Ventral tegmental area dopaminergic lesion-induced depressive phenotype in the rat is reversed by deep brain stimulation of the medial forebrain bundle.

DBS of the medial forebrain bundle (MFB) has been investigated clinically in major depressive disorder patients with rapid and long-term reduction of symptoms. In the context of chronic bilateral high frequency deep brain stimulation (DBS) of the MFB, the current study looked at the impact of lesioning the ascending dopaminergic pathway at the level of the ventral tegmental area (VTA). Sprague-Dawley female rats were given bilateral injection of 6-OHDA into the VTA (VTA-lx group) or were left unlesioned (control group). Later, all animals received bilateral microelectrode implantation into the MFB followed by chronic continuous stimulation for 3 weeks. Behavioral tests were performed as baseline and following MFB-DBS, along with histological analysis. Pre-stimulation baseline testing of the VTA-lx animals indicated depressive-like phenotype in comparison with controls. Response to MFB-DBS varied according to (i) the degree of dopaminergic depletion: animals with severe mesocorticolimbic dopamine depletion did not, whilst those with mild dopamine loss responded well to stimulation; (ii) environmental conditions and the nature of the behavioral tests, e.g., stressful vs non-stressful situations. Neuromodulation-induced c-fos expression in the prelimbic frontal cortex and nucleus accumbens was also dependent upon integrity of the dopaminergic ascending projections. Our results confirm a potential role for dopamine in symptom relief observed in clinical MFB-DBS. Although mechanisms are not fully understood, the data suggests that the rescue of depressive phenotype in rodents can work via both dopamine-dependent and independent mechanisms. Further investigations concerning the network of depression using neuromodulation platforms in animal models might give insight into genesis and treatment of major depression disorder.

Long-term characterization of the Flinders Sensitive Line rodent model of human depression: Behavioral and PET evidence of a dysfunctional entorhinal cortex.

The etiology of depression is unknown but has been associated with dysregulation of neuronal activity at numerous loci on the limbic-cortical circuitry. The Flinders Sensitive Line (FSL) is a validated rodent model of human depression with spontaneously emerging behavioral and physiological phenotype, however, the durability and robustness of the phenotypes have not been described. The objective of the current study was to evaluate longitudinal dynamics of the depressive-like symptoms in this animal model. FSL and control rats of both genders were assessed over 8 months, characterizing their performance at different time points on motor, sensorimotor and complex learning/memory based tasks. Changes over time in physiological parameters, such as corticosterone and blood glucose levels, were monitored. Regional glucose metabolism, used as a marker of neuronal activity, was assessed at different time points using F18-FDG Positron Emission Tomography (PET). Results show that certain deficits at 2-3 months--on tests such as the Elevated Plus Maze, Object Recognition, and the Forced Swim Test--were transitory and the phenotype was no longer present when re-testing at 6-7 months of age. However, a stable impairment was detected on a learning and memory task, particularly indicating dysfunction in retention of spatial information. Furthermore, at multiple time points, the PET scan indicated a significate bilateral, hypo-metabolism in the temporal lobes in the FSL rats compared to healthy controls. The data suggests possible alterations of entorhinal cortex metabolism concomitant with specific behavioral changes and supports the importance of understanding the dynamics and the time and gender dependence of the phenotypes present.