Establishing a learned-helplessness effect paradigm in C57BL/6 mice: Behavioural evidence for emotional, motivational and cognitive effects of aversive uncontrollability per se

Pryce, Christopher R.; Azzinnari, Damiano; Sigrist, Hannes; Gschwind, Tilo; Lesch, Klaus‐Peter; Seifritz, Erich

doi:10.1016/j.neuropharm.2011.08.012

Cited by 40 publications

(39 citation statements)

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“…However, 5-HTT polymorphisms are undoubtedly pleiotropic. For example, 5-HTT HET mice also exhibit increased reactivity to fear-inducing stimuli relative to WT (Pryce et al, 2012), as do healthy human carriers of the "short" 5-HTTLPR polymorphism relative to "long" allele carriers (Hariri et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Establishing a probabilistic reversal learning test in mice: Evidence for the processes mediating reward-stay and punishment-shift behaviour and for their modulation by serotonin

Ineichen¹,

Sigrist²,

Spinelli³

et al. 2012

Neuropharmacology

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Valid animal models of psychopathology need to include behavioural readouts informed by human findings. In the probabilistic reversal learning (PRL) task, human subjects are confronted with serial reversal of the contingency between two operant stimuli and reward/punishment and, superimposed on this, a low probability (0.2) of punished correct responses/rewarded incorrect responses. In depression, