Research reportBehavioral characteristics of rats predisposed to learned helplessness: Reduced reward sensitivity, increased novelty seeking, and persistent fear memories
Introduction
Inescapable electric shock prevents animals from subsequently learning an escape response, a phenomenon termed learned helplessness [30]. Learned helplessness in animals has been used as a model of depression [14] and of post-traumatic stress disorder (PTSD) [10], [33]. However, most people do not develop depression or PTSD following stress or a traumatic event. While nearly half of all U.S. adults experience at least one traumatic event in their lifetime, only 5–10% develop PTSD [22]. This points to individual differences in susceptibility to stress, and epidemiological studies show that 40–50% of the risk for depression and 30% for PTSD is genetic [9], [38], [47]. Greater knowledge of these predispositional factors would be beneficial to identify at-risk individuals and to develop more effective treatments.
Just as humans show individual differences in susceptibility to these disorders, only 5–20% of rats develop learned helplessness following 20 min of 0.8 mA footshock [15]. Hypothesizing that these individual differences in stress vulnerability had a genetic basis, Henn and Edwards bred Sprague–Dawley rats that demonstrated greater susceptibility to helplessness [13]. Twenty-four hours after the inescapable shock session, rats were tested in an escape paradigm where footshock could be eliminated with a single lever press. Animals with more than 10 failures out of 15 trials were considered helpless, and were mated across subsequent generations, avoiding inbreeding with siblings. The first four generations of selective breeding more than doubled the percentage of helplessness-susceptible offspring [15], and genetic vulnerability continued to increase until a plateau was reached in the 25th generation, when 95% of rats began to show helpless behavior [25]. We call this susceptible strain “congenitally helpless” to emphasize that the rats used in this study did not undergo learned helplessness training.
Outside of their helpless response to electric shock, congenitally helpless rats have not been extensively characterized in terms of behavior. In this study, we assessed these rats on behaviors interpreted as reflecting the three temperament dimensions outlined in Cloninger's theory of personality: reward dependence, novelty seeking, and behavioral inhibition (harm avoidance) [4].
Responsiveness to reward in rodents is usually monitored by consumption of a weak sucrose solution [50]. Vollmayr et al. showed that, under a progressive ratio schedule of reinforcement (in which the responses required to receive reward are steadily increased), congenitally helpless rats were less willing to work for a 7% sucrose reward, pressing the operant bar four times less frequently than controls. Congenitally helpless rats gave up entirely if more than 7 presses were required, whereas control rats were willing to press the lever up to an average of 18 times [48]. This study suggests that congenitally helpless rats are low in reward dependence. Here, we tested if this motivational deficit would also manifest as a simple reduction in sucrose drinking time.
Novelty seeking is characterized by an intense response to novel stimuli which leads to frequent exploratory activity [4]. The most popular test of rodent exploratory behavior is the open field [36]. One might predict either increased or decreased open field activity in an animal model, since both psychomotor agitation and retardation have been linked to depression. However, the increased novelty seeking observed in PTSD [37], [49] would predict increased open field activity. In fact, Vollmayr et al. found that congenitally helpless rats showed increased locomotion in the open field test, but only during the first 5 min [48]. Congenitally helpless rats do not appear to show persistent hyperactivity or hypoactivity as part of their phenotype, but rather seem predisposed to increase locomotion in response to novelty. Here, we attempted to replicate this finding that congenitally helpless rats are high in novelty seeking and to extend the results to include measures of rearing and thigmotaxis, which were not assessed by Vollmayr et al. [48]. Thigmotaxis is the preference for the peripheral versus the central part of the open field, and is considered an index of anxiety since many anxiolytic drugs reduce thigmotaxis, increasing time spent in the central part of the field [36]. In addition, on the second day of testing we used a variant of the open field called the light–dark test to assess anxiety. In this version, half of the field is covered by a dark box with a small opening, and the animal is allowed to move freely between the bright and dark compartments. Animals that show a strong preference for the dark field may be characterized as anxious or withdrawn, and animals that spend increased time in the light field have been characterized as impulsive or sensation-seeking [18]. Finally, we repeated the open field test on the third day as a more stringent test of whether any group differences observed on the first day were due to novelty.
Behavioral inhibition is characterized by an intense response to signals of aversive stimuli [4]. By definition, behavioral assessment of this dimension requires a signal which predicts an aversive stimulus. Therefore, we first conditioned rats to fear a tone by exposing them to tone-shock pairings. Since PTSD involves intrusions of traumatic memories into non-traumatic contexts, we were interested to see how behavior would be affected by the presentation of these fear-conditioned tones in an environment that the rats had previously explored and considered safe. We therefore returned the rats to the open-field apparatus where we attempted to extinguish the tone-shock association by exposing the rats to multiple presentations of the tone. We predicted that congenitally helpless rats would be high in behavioral inhibition, as reflected by enhanced tone-evoked immobility in the open field. We also predicted that congenitally helpless rats would be resistant to fear extinction. These predictions were based on findings that higher behavioral inhibition is related to severity of depression and to mood disorders in general [3], [5], [28], [46], [51]. Moreover, extinction deficits have been implicated in PTSD [2], and PTSD patients have shown both stronger acquisition [29] and reduced extinction [29], [32] of aversively conditioned responses.
Section snippets
Subjects
Experimental subjects were Sprague–Dawley congenitally helpless males (n = 23) and females (n = 21) bred in our laboratory, and control subjects were randomly bred Sprague–Dawley males (n = 12) and females (n = 12) obtained from a commercial animal supplier (Harlan). Rats were separated from their mothers on postnatal day 21. All subjects were group housed three to five to a cage (45 cm × 24 cm × 21 cm) in a temperature-controlled room (22 ± 1 °C). They were maintained on a 12 h/12 h light/dark cycle (lights on at
Open-field and light–dark activity
With the exception of rearing duration and exit latency measures (see below), open-field data were analyzed with a 2 × 2 × 3 × 10 (Group × Sex × Session × Time) repeated measures multivariate analysis of variance (MANOVA), with session (novel, light–dark, or familiar open field) and time (in minutes) serving as repeated measures. All measures showed significant main effects of session and time: subjects always decreased activity over time within sessions, and, between sessions, they were most active in the
Discussion
Congenitally helpless rats showed decreased consumption of a sweet solution, increased exploratory behavior and decreased fearfulness in the novel open field and light–dark tests, and dramatically persistent freezing to a fear-evoking tone, even after multiple extinction trials. It may seem paradoxical that increased exploratory behavior in novel environments should co-exist with reduced reward sensitivity and increased persistence of fear conditioning. However, a large body of evidence from
Acknowledgements
We thank Prof. Dr. Fritz Henn, Dr. Emmeline Edwards, and Dr. Barbara Vollmayr for providing rat breeding pairs; and Timothy Hofstra, David Kahn, and René Colorado for their technical assistance. This work was supported by NIH National Research Service Award F31 MH65743 to JS and NIH Grant R01 NS37755 to FGL.
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2019, Neuroscience and Biobehavioral ReviewsCitation Excerpt :How might the latter come to pass? Individuals afflicted with reward deficiency may possess a character trait of novelty seeking (Bardo et al., 1996; Dellu et al., 1996) driving their engagement in stressogenic and even traumatic situations with subsequent emergence of PTSD (Richman and Frueh, 1997; Shumake et al., 2005). Such people may be additionally prone for the development of PTSD due to low reward/motivational capacity making it difficult to cope with stressful situations (Charney, 2004), to the point of helplessness (Bergamini et al., 2016), which is an important precursor for the development of PTSD (Salcioglu et al., 2017).