Barbara Vollmayr

Stress models of depression: forming genetically vulnerable strains

Among the most useful models for depressive disorders are those, which involve a stress induced change in behaviour. Learned helplessness is one such model and is induced through exposure to uncontrollable and unpredictable aversive events. Learned helplessness as induced in rats using foot shock is well characterized and has good face validity and predictive validity as a model of depression, including alterations in HPA axis activity and REM sleep characteristic of depression. The data concerning the validity will be briefly reviewed. The model can also be used to look at the role of genetics through selective breeding. These studies will be reviewed and the utility of the genetic strains for understanding the interaction of stress and affect will be examined. A second model of depression using exposure to chronic stress also has high face and predictive validity. A new form of this approach, recently described, also is suitable for the examination of genetic factors leading to depressive like behaviour and this will be presented.

Reduced cell proliferation in the dentate gyrusis not correlated with the development of learned helplessness

BACKGROUND A plethora of indirect findings suggests that mood disorders may be caused by or result in structural changes in the brain, namely decreased hippocampal cell proliferation. METHODS To test for these hypotheses, we used a rat model of depression, learned helplessness. Moderate unpredictable and inescapable foot shocks induced learned helplessness only in a portion of the rats. Rats that showed helpless behavior were compared to those behaving normally after inescapable shock. Proliferating cells in the dentate gyrus were labeled with BrdU (bromodeoxyuridine). RESULTS Helpless behavior appeared before the decrease of dentate gyrus cell proliferation was maximal. Cell proliferation was decreased to the same extent in animals that developed helplessness as those that were not helpless. Furthermore, immobilization stress, which reduced the rate of cell proliferation, did not induce learned helplessness. CONCLUSION These results are in line with reports that the rate of dentate gyrus cell proliferation is acutely down-regulated by stress, but the development of helpless behavior does not correlate with this process. Further studies will have to clarify if during learned helpless behavior neurogenesis is impaired by altered differentiation or survival of cells.

Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats.

INTRODUCTION The neurotrophin brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are a central part of the molecular concepts on neuroplastic changes associated with stress, anxiety and depression. An increasing number of studies uses serum BDNF levels as a potential indicator for central nervous system alterations. METHODS To analyze the relationship between brain tissue and serum BDNF and NGF levels, we used electroconvulsive shocks (ECS), an animal model of electroconvulsive therapy, and studied the temporal profile of neurotrophin expression in the hippocampus, prefrontal cortex and serum. 88 male Sprague-Dawley rats received single or serial ECS treatments and were killed between 3 hours and 14 days after the last treatment. RESULTS We found a 2.8-fold rise for BDNF (1.3-fold for NGF) in the prefrontal cortex, and a 2.2-fold rise (1.2-fold for NGF) in the hippocampus after 5 ECS sessions. The temporal expression profile and correlation analyses between tissue and serum BDNF indicate that BDNF crosses the blood-brain barrier. No such correlation was found for NGF. DISCUSSION The time course of central and peripheral BDNF changes may significantly differ. However, we demonstrate substantial evidence that it can be justified to measure serum BDNF levels with a time delay to monitor brain tissue neurotrophin alterations.

Neurogenesis and depression: etiology or epiphenomenon?

The concept that decreased neurogenesis might be the cause of depression is supported by the effects of stress on neurogenesis and the demonstration that neurogenesis seems to be necessary for antidepressant action. Data from the animal models tested to date show that decreasing the rate of neurogenesis does not lead to depressive behavior. Furthermore, evidence shows that an effective treatment for depression, transcranial magnetic stimulation, does not alter rates of neurogenesis. On the basis of these findings, it is suggested that neurogenesis might play a subtle role in depression but that it is not the primary factor in the final common pathway leading to depression.

Learned helplessness in the rat: improvements in validity and reliability

Major depression has a high prevalence and a high mortality. Despite many years of research little is known about the pathophysiologic events leading to depression nor about the causative molecular mechanisms of antidepressant treatment leading to remission and prevention of relapse. Animal models of depression are urgently needed to investigate new hypotheses. The learned helplessness paradigm initially described by Overmier and Seligman [J. Comp. Physiol. Psychol. 63 (1967) 28] is the most widely studied animal model of depression. Animals are exposed to inescapable shock and subsequently tested for a deficit in acquiring an avoidance task. Despite its excellent validity concerning the construct of etiology, symptomatology and prediction of treatment response [Clin. Neurosci. 1 (1993) 152; Trends Pharmacol. Sci. 12 (1991) 131] there has been little use of the model for the investigation of recent theories on the pathogenesis of depression. This may be due to reported difficulties in reliability of the paradigm [Animal Learn. Behav. 4 (1976) 401; Pharmacol. Biochem. Behav. 36 (1990) 739]. The aim of the current study was therefore to improve parameters for inescapable shock and learned helplessness testing to minimize artifacts and random error and yield a reliable fraction of helpless animals after shock exposure. The protocol uses mild current which induces helplessness only in some of the animals thereby modeling the hypothesis of variable predisposition for depression in different subjects [Psychopharmacol. Bull. 21 (1985) 443; Neurosci. Res. 38 (200) 193]. This allows us to use animals which are not helpless after inescapable shock as a stressed control, but sensitivity, specificity and variability of test results have to be reassessed.

Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression.

BACKGROUND It has been widely accepted that glial pathology and disturbed synaptic transmission contribute to the neurobiology of depression. Apart from monoaminergic alterations, an influence of glutamatergic signal transduction has been reported. Therefore, gene expression of glutamate transporters that strictly control synaptic glutamate concentrations have to be assessed in animal models of stress and depression. METHODS We performed in situ-hybridizations in learned helplessness rats, a well established animal model of depression, to assess vGluT1 and EAAT1-4. Sprague-Dawley rats of two inbred lines were tested for helpless behavior and grouped into three cohorts according to the number of failures to stop foot shock currents by lever pressing. RESULTS Helpless animals showed a significantly suppressed expression of the glial glutamate transporter EAAT2 (rodent nomenclature GLT1) in hippocampus and cerebral cortex compared to littermates with low failure rate and not helpless animals. This finding was validated on protein level using immunohistochemistry. Additionally, expression levels of EAAT4 and the vesicular transporter vGluT1 were reduced in helpless animals. In contrast, the transcript levels of EAAT1 (GLAST) and EAAT3 (EAAC1) were not significantly altered. CONCLUSIONS These results strongly suggest reduced astroglial glutamate uptake and implicate increased glutamate levels in learned helplessness. The findings are in concert with antidepressant effects of NMDA-receptor antagonists and the hypotheses that impaired astroglial functions contribute to the pathogenesis of affective disorders.

Neurogenesis and depression: what animal models tell us about the link

There is growing evidence that stress causes a decrease of neurogenesis in the dentate gyrus and antidepressant treatment in turn stimulates the cell proliferation in the dentate gyrus. This has led to the hypothesis that a decreased neurogenesis might be linked to the pathophysiology of major depression. The article reviews the relationship of depressive-like behavior and neurogenesis in three animal models of depression with high validity: learned helplessness, chronic mild stress and chronic psychosocial stress of the tree shrew. All animal models provide evidence that stress which can lead to depressive-like behavior, in parallel causes a decrease of neurogenesis; vice versa, antidepressant treatment is able to revert not only behavioral changes but also to normalize neurogenesis. But the animal models argue against the notion that decreases of neurogenesis are the cause or the consequence of depressive-like behavior since depressive-like behavior can occur without impairments in neurogenesis and decreasing neurogenesis does not neccessarily lead to depressive-like behavior. This suggests that neurogenesis does not directly control affect but is tightly connected to the modulation of affect by stress and antidepressant measures.

Rats with congenital learned helplessness respond less to sucrose but show no deficits in activity or learning.

Inbred rat strains for congenital learned helplessness (cLH) and for congenital resistance to learned helplessness (cNLH) were investigated as a model to study genetic predisposition to major depression. Congenitally helpless rats respond less to sucrose under a progressive ratio schedule. This is not confounded by locomotor hypoactivity: in contrast, cLH rats show a slight hyperactivity during the first 5 min of an open field test. cLH rats acquire operant responding to sucrose as readily as cNLH rats and exhibit normal memory acquisition and retrieval in the Morris water maze, thus ruling out general learning deficits as the cause of the decreased response to sucrose. Reduced total responses and reduced breaking points for sucrose in the cLH strain argue for anhedonia, which is an analogue to loss of pleasure essential for the diagnosis of major depressive episodes, and thus confirm the validity of congenitally learned helpless rats as a model of major depression.

Stress models of depression

Abstract In order to understand the molecular changes underlying major depression animal models are needed. The best animal model of depression simulates the etiology and replicates symptoms, course and treatment of human depression. This article reviews the two most valid and best established animal models of depression, learned helplessness and chronic mild stress. Both models use uncontrollable stress to induce depressive like behavior, both have excellent face validity and replicate anhedonia and anergia in analogy to loss of interest and pleasure, one of two essential features of depression. In addition, both models demonstrate a variety of less specific symptoms like changes in locomotion, impaired learning ability, sleep alterations, loss of weight and decrease of sexual behavior. Endocrine disturbances of major depression as hypercortisolemia and dexamethasone non-suppression are also simulated in the two animal models. Neurobiological changes accompanying the depressive like behavior include dynamic changes of the monoamine systems and several peptide systems including the opioid system. Behavioral and neurobiological changes can be renormalized in both models by antidepressant treatment, which adds predictive validity to these models.

Pharmacological inhibition of the lateral habenula improves depressive-like behavior in an animal model of treatment resistant depression.

Identifying new treatment approaches for treatment resistant depression (TRD) is an important topic for translational psychiatry. Functional inhibition of the lateral habenula (LHb) has recently been claimed to offer such an option for TRD. Rats which are bred for high susceptibility to develop learned helplessness provide a genetic model for TRD. We used the gamma-aminobutyric acid agonist muscimol to inhibit the LHb in Sprague-Dawley rats with congenital learned helplessness (cLH). Stereotactic pharmacological inhibition of the LHb exerted antidepressive effects in treatment resistant cLH rats.