Behavioral animal models of depression

Depression is a chronic, recurring and potentially life-threatening illness that affects up to 20% of the population across the world. Despite its prevalence and considerable impact on human, little is known about its pathogenesis. One of the major reasons is the restricted availability of validated animal models due to the absence of consensus on the pathology and etiology of depression. Besides, some core symptoms such as depressed mood, feeling of worthlessness, and recurring thoughts of death or suicide, are impossible to be modeled on laboratory animals. Currently, the criteria for identifying animal models of depression rely on either of the 2 principles: actions of known antidepressants and responses to stress. This review mainly focuses on the most widely used animal models of depression, including learned helplessness, chronic mild stress, and social defeat paradigms. Also, the behavioral tests for screening antidepressants, such as forced swimming test and tail suspension test, are also discussed. The advantages and major drawbacks of each model are evaluated. In prospective, new techniques that will be beneficial for developing novel animal models or detecting depression are discussed.     

Neurogenesis and helplessness are mediated by controllability in males but not in females.

BACKGROUND: Numerous studies have implicated neurogenesis in the hippocampus in animal models of depression, especially those related to controllability and learned helplessness. Here, we tested the hypothesis that uncontrollable but not controllable stress would reduce cell proliferation in the hippocampus of male and female rats and would relate to the expression of helplessness behavior. METHODS: To manipulate controllability, groups of male and female rats were trained in one session (acute stress) or over seven sessions (repeated stress) to escape a footshock, whereas yoked control subjects could not escape but were exposed to the same amount of stress. Cell proliferation was assessed with immunohistochemistry of bromodeoxyuridine (BrdU) and immunofluorescence of BrdU and neuronal nuclei (NeuN). Separate groups were exposed to either controllable or uncontrollable stress, and their ability to learn to escape during training on a more difficult task was used as a behavioral measure of helplessness. RESULTS: Acute stress reduced cell proliferation in males but did not affect proliferation in the female hippocampus. When animals were given the opportunity to learn to control the stress over seven days, males produced more cells than the yoked males without control. Repeated training with controllable stress did not influence proliferation in females. Under all conditions, males were more likely than females to express helplessness behavior, even males that were not previously stressed. CONCLUSIONS: The modulation of neurogenesis by controllability was evident in males but not in females, as was the expression of helplessness behavior, despite the fact that men are less likely than women to experience depression.     

成年脑内的神经发生与抑郁症

哺乳动物成年后中枢神经系统内仍存在神经发生，成体脑内神经发生的调节因素及其与海马的功能联系是目前研究的热点。海马作为成体脑内神经发生最为活跃的区域之一，对各种应激刺激也最为敏感。同时，海马是参与情绪调控的主要脑区之一，是抑郁症机制研究的结构基础。影响神经发生的许多因素同时也和抑郁症的病因与预后有关。目前成体脑内神经发生和抑郁症的关系已成为抑郁症机制研究的新方向。     

Validation criteria for animal models of human mental disorders: Learned helplessness as a paradigm case

1. Three sets of criteria are proposed for assessing animal models of human mental disorders: predictive validity (performance in the test predicts performance in the condition being modelled), face validity (phenomenological similarity) and construct validity (theoretical rationale).

2. The problems inherent in each of these validation procedures are discussed, and their application to the learned helplessness model of depression is examined.

3. It is concluded that whilst the model has good predictive validity, important questions about face validity remain unanswered, and construct validity has not yet been established.

4. The distinctions between animal models and some related experimental procedures are also discussed.     

Pre-clinical trials in Duchenne dystrophy: what animal models can tell us about potential drug effectiveness

The symptomatic pharmacological therapy of Duchenne dystrophy is poor, glucocorticoids being the sole compounds showing a certain efficacy, although their use is restricted by serious side effects. Pre-clinical trials of prompt-to-use drugs need reliable animal models of the human disease to predict drug effectiveness in patients. The exercised mdx mouse develops a typical pattern of muscle weakness in vivo, which has already been used as an index on which to evaluate drug effectiveness. We have demonstrated that the macroscopic conductance to chloride ion, an index of degeneration-regeneration events occurring in mdx mouse muscles, is specifically impaired by a chronic exercise protocol and is sensitive to the action of in vivo administered drugs acting either by stimulating regeneration (insulin-like growth factor-1 and steroids) or by counteracting calcium-induced degeneration or inflammation (Taurine and steroids). The monitoring of conductance to chloride ion also allows the evaluation of false positive compounds, effective on mouse strength in vivo but not at muscle level, and the functional correlation with other cellular parameters.     

