disease is inherited and not necessarily triggered by salient chronic stress. We therefore provide a novel multifactorial genetic rat model for depression-related behaviors. The model can be used to further study the etiology of the disease and suggest molecular correlates and possible treatments for the disease.

Lower levels of brain‐derived neurotrophic factor are associated with melancholic psychomotor retardation among depressed inpatients

“…33 Data from animal studies show that decreased performance in a forced swimming test among "depressed" rats was accompanied by a reduction in BDNF levels in the hippocampus. 49 Our study has some limitations. First, although melancholic depression is often severe, not all severe depression is necessarily melancholic.…”

“…However, areas such as the nucleus accumbens and the amygdala may have enhanced expression of BDNF among depressed patients . Data from animal studies show that decreased performance in a forced swimming test among “depressed” rats was accompanied by a reduction in BDNF levels in the hippocampus . However, we should note that the presence of psychomotor retardation (the most severe clinical sign of depression) is not an accidental finding in the depression construct; indeed, according to Rasch analysis, patients who present this sign are the most likely to have the other symptoms too.…”

Increased relapse to cocaine‐seeking in a genetic model for depression

“…Animals from the genetic model developed in our lab were selectively bred according to measurements of three separate behavioral tests for depression, as detailed in Gersner et al and Moshe et al Briefly, rats from each generation were challenged with the FST, the sucrose preference test, and home‐cage locomotion. The FST was performed in a custom‐built cylindrical water tank, where rats were placed in the water for 10 minutes, and their behavior was video recorded and analyzed with a custom‐built algorithm as described previously to produce the mobility score.…”

“…Here, we investigated the effects of depressive‐like states on different stages of cocaine SA in the conflict model. Depressed‐like states were induced through the common model of chronic‐mild stress (CMS), and by selective breeding of our genetic model termed depressed rat line (DRL) . The DRL model was produced through a multifactorial selective breeding procedure based on three independent measures of core depressed‐like behaviors.…”

“…The DRL model was produced through a multifactorial selective breeding procedure based on three independent measures of core depressed‐like behaviors. DRL rats display several behavioral and neurochemical alterations found in other validated models for depression, including reduced sucrose preference, reduced immobility in the forced swim test (FST), decreased exploration in the open field test and reduced BDNF levels in the dorsal hippocampus . Importantly, the two depression models differ in their response to antidepressant treatments: while the effects of CMS are restored by both antidepressant medications and electroconvulsive therapy (ECT) , DRL rats respond only to ECT.…”