Cell Tissue Res (2013) 354:171–178 DOI 10.1007/s00441-013-1654-2

REVIEW

Learned helplessness: unique features and translational value of a cognitive depression model

Barbara Vollmayr & Peter Gass

Received: 5 April 2013 /Accepted: 3 May 2013 /Published online: 13 June 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract The concept of learned helplessness defines an Overmier and Seligman (1967) were the first to observe escape or avoidance deficit after uncontrollable stress and is an escape and avoidance deficit in dogs exposed to uncon- regarded as a depression-like coping deficit in aversive but trollable shock and termed it “learned helplessness”. Mon- avoidable situations. Based on a psychological construct, it grel dogs easily learned to jump across a hurdle in a shuttle ideally complements other stress-induced or genetic animal box in order to escape from foot shock, but dogs pre- models for major depression. Because of excellent face, exposed to inescapable shocks while strapped in a harness construct, and predictive validity, it has contributed to the did not attempt to escape when it was possible and remained elaboration of several pathophysiological concepts and has still during the shock. Controllability of the shock (and not brought forward new treatment targets. Whereas learned shock per se) was described to be the crucial factor deter- helplessness can be modeled not only in a broad variety of mining the response deficit by experiments demonstrating mammals, but also in fish and Drosophila, we will focus normal escape responses after escapable shock but escape here on the use of this model in rats and mice, which are failures after uncontrollable shock of the same amount and today the most common species for preclinical in vivo duration (Seligman and Maier 1967). Furthermore, pre- research in psychiatry. exposure to escapable shock was shown to mitigate the deleterious effects of inescapable shock supporting the hy- Keywords Major depression . Learned helplessness . pothesis that uncontrollable shock prevented escape because Animal model . Cognitive theory . Uncontrollable stress individuals had learned that shock termination was indepen- dent of their responses. As soon became obvious, the phenomenon of learned Introduction helplessness also occurs in many other species such as rats and mice (Anisman and Merali 2001; Chourbaji et al. 2005; Learned helplessness was one of the earliest paradigms used Maier and Testa 1975; Vollmayr and Henn 2001) and has to model depression (Seligman et al. 1968). Together with been translated even to non-mammals such as zebra fish the chronic mild stress (see Wiborg 2013)andchronic (Okamoto et al. 2012). For humans, the experience of help- psychosocial stress models (O’Leary and Cryan 2013), it lessness does not always generalize to new situations, and so belongs to the (environmental) stress models of depression. the paradigm has been reformulated and has stimulated the Derived from experimental psychology, learned helpless- development of attribution theory postulating that a global, ness is based on the idea that an event is not negative per stable, and internal attributional style for bad outcomes pro- se, but that the emotions that it causes depend on the in- motes the generalization of learned helplessness and pre- dividual’s cognitive appraisal. Lazarus (1966) focused on disposes for depression (Abramson et al. 1978; Alloy et al. the effects of stress and proposed that stress reactions such 1984; Raps et al. 1982). as depression are dependent not only on the situation, but also on the individual. Methodological aspects B. Vollmayr (*) : P. Gass RG Animal Models in Psychiatry, Department of Psychiatry and Classically, a triadic design with two control groups is used Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany to study the effects of uncontrollable stress (Drugan et al. e-mail: [email protected] 1997). One group is exposed to shocks that can be 172 Cell Tissue Res (2013) 354:171–178 controlled, e.g., by shuttling (escaping), lever pressing, reproducibility of the experiments (Musty et al. 1990; or wheel turning (Chourbaji et al. 2005; Maier and Vollmayr and Henn 2001). Testa 1975; Vollmayr and Henn 2001). Animals of the second group subjected to uncontrollable stress are “yoked” to the animals of the first group, meaning that Consequences of uncontrollable stress each animal is connected to an animal of the first group receiving shocks of the same amount, duration, and The uncontrollability of the aversive stimuli in the pattern. For these animals, the shocks appear uncontrol- learned helplessness paradigm (usually mild electro- lable, unpredictable, and unavoidable. A third group is shocks) has consequences in several behavioral domains not exposed to stress. Thus, animals exposed to uncon- (Maier 1984). Escape and avoidance deficits are patho- trollable shocks can be compared with animals exposed gnomonic for learned helplessness and have been to controllable shocks (of exactly the same physical explained by various approaches. With regard to loco- quality) and to unstressed controls. Whereas this design motion, animals exposed to uncontrollable shock are allows excellent discrimination of the effects