Learned helplessness and animal models of depression

The degree to which organisms can exert control over events to which they are exposed has a strong impact on behavior and physiological functioning. Effects caused by the uncontrollability of events that are beyond the organism's control rather than by the events per se have been called learned helplessness effects. The present paper reviews such learned helplessness effects. At a behavioral level, uncontrollable aversive events result in associative, motivational, and emotional deficits. At a neurochemical level, uncontrollable but not controllable aversive events have been reported to lead to disturbances in cholinergic, noradrenergic, dopaminergic, serotonergic, and GABAergic systems. However, there are interpretive difficulties in this literature, and these are discussed. The controllability/uncontrollability of aversive events has a role in producing stress-induced analgesia and the activation of endogenous opiate systems. These relationships are reviewed. It is proposed that the learning that aversive events cannot be controlled activates an opiate system. The research reviewed is related to depression, and the general issue of animal models of depression is discussed. It is concluded that no experimental paradigm can be a model of depression in some general sense, but can only model a particular aspect. Learned helplessness may model "stress and coping".     

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.     

Reduced cell proliferation in the dentate gyrus is 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.     

Neural dynamics of psychotherapy: what modeling might tell us about us.

A neural network theory is proposed for some of the effects of verbal psychotherapy in individuals who are not seriously disturbed but seeking to function more effectively. The network theories are built on a combination of the supervised ARTMAP network and competitive attractor dynamics. The modeling exercise leads to some guidelines for psychotherapists that involve both cognitive and emotional reinforcement in a climate closer to skill learning than to medical treatment.     

Children's play narratives: what they tell us about lesbian-mother families

Play narratives can offer a unique insight into the child's internal world. This study compared the play narratives of children in 38 lesbian-mother families; 73 two-parent, heterosexual-mother families; and 58 single-heterosexual-mother families recruited from a general population sample. Findings indicated positive mother-child relationships and well-adjusted children. Girls' narratives showed more affection than boys' and were more strongly associated with mothers' interview measures, suggesting that girls' play narratives reveal a more accurate picture of family relationships.     

From traumatic brain injury to posttraumatic epilepsy: What animal models tell us about the process and treatment options

A large number of animal models of traumatic brain injury (TBI) are already available for studies on mechanisms and experimental treatments of TBI. Immediate and early seizures have been described in many of these models with focal or mixed type (both gray and white matter damage) injury. Recent long-term video-electroencephalography (EEG) monitoring studies have demonstrated that TBI produced by lateral fluid-percussion injury in rats results in the development of late seizures, that is, epilepsy. These animals develop hippocampal alterations that are well described in status epilepticus–induced spontaneous seizure models and human posttraumatic epilepsy (PTE). In addition, these rats have damage ipsilaterally in the cortical injury site and thalamus. Although studies in the trauma field provide a large amount of information about the molecular and cellular alterations corresponding to the immediate and early phases of PTE, chronic studies relevant to the epileptogenesis phase are sparse. Moreover, despite the multiple preclinical pharmacologic and cell therapy trials, there is no information available describing whether these therapeutic approaches aimed at improving posttraumatic recovery would also affect the development of lowered seizure threshold and epilepsy. To make progress, there is an obvious need for information exchange between the trauma and epilepsy fields. In addition, the inclusion of epilepsy as an outcome measure in preclinical trials aiming at improving somatomotor and cognitive recovery after TBI would provide valuable information about possible new avenues for antiepileptogenic interventions and disease modification after TBI.     

Two different putative genetic animal models of childhood depression.

BACKGROUND: In an attempt to model childhood depression, we examined whether existing genetic animal models of depression in adult rats are also valid in prepubertal rats. METHODS: Two different "depressed" rat lines were studied: the Flinders Sensitive Line (FSL) and their controls, Sprague-Dawley (SD); and the Wistar Kyoto (WKY) line and their controls, Wistar. We hypothesized that male prepubertal FSL and WKY rats would show increased swim test immobility and different patterns of social play and of basal plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) compared with control rats. RESULTS: Prepubertal FSL and WKY rats exhibited significantly longer duration of immobility than control rats in the swim test. The FSL rats demonstrated significantly higher levels of social play behaviors and lower levels of corticosterone and ACTH compared with SD control rats, whereas WKY rats demonstrated significantly lower levels of social play behaviors and higher plasma levels of corticosterone and ACTH compared with Wistar control rats. CONCLUSIONS: The results might suggest that prepubertal FSL and WKY rats are both putative genetic animal models of childhood depression, exhibiting separate patterns and symptoms of childhood depression.     

