From clinical studies it is known that recurrent depressive episodes associate with a reduced hippocampal volume. Conversely, preclinical studies have shown that chronic antidepressant treatment increases hippocampal neurogenesis. Consequently, it has been suggested that a deficit in hippocampal neurogenesis is implicated in the pathophysiology of depression. To study a potential correlation between recovery and hippocampal cytogenesis, we established the chronic mild stress (CMS) rat model of depression. When rats are subjected to CMS, several depressive symptoms develop, including the major symptom anhedonia. Rats were exposed to stress for 2 weeks and subsequently to stress in combination with antidepressant treatment for 4 consecutive weeks. The behavioral deficit measured in anhedonic animals is a reduced intake of a sucrose solution. Prior to perfusion animals were injected with bromodeoxyuridine (BrdU), a marker of proliferating cells. Brains were sectioned horizontally and newborn cells positive for BrdU were counted in the dentate gyrus and tracked in a dorsoventral direction.CMS significantly decreased sucrose consumption and cytogenesis in the ventral part of the hippocampal formation. During exposure to the antidepressant escitalopram, given as intraperitoneally dosages of either 5 or 10 mg/kg/ day, animals distributed in a bimodal fashion into a group, which recovered (increase in sucrose consumption), and a subgroup, which refracted treatment (no increase in sucrose consumption). Chronic treatment with escitalopram reversed the CMS-induced decrease in cytogenesis in the dentate gyrus of the ventral hippocampal formation, but in recovered animals only. Our data show a correlation between recovery from anhedonia, as measured by cessation of behavioral deficits in the CMS model, and an increase in cytogenesis in the dentate gyrus of the ventral hippocampal formation.

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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.

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The development of depression as well as recovery from depression is most likely accompanied by a change in protein expression profiles. The purpose of the present study was to quantitatively investigate global protein expression differences independent of any hypothesis describing depression etiology and recovery. Thus two-dimensional differential in-gel electrophoresis was employed to compare the ventral hippocampal proteomes between different treatment groups in the chronic mild stress (CMS) model of depression. The CMS paradigm induces anhedonic behaviour, which is a major symptom of depression, by exposing rats to a series of mild stressors for 7 weeks, with antidepressant treatment during the last 4 weeks. In the CMS model, animals were split into six different groups at the end of treatment; unchallenged control escitalopram (n = 12), unchallenged control vehicle (n = 12), CMS vehicle (n = 12), CMS escitalopram responders (n = 11), CMS escitalopram non-responders (n = 13) and CMS resilient (stress resistant) (n = 12). Protein levels in the ventral rat hippocampus were compared between the groups to provide putative markers of anhedonia, escitalopram resistance, and stress resilience. Twenty-eight candidate protein spots were selected, of which 13 were successfully identified using tandem mass spectrometry. DRP-2 (dihydropyrimidinase-related protein-2) was a potential marker for escitalopram resistance, whereas alpha-SNAP and beta-SNAP were associated with stress resilience. Furthermore, several molecular chaperones and cytoskeleton organisers were identified as being differentially expressed. Our data indicate that neuronal adaptation is an essential element of depression etiology and recovery, suggesting the involvement of cellular plasticity in the underlying molecular mechanism.

In major depression, one line of research indicates that a dysfunctional GABAergic inhibitory system is linked to the appearance of depressive symptoms. However, as the mechanistic details of such GABAergic deficit are largely unknown, we undertook a functional investigation of the GABAergic system in the rat chronic mild stress model of depression. Adult rats were exposed to an eight-week long stress protocol leading to anhedonic-like behavior. In hippocampal brain slices, phasic, and tonic GABA(A) receptor-mediated currents in dentate gyrus granule cells were examined using patch-clamp recordings. In granule cells, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was reduced to 41% in anhedonic-like rats, which was associated with a reduced probability of evoked GABA release. Using immunohistochemical analysis, there was no change in the number of parvalbumin-positive interneurons in the dentate gyrus. Notably, we observed a 60% increase in THIP-activated tonic GABA(A) mediated current in anhedonic-like rats, suggesting an upregulation of extrasynaptic GABA(A) receptors. Finally, five weeks treatment with the antidepressant escitalopram partially reversed the sIPSCs frequency. In summary, we have revealed a hippocampal dysfunction in the GABAergic system in the chronic mild stress model of depression in rats, caused by a reduction in action potential-dependent GABA release. Since the function of the GABAergic system was improved by antidepressant treatment, in parallel with behavioral read outs, it suggests a role of the GABAergic system in the pathophysiology of depression.

Several clinical and preclinical studies have indicated that hippocampal shrinkage and decreased neurogenesis are implicated in the pathology of depression. Recent animal studies have shown, however, that the development of depression-related symptoms may take place through neurogenesis-independent pathways. To evaluate whether the stress-induced morphological changes in the hippocampal formation are causally related to the development of anhedonia-like symptoms, we combined the chronic mild stress (CMS) rat model of depression with stereological estimations of the number of proliferating progenitors, the total number of granule cells, and the volume of the ventral hippocampal formation (VHF). First, we found that stress-susceptible and stress-resilient animals, as categorized according to the behavioral read-out, both have a decrease in hippocampal cell proliferation. Our results also indicated that the anhedonia-like state in CMS rats develops prior to maximal suppression of cell proliferation, but correlates with a reduction in the total number of granule cells in the VHF. Furthermore, recovery from depression-related symptoms correlated with re-establishment of proliferation rates, but not with the total number of granule cells. Notably, decreases in the number of granule cells occurred independently of the induction of an anhedonia-like phenotype. There were no stress-induced changes in the volume of the VHF. We conclude that cell proliferation and a reduction in the total number of granule cells in the VHF are triggered by chronic stress, but do not associate with development of an anhedonia-like state in rats.

BackgroundThe use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia.MethodsFirst, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion.ResultsScreening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours.ConclusionsOur data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.