attributable less active later and tolerate stress passively. Thus, to uncontrollability from general stress effects, important escape deficits have been explained to be secondary to concerns have been raised: differences in individual locomotor deficits, and the term “learned inactivity” has stress reactivity might increase random error, and a been coined (Seligman et al. 1980;WeissandSimson systematic bias might be induced in the controllable 1986). Whereas decreased locomotion could be a stress group by the necessity to exclude poor learners, confounding factor for causing associative learning def- because their resulting large shock amounts overstress icits in the typical readout of the learned helplessness them and their yoked counterparts (Drugan et al. 1997). paradigm (escape deficits in shuttlebox or lever-pressing However, individual differences in stress reactivity are paradigms), the Y-maze allows the two aspects to be not necessarily a limitation of the paradigm; they can also be segregated; unchanged response speed and decreased seen as an opportunity to study vulnerability and resilience choice accuracy after uncontrollable stress clearly argue to stress. When uncontrollable shocks of only moderate for a deficit in associative learning (Jackson et al. intensity are applied, behavioral variation is increased, and 1980), whereas learning in general might be even in- animals demonstrating coping deficits can be compared creased under certain circumstances (Servatius and with those showing no or little escape deficits after stress Shors 1994). Moreover, the deficit of the animals to (Vollmayr and Henn 2001). initiate responses can also be interpreted as a motiva- Several technical considerations are critical for the reli- tional deficit. This is supported by decreased effort ability of the paradigm. Reliable shock application is essen- when the demands are raised under a progressive ratio tial and has to be controlled vigorously. Grids are often used scheme (Vollmayr et al. 2004). to apply foot shocks, but it must be ensured that animals Most notably, uncontrollable stress causes several cannot reduce or avoid shocks by certain postures (e.g., changes in affectivity. In addition to the analogs of touching the grid only with their fur, placing their feet on depressive symptoms (see next paragraph), increased rods of the same potential; Vollmayr and Henn 2001). Elec- fear conditioning and aggression have been described trodes taped to the tail overcome these problems but limit (Maier 1984). the mobility of the animals and are used therefore only in Finally, uncontrollable stress also has somatic conse- small chambers in which the animals cannot turn anyway, quences such as gastric ulcers (Weiss 1978) and opiate- thereby adding restraint stress to the electroshocks (Drugan mediated analgesia (Jackson et al. 1979; MacLennan et al. et al. 1997). In addition to proper stimulus application, the 1982). escape response has to be selected species-specifically, aiming for tasks of medium difficulty. Tasks have to be easy enough to be learned by stress-naive animals, but if they are Validity as a model of depression too easy, no impairment will be caused by the uncontrollable shock. Although lever-press or wheel-turning paradigms are We urgently need to advance antidepressant treatment. appropriate for rats (Drugan et al. 1997; Vollmayr and Henn In this process, animal models are essential tools for 2001), shuttle boxes give better results for mice (Chourbaji understanding the pathophysiology of major depression, et al. 2005). Finally, reproducibility also depends on data but many of the results found in animals do not trans- analysis with more stringent criteria enhancing reliability, late to humans, and few give rise to clinical progress. i.e., the calculation of escape or avoidance failures instead of Willner (1984) has stated that three different aspects of delayed responses increases the separation between animals validity in animal models should met to be of transla- exposed to uncontrollable shock and controls and the tional use: Cell Tissue Res (2013) 354:171–178 173

Construct validity indicates that a model is based on mirrors the vegetative and neuroendocrine alterations mechanisms found to be important in the etiology and experienced during depression, such as REM-sleep- pathogenesis of major depression. Depression is a com- associated changes, increased basal corticosterone levels, plex disorder with genetic factors determining the risk and dexamethasone non-suppression (Adrien et al. 1991; in strong interaction with environmental factors. Henn and Vollmayr 2005). Among environmental variables, stressful life events Predictive validity is high if a model predicts effective stand out as a potent risk factor for major depression antidepressant treatment. Sherman et al. (1982) have (Fava and Kendler 2000). Stress therefore is commonly shown that a wide variety of antidepressants, including used to induce analogs of depressive symptoms in tricyclic antidepressants, selective 5HT-reuptake inhib- animals (Nestler and Hyman 2010). Lazarus (1966) itors, and MAO-inhibitors, improve helpless behavior has pointed out that the effects of stress in general are after chronic