A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is upregulated in the hippocampus by antidepressant treatments, and centrally administered BDNF can produce antidepressant-like effects in rodent behavioral models of depression. BDNF-regulated signaling pathways are thus potential targets for investigation of antidepressant mechanisms. METHODS: We examined the effects of inhibition of MAPK kinase (MEK) in mouse behavioral models for depression including interactions with effects of antidepressant drugs. We also assessed the behavioral consequences of a heterozygous gene deletion for BDNF combined with MEK inhibition or stress. RESULTS: Acute administration of the MEK inhibitor PD184161 produced depressive-like behavior. PD184161 blocked the antidepressant-like effects of desipramine and sertraline in the forced swim test and blocked the effects of desipramine in the tail suspension test. Heterozygous deletion of BDNF alone did not influence behavior in the forced swim test but resulted in a depressive phenotype when combined with a low-dose MEK inhibitor or stress exposure. CONCLUSIONS: We demonstrate that acute blockade of MAPK signaling produces a depressive-like phenotype and blocks behavioral actions of antidepressants. We also demonstrate in BDNF heterozygous knockout mice an example of a how a defined genetic alteration can confer vulnerability to a pharmacologic or environmental challenge resulting in a depressive behavioral phenotype.     

Enhanced long-term synaptic depression in an animal model of depression.

BACKGROUND: A growing body of evidence suggests a disturbance of brain plasticity in major depression. In contrast to hippocampal neurogenesis, much less is known about the role of synaptic plasticity. Long-term potentiation (LTP) and long-term depression (LTD) regulate the strength of synaptic transmission and the formation of new synapses in many neural networks. Therefore, we examined the modulation of synaptic plasticity in the chronic mild stress animal model of depression. METHODS: Adult rats were exposed to mild and unpredictable stressors for 3 weeks. Thereafter, long-term synaptic plasticity was examined in the hippocampal CA1 region by whole-cell patch clamp measurements in brain slices. Neurogenesis was assessed by doublecortin immunostaining. RESULTS: Exposure to chronic mild stress facilitated LTD and had no effect on LTP. Chronic application of the antidepressant fluvoxamine during the stress protocol prevented the facilitation of LTD and increased the extent of LTP induction. Neurogenesis in the dentate gyrus was impaired after chronic stress. CONCLUSIONS: In addition to neurogenesis, long-term synaptic plasticity is an important and ubiquitous form of brain plasticity that is disturbed in an animal model of depression. Facilitated depression of synaptic transmission might impair function and structure of brain circuits involved in the pathophysiology of major depression. Antidepressants might counteract these alterations.     

Perinatal depression: Heterogeneity of disease and in animal models

Perinatal depression (PND) can have either an antepartum or postpartum onset. Although the greatest risk factor for PND is previous depression history, de novo PND occurs with the majority of cases occurring in the postpartum. Timing of depression can impact etiology, prognosis, and response to treatment. Thus, it is crucial to study the impact of the heterogeneity of PND for better health outcomes. In this review, we outline the differences between antepartum and postpartum depression onset of PND. We discuss maternal physiological changes that differ between pregnancy and postpartum and how these may differentially impact depression susceptibility. We highlight changes in the maternal steroid and peptide hormone levels, immune signalling, serotonergic tone, metabolic factors, brain morphology, and the gut microbiome. Finally, we argue that studying the heterogeneity of PND in clinical and preclinical models can lead to improved knowledge of disease etiopathology and treatment outcomes.     

