Research reportRats with congenital learned helplessness respond less to sucrose but show no deficits in activity or learning
Introduction
Animal models are needed to investigate the neurobiology underlying major depression [28], [29]. Learned helplessness is a well established stress model of major depression with good construct validity [42], [43]: uncontrollable and unpredictable stress induces learned helplessness in the rat [33], [34]. The model shows good face validity with vegetative changes such as weight loss, loss of libido, and increased REM sleep [1], [7], [8]. Endocrine changes with decreased dexamethason suppression during learned helplessness and pharmacological specificity for antidepressant drug treatment also argue for an animal model of major depression [15], [36]. Moreover, reduced behavioral plasticity of learned helplessness goes along with alterations in monoaminergic systems [9], [10], [11], [12], [25]. Learned helplessness lasts for more than 1 week which is comparable to the duration of human depressive episodes if the rats’ much shorter life span is considered [17], [41]. In our paradigm moderate stress induces learned helplessness only in a portion of susceptible animals, thus modeling the human susceptibility to depression [40]. By selectively breeding learned helpless animals and non-learned helpless, respectively, two lines have been developed: one shows congenital learned helplessness (cLH) the other one exhibits resistance to learned helplessness (cNLH) [18].
A loss of pleasure (anhedonia) and interest in nearly all activities is an essential feature of major depressive episodes. Anhedonia is commonly tested in rats as a decreased consumption of sweet palatable solutions [44]. More specific than total intake of sucrose, operant responding for sucrose under a progressive ratio (PR) schedule can be used to assess the motivational state of the responding animals [23]. The breaking point where an animal stops responding determines how much effort an animal is willing to exert to gain access to an reinforcing substance [24]. The breaking point therefore can be used to assess the effectiveness of the reinforcement which is determined by the reinforcer and the hedonic capacity of the individual, but also to compare the persistence of the animals to exert sustained effort over time [32]. We thus used the PR schedule to measure differences in anhedonia in cLH and cNLH rats.
Section snippets
Animals
By selecting for susceptibility for learned helplessness, two lines of rats were generated: cLH (congenitally learned helpless) and cNLH (congenitally non-helpless). Breeding of the helplessness colonies has been described [21], [22], [37], [38], [39]. Briefly, Sprague–Dawley rats were tested in the learned helplessness paradigm [40]. Twenty-four hours after a total of 20 min uncontrollable and unpredictable 0.8 mA footshocks, the rats were tested in an escape paradigm where foot shock could be
Results
Animals from both strains learned to press the lever for sucrose during a 24-h session on a FR1 and did not differ in FR1 responses for sucrose during the training sessions for 24 or 1 h, no matter if tested after water deprivation or without water deprivation. After 24 h water deprivation, cLH rats had 214±40 lever presses during a 1-h session, whereas cNLH rats responded 210±36 times. Without water deprivation, lever presses were reduced to 116±39 h−1 in cLH and 133±36 h−1 in cNLH. However,
Discussion
Essential features of major depressive episodes are either depressed mood or a marked loss of interest and pleasure in nearly all activities. Communication of changes in mood and thoughts during depressive episodes relies on language and is not testable in animal models. Therefore, anhedonia or the reduced capacity to experience pleasure is an important analogue of major depression in animal models [42], [43]. The consumption of sweet palatable solutions or pellets as a measure of hedonia is
Acknowledgements
The authors thank Dr. B. Krumm for help with statistical analysis, Dr. C. Sanchis Segura for helpful comments on the manuscript, and C. Zacher and H. Schamber for excellent technical assistance. This work was supported by the Deutsche Forschungsgemeinschaft to B.V. (VO 621 3-1) and P.G. (GA 427 4-1).
References (46)
- et al.
Sleep–wakefulness patterns in the helpless rat
Physiol. Behav.
(1991) - et al.
Chronic mild stress has no effect on responding by rats for sucrose under a progressive ratio schedule
Physiol Behav.
(1998) Food reward: brain substrates of wanting and liking
Neurosci. Biobehav. Rev.
(1996)Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns
Neurosci. Biobehav. Rev.
(2000)- et al.
Diurnal variation in the effect of chronic mild stress on sucrose intake and preference
Physiol. Behav.
(1997) - et al.
Suppression of feeding and body weight by inescapable shock: modulation by quinine adulteration stress reinstatement and controllability
Physiol. Behav.
(1989) - et al.
Stressors in the learned helplessness paradigm: effects on body weight and conditioned taste aversion in rats
Physiol. Behav.
(1988) - et al.
5-HT1b receptors in an animal model of depression
Neuropharmacology
(1991) - et al.
Presynaptic serotonin mechanisms in rats subjected to inescapable shock
Neuropharmacology
(1992) - et al.
In vitro neurotransmitter release in an animal model of depression
Neurochem. Int.
(1992)
Chronic mild stress and sucrose consumption: validity as a model of depression
Physiol. Behav.
Animal models for the study of antidepressant activity
Brain Res. Protoc.
Dexamethasone suppression test in helpless rats
Biol. Psychiatry
Genetic predisposition and the development of posttraumatic stress disorder in an animal model
Biol. Psychiatry
Differential development of the stress response in congenital learned helplessness
Int. J. Dev. Neurosci.
Hippocampal neuropeptide Y mRNA is reduced in a strain of learned helpless resistant rats
Mol. Brain Res.
Sucrose consumption as an hedonic measure following chronic unpredictable mild stress
Physiol. Behav.
Preclinical models: status of basic research in depression
Biol. Psychiatry
Neurobiology of depression
Neuron
Chronic mild stress-induced anhedonia: greater effect in a genetic rat model of depression
Physiol. Behav.
Specificity of the learned helplessness model of depression
Pharmacol. Biochem. Behav.
Hypermetabolism of paraventricular hypothalamus in the congenitally helpless rat
Neurosci. Lett.
Dissociation of septo-hippocampal metabolism in the congenitally helpless rat
Neuroscience
Cited by (93)
Treatment-resistant depression with anhedonia: Integrating clinical and preclinical approaches to investigate distinct phenotypes
2022, Neuroscience and Biobehavioral ReviewsModeling treatment-resistant depression in the preclinical setting
2022, Managing Treatment-Resistant Depression: Road to Novel TherapeuticsA study of limbic brain derived neurotrophic factor gene expression in male Sprague-Dawley rats trained on a learned helplessness task
2019, Behavioural Brain ResearchCitation Excerpt :In rodents, LH can be studied using a procedure pioneered by Overmier and Seligman (1967), [23] characterized by behavioural passivity in response to an aversive controllable stressor, based on previous experience with an uncontrollable stressor. In addition to observing a decreased escape effort [23], LH animals display other depressive-like behaviours including weight loss, sleep disturbances [24] and decreased sucrose as well as saccharine intake [25,26]. Interestingly, antidepressant medications can reverse LH in rodents [27,28].
The impact of sugar consumption on stress driven, emotional and addictive behaviors
2019, Neuroscience and Biobehavioral ReviewsTranslational Assessments of Reward and Anhedonia: A Tribute to Athina Markou
2018, Biological Psychiatry