but not after acute administration, closely dependent on the affected individual’s appraisal, with resembling the lag of antidepressant action in clinical uncontrollability particularly contributing to negative trials. Neither aspect is fulfilled by many other depres- emotions. Learned helplessness is derived from the sion models. Moreover, other psychopharmacologic cognitive theory of depression, which has led to cogni- substances, such as antipsychotics and anxiolytics, do tive behavioral therapy for depression, a successful and, not promote recovery from learned helplessness, indi- to date, the most influential form of psychotherapy. The cating the excellent specificity of the model. Further- cognitive theory postulates that “maladaptive represen- more, a course of electroconvulsive seizures, known as tations of the self, world and future […] activated by the gold standard in treatment-resistant depression, re- matching life experiences” are central in the etiology verses learned helplessness with effect sizes superior to and maintenance of major depression (Clark and Beck pharmacologic antidepressant measures (Sartorius et al. 2010). Within this framework, learned helplessness is 2003). In conclusion, the profile of antidepressant treat- an assumption activated by the experience of uncon- ment has been reproduced with remarkable similarity in trollable stress. Consistent with the prediction of cog- learned helpless animals, and beyond that, the model nitive theory for a “processing bias for schema- has recently predicted the habenula as a new treatment congruent information” (Clark and Beck 2010), a neg- target (see below). ative bias has been observed not only in depressed humans (Everaert et al. 2012), but also in rats bred for learned helplessness (Enkel et al. 2010; Richter et al. Neurotransmitters, signal transduction, and plasticity 2012). Thus, as an animal model of depression, learned helplessness is uniquely based on a general For decades, research directed at understanding the neuro- theory that translates from clinical psychology to chemical mechanisms underlying learned helplessness has non-human animals with excellent construct validi- focused on the monoamines. Work from Stephen Maier’s ty. Based on a psychological construct, it has the laboratory has demonstrated that uncontrollable stress acti- potential to complement transgenic animals that vates and sensitizes 5HT-neurons in the dorsal raphe, which model genetic polymorphisms found to be associat- in turn leads to behavioral symptoms of learned helplessness, ed with affective disorders. such as enhancement of fear conditioning and escape deficits Face validity describes the similarity of the animal (Amat et al. 2005). Weiss and coworkers have demonstrated model to the symptoms of depression. Many of the that uncontrollable shock causes reduced release of norepi- hallmarks of depression, such as feelings of guilt or nephrine in the locus coeruleus, and that the subsequent

suicidal thoughts, depend on consciousness and on blockade of α2-receptors mediates the reduced motor activity verbal expression and cannot be studied in non-human that is part of the learned helpless phenotype (Weiss and animals. Others, such as psychomotor changes, can be Simson 1986). Finally, phasic dopamine signaling in response easily translated from species to species but are of little to prediction, escape, and avoidance to aversive stimuli drives specificity for the diagnosis of depression. Therefore, escape and avoidance-learning, and decreased dopamine sig- analogs of the core symptoms of depression are of naling secondary to overactivation of the habenula seems to particular importance for good face validity. In learned underlie the coping deficits in learned helplessness (Ilango et helplessness, decreased sensitivity and responsivity to al. 2012; Shumake et al. 2010). In summary, learned helpless- the rewarding properties of sucrose and decreased in- ness is accompanied by widespread changes in monoaminer- tracranial self-stimulation are indicators of anhedonia in gic systems. Vice versa, antidepressant treatment of various analogy to loss of pleasure and interest during depres- modalities induces plastic changes, e.g., of norepinephrine sion (Sanchis-Segura et al. 2005; Vollmayr et al. 2004; beta receptors in this model (Henn et al. 2002). Learned Zacharko et al. 1983). Learned helplessness furthermore helplessness can be reversed by chronic but not acute 174 Cell Tissue Res (2013) 354:171–178 treatment with monoaminergic antidepressants, thus reflecting mechanisms (see below); the brain stem monoaminergic another important feature of human depression. nuclei, such as the ventral tegmentum, dorsal raphe The puzzle of this delay in therapeutic response has been nucleus, and locus coeruleus, mediate numerous stress addressed by the hypothesis of a common final pathway of responses via ascending projections to the nucleus various antidepressant treatment mechanisms; this hypothe- accumbens, hippocampus, amygdala, and the neocortex sis has strongly stimulated depression research (Duman et and are modulated themselves by the habenula (Amat et al. 1997). It postulates changes of neurotrophic factors, such al. 2001;McEwen2012). The