Increase of hippocampal glutamate after electroconvulsive treatment: A quantitative proton MR spectroscopy study at 9.4 T in an animal model of depression

Abstract

Objectives. Recent evidence suggests that alterations in hippocampal glutamate and γ-aminobutyric acid (GABA) are associated with the pathomechanism of depression and treatment effects of electroconvulsive therapy (ECT). Thus, proton magnetic resonance spectroscopy (¹H MRS) at a 9.4 T animal system seems a promising tool to study underlying mechanisms since it allows for an accurate quantification of metabolites with distinction of glutamate, GABA and glutamine, as well as separation of taurine from choline. Methods. A well-validated animal model of treatment resistant depression (congenital learned helpless rats = cLH) was investigated by hippocampal in vivo ¹H MRS with and without a 1-week course of electroconvulsive shocks (ECS), an animal model of ECT, and compared to wild type (WT) animals, while saline and clomipramine injections served as additional controls. Results. Untreated cLH rats showed significantly lower glucose and higher taurine concentrations compared to WT animals. Besides alterations on these metabolites, ECS increased glutamate in WT and cLH and choline in cLH rats. Moreover, correlations between glutamate and GABA concentrations with learned helpless behaviour were revealed. Conclusions. These findings support the idea of disordered hippocampal metabolism in an animal model of treatment resistant depression and suggest an early impact of ECS on MR-detectable hippocampal metabolites.     

Altered protein kinase a in brain of learned helpless rats: effects of acute and repeated stress.

BACKGROUND: Stress-induced learned helplessness (LH) in animals serves as a model of behavioral depression and some aspects of posttraumatic stress disorder. We examined whether LH behavior is associated with alterations in protein kinase A (PKA), a critical phosphorylating enzyme, how long these alterations persist after inescapable shock (IS), and whether repetition of IS prolongs the duration of LH behavior and changes in PKA. METHODS: Rats were exposed to IS either on day 1 or twice, on day 1 and day 7. Rats were tested for escape latency on days 2 and 4 after day 1 IS or days 2, 8, and 14 after day 1 and day 7 IS. [(3)H]cAMP (cyclic adenosine monophosphate) binding, catalytic activity and expression of PKA subunits were determined in frontal cortex and hippocampus. RESULTS: Higher escape latencies were observed in rats tested on day 2 after single IS and on day 14 after repeated IS. Concurrently, reduced [(3)H]cAMP binding, PKA activity, and expression of selective PKA RIIbeta and Calpha and Cbeta subunits were observed in the brains of these rats. CONCLUSIONS: Repeated IS prolongs the duration of LH behavior, and LH behavior is associated with reductions in apparent activity and expression of PKA. These reductions in PKA may be critical in the pathophysiology of depression and other stress-related disorders.     

Neurogenesis and neuroadaptation

Adult neurogenesis has been established as a further mechanism of neural plasticity in the adult nervous system, and numerous studies are beginning to provide insights into the functional purposes and consequences for this new mode of neuroadaptation. These studies have approached the problem from a molecular scale, attempting to identify signaling factors that regulate stem cell function, as well as a systems or behavioral level, attempting to establish correlative and potentially causal links between neurogenesis and behavior. These two approaches have begun to reveal several potential functions for adult hippocampal neurogenesis, including adaptive roles in learning and memory, adaptation to novel environments, potential links to depression and moods, and possible responses to injury. The further implementation and convergence of these two approaches and the development of new methods to study the problem will yield further insights into both what are the many neuroadaptive roles of neurogenesis and potential means to harness it for neuroregeneration.     

Serotonergic hyperinnervation of the frontal cortex in an animal model of depression,the bulbectomized rat

We studied the influence of olfactory bulbectomy in rats on three different parameters of serotonin (5-HT) presynapses, 5-HT transporter density, tryptophan hydroxylase apoenzyme concentration, and the levels of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) in various brain regions. Compared with sham-operated controls, the B_max values of [³H]paroxetine binding, the apoenzyme concentration of tryptophan hydroxylase and the level of 5-HIAA, and, therefore, the 5-HIAA/5-HT ratio were significantly and selectively increased in the frontal cortex of bulbectomized rats, measured 12 weeks after surgery. The most likely explanation of the concomitant increase in levels of all three markers of 5-HT presynapses in the frontal cortex is an increased density of 5-HT innervation in this remote projection field of the raphe nuclei. It is suggested that the bulbectomy-associated axotomy of 5-HT fibers projecting to the bulb stimulates collateral sprouting and synaptogenesis, especially in the frontal cortex. The resulting 5-HT hyperinnervation must be expected to alter global neuronal activity in this region and to impair the balance of information flow between this and other brain regions, resulting in a multitude of secondary behavioral and neurochemical changes. The frontocortical abnormalities observed by brain imaging studies in the brains of depressed patients may also be explained by a selective 5-HT hyperinnervation of this brain region. J. Neurosci. Res. 54:109–116, 1998. © 1998 Wiley-Liss, Inc.