Decreased cell proliferation in the dentate gyrus does not associate with development of anhedonic-like symptoms in rats.

Depressive disorders have been proposed to be caused by stress-induced down-regulation of hippocampal neurogenesis. Nevertheless, several reports have recently pointed out that, in rodent models of depression, suppression of generation of new hippocampal neurons is not by itself sufficient to induce the development of depression-related symptoms. In the present study, we used the cell proliferation blocker methylazoxymethanol (MAM) and the rat chronic mild stress (CMS) model of depression to challenge the neurogenic theory of depression. In order to achieve a comparable reduction in hippocampal cytogenesis, rats were either chronically treated with MAM for 2 weeks, or subjected to an 8 week regime of chronic mild stress. Consumption of a palatable sucrose solution was monitored once a week to assess the development of anhedonic behavior. Prior to terminal perfusion, the animals were injected with bromodeoxyuridine, a marker of proliferating cells. The number of proliferating cells and total cell number and volume were estimated for the granule cell layer of the ventral hippocampal formation. Unlike CMS, chronic injections with MAM did not induce anhedonia-like symptoms in rats. Both MAM-treated and CMS-exposed groups of rats showed a comparable significant reduction in cell proliferation in the granular cell layer of the ventral hippocampal formation. However, the total cell number was reduced for CMS-exposed rats only while the granule cell layer volume was conserved for both groups. Our results show that suppression of cell proliferation in the hippocampal formation is not an absolute factor for induction of an anhedonia-like state in rats. However, it may still represent an important causal factor for vulnerable subjects.

Stress sensitivity and resilience in the chronic mild stress rat model of depression; an in situ hybridization study.

We used the validated chronic mild stress (CMS) paradigm to induce anhedonia, a core symptom of major depression, in rats. Thirty percent of animals exposed to CMS are resistant to the development of anhedonia, whereas the remaining are responsive, CMS resilient and CMS sensitive, respectively. We used in situ hybridization to elucidate the molecular mechanisms, which may be involved in the development of anhedonia during CMS. In the CA3 of the ventral hippocampus, we found upregulation of brain-derived neurotrophic factor (BDNF) mRNA in the CMS resilient group indicating protective role of BDNF in stress. Moreover, in the CA3 we found downregulation of vascular endothelial growth factor (VEGF) mRNA in the CMS sensitive group. Downregulation of VEGF suggests impaired hippocampal function, caused by loss of trophic factor neuroprotective support, as part of a previously uncharacterized mechanism for development of anhedonia. CMS induced anhedonia was not related to mRNA expression differences of the dopamine receptors D(1) and D(2), enkephalin, dynorphin, the NMDA receptor subtype NR2B in the ventral striatum, BDNF expression in the dentate gyrus, nor corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) in the paraventricular nucleus of the hypothalamus. In particular, HPA axis seems to be activated in the CMS resilient group suggesting other pathways protecting against stress sensitivity. We applied the restraint stress procedure to compare effects of a faster and simpler form of stress to CMS and found the latter to be more valid as rats probably easier adapt to restraint stress. Finally, we used the conditioned place preference model to demonstrate a clear tendency towards a distinct morphine induced behavioral difference between CMS resilient and CMS sensitive animals.

Molecular pathways associated with stress resilience and drug resistance in the chronic mild stress rat model of depression: a gene expression study.

The current antidepressant drugs are ineffective in 30 to 40% of the treated patients; hence, the pathophysiology of the disease needs to be further elucidated. We used the chronic mild stress (CMS) paradigm to induce anhedonia, a core symptom of major depression, in rats. A fraction of the animals exposed to CMS is resistant to the development of anhedonia; they are CMS resilient. In the CMS-sensitive animals, the induced anhedonic state is reversed in 50% of the animals when treating with escitalopram, whereas the remaining animals are treatment resistant. We used the microarray and the real-time quantitative reverse transcription polymerase chain reaction technique, as well as the ingenuity pathway analysis software to identify the differential gene expression pathways, which are associated with the occurrence of the treatment resistance and the stress-resilient rats. In the hippocampus, we found a significant upregulation of apoptotic pathways in the treatment-resistant animals and significantly increased expression levels of genes involved in hippocampal signaling in the CMS-resilient rats. We hypothesize that sensitivity to the stress-induced anhedonia in rats is correlated with the impairment of hippocampal neurogenesis.