prefrontal cortex (PFC) as brain-derived neurotrophic factor (BDNF), as a common exerts top-down control over these circuits. As outlined denominator of diverse signal transduction cascades activat- above, controllability of the stressor is a critical factor ed by the various modes of antidepressant treatment. determining pathophysiological sequelae. Whereas un- Antidepressant-like effects of midbrain and hippocampal controllable stress leads to learned helplessness, control- BDNF infusion indicate an important role of BDNF in the lable stress has less severe consequences. Amat and pathophysiology of learned helplessness (Shirayama et al. coworkers (2005) have elegantly demonstrated that the 2002; Siuciak et al. 1997), but studies of BDNF mRNA and medial PFC of the rat, an analog to the human anterior protein have yielded equivocal results (Aznar et al. 2010; cingulate gyrus, detects controllability of the stressor Bland et al. 2007; Schulte-Herbrüggen et al. 2006b; and subsequently inhibits biochemical and behavioral Vollmayr et al. 2001). A study of heterozygous BNDF stress responses. Notably, the activity of the medial knockout mice has reported increased learned helplessness PFC and its top-down control have been found to ac- (MacQueen et al. 2001), but this finding might have been company the effects of antidepressant treatment, and confounded by the altered pain sensitivity of BDNF+/− mice deep-brain stimulation of this region is effective in (Chourbaji et al. 2004, 2008a). In agreement with the con- treatment-resistant depression in humans and in learned cept that stress-evoked or genetically induced reductions of helpless rats (Hamani et al. 2010, 2011). BDNF increase learned helplessness, recent findings have Altered responsiveness of the hypothalamic-pituitary- demonstrated that environmental enrichment (leading to an adrenal (HPA) axis has been conceptualized as a key mech- increase in BDNF) renders mice more resilient to becoming anism in the pathogenesis of depression (Holsboer 2000). helpless (Chourbaji et al. 2005, 2012). Thus, in patients with severe major depression, diminished Together with the neurotrophin hypothesis of depression, glucocorticosteroid receptor expression or functioning has the concept has been proposed that decreased adult hippo- been postulated as a causative factor for a deficient feedback campal neurogenesis represents a cellular mechanism in the action of cortisol and can explain the increased HPA func- pathophysiology of depression (Jacobs et al. 2000). The tion and stress sensitivity of these patients. An alternative paradigm of learned helplessness, however, was among the view sees the primary cause of the HPA dysregulation in an first to detect an oversimplification of this theory demon- upregulation of hypothalamic corticotropin-releasing hor- strating that decreased neurogenesis is neither necessary nor mone (CRH) leading secondarily to corticosteroid receptor sufficient to induce learned helplessness (Henn and downregulation in the limbic system and the hypothalamus, Vollmayr 2004; Vollmayr et al. 2003, 2007; see also Tanti thus perpetuating the disease state. In contrast to other and Belzung 2013). molecules related to depression, glucocorticoid receptor ex- Electrophysiology has also revealed the long-lasting pression and function has not yet been studied in normal changes of plasticity after uncontrollable shock. As was rodents subjected to a learned helplessness protocol early noted, inescapable shock impairs long-term potentia- (Schulte-Herbrüggen et al. 2006a). However, evidence is tion (LTP) in hippocampal slices (Shors et al. 1989). Ac- available for altered glucocorticoid-receptor-mediated sig- cordingly, it causes the long-lasting inhibition of in vivo naling in inbred congenital learned helpless rats (Lachman LTP. The model, however, has revealed dissociation be- et al. 1993;Vollmayretal.2001). Similar evidence is tween the disrupting effects of inescapable shock on LTP derived from mice with genetically altered glucocorticoid and the behavioral induction of learned helplessness, indi- receptor expression (Gass et al. 2001; Kellendonk et al. cating that the modulation of hippocampal LTP does not 2002; Reichardt et al. 1998). Mice with a 50% reduction underlie learned helpless behavior, but does underpin other of glucocorticoid receptors in the brain show a regular effects of uncontrollable stress (Ryan et al. 2010). circadian HPA axis activity but exhibit significantly in- creased stress sensitivity. On the behavioral level, this cor- relates with a high vulnerability to develop learned Anatomical and functional systems helplessness (Ridder et al. 2005). Conversely, mice with a stress-resistant HPA axis attributable to the overexpression Uncontrollable stress induces changes in widespread brain of glucocorticoid receptors demonstrate resilience to the circuits: the hypothalamus and pituitary activate neuroendocrine induction of learned helplessness (Ridder et al. 2005). These Cell Tissue Res (2013) 354:171–178 175 findings strengthen the construct validity of learned help- function of new candidate genes that are involved in lessness as a depression model. depression-like behavior and that have been identified in genetic analyses in large human cohorts of patients with depression (Uher 2013). Translational value In the latest research development for new antidepressant principles, a single injection of the N-methyl-D-aspartate Learned helplessness thus has contributed much to our receptor antagonist ketamine has been shown to have understanding of the mechanisms of depression, but the rapid and long-lasting antidepressive effects (Zarate et value of an animal model first and foremost is determined al. 2006). The learned helplessness paradigm has en- by its prediction of new treatment options. Most animal abled some of the molecular mechanisms underlying models, however, fail to translate to the clinical (Insel and this antidepressant response to be deciphered, e.g., the Sahakian 2012). With roughly 20% of patients not remitting involvement of mammalian target of rapamycin fully with available treatment options, treatment-resistant (mTOR)-dependent synapse formation and deactivation depression is a major problem (Rush et al. 2006). Selective of eukaryotic elongation factor 2 resulting in increased inbreeding of learned helpless rats has yielded a strain with translation of BDNF (Autry et al. 2011;Lietal.2010). congenital learned helplessness (cLH) displaying treatment- These mechanisms depend on intact glutamate receptors resistant helplessness even without exposure to uncontrolla- of the AMPA (α-amino-3-hydroxy-5-methylisoxazole-4- ble shock (Henn and Vollmayr 2005; Sartorius et al. 2007). proprionic acid) type (Maeng et al. 2008),theroleof The metabolism of the lateral habenula was found to be which in learned helplessness had been described earlier hyperactive in cLH rats (Shumake et al. 2003). Based on (Chourbaji et al. 2008b). anatomical findings and functional human and primate stud- ies, this has led to the hypothesis that the lateral habenula might be hyperactive during major depression and might be Concluding remarks a new treatment target (Sartorius and Meyer-Lindenberg 2009). As a proof-of-concept, inhibition of the lateral Learned helplessness is a depression model with excel- habenula by intracerebral injections of the gamma lent face, construct, and predictive validity in rats and aminobutyric acid agonist muscimol decreases learned help- mice. In contrast to simple tests for putative depression- less behavior in treatment-resistant cLH rats (Winter et al. like behavior, such as the forced swim test and tail 2011). Most importantly, the concept intruigingly seems to suspension test with mainly predictive validity (see translate to humans and to be effective in treatment-resistant O’Leary and Cryan 2013), learned helplessness is not major depression: in a first case report, the inhibition of the a high throughput model. However, similar to chronic habenula by deep brain stimulation has resulted in recovery mild stress models (see Tanti and Belzung 2013), the (Sartorius et al. 2010). origin and natural course of helplessness and its re- Another translational value derives from learned help- sponse to antidepressant therapy resemble the course lessness being a valid model for testing gene-phenotype of human depression. Furthermore, several pathophysio- relationships in transgenic rodent strains (Uran et al. logical concepts of depressive disorders and specific 2005). In this respect, the role of glucocorticoid receptor biomarkers have been validated with this model, and it gene expression has been validated: decreased expres- has predicted the habenula as a region centrally impor- sion renders mice more susceptible to develop learned tant in the pathophysiology of depression and antide- helplessness, whereas increased expression makes them pressant therapy. In comparison with transgenic models more resilient (Ridder et al. 2005). Although monoam- used to investigate the consequences of genetic modifi- inergic neurotransmission does not play a prominent cations, the approach involving strains bred for learned role in glucocorticoid receptor mutant strains, glucocor- helplessness is diametrically opposed: they are conven- ticoid receptor down- or upregulation is associated with tionally bred for a phenotype relying on a valid psycholog- the long-term down- or upregulation of BDNF, respec- ical construct. Advancing these strains to genetically tively (Schulte-Herbrüggen et al. 2006b, 2007), indicat- homogeneous animals holds promise for the identification ing a close link between the HPA-axis concept of of new complex pathways of genes and epigenetic modifi- depression and the neurotrophin hypothesis (Chourbaji cations contributing to depression. As a unique feature, et al. 2011). Moreover, the role of inflammatory and learned helplessness might reflect important cognitive neuroimmune modulatory factors for the development of changes associated with depressive disorders. It may thus learned helplessness has been elaborated (Beurel et al. contribute to identifying new targets for antidepressant 2013; Chourbaji et al. 2006). In the future, learned treatment, possibly with specific efficacy for the cognitive helplessness paradigms can be used to analyze the features of the disorder. 176 Cell Tissue Res (2013) 354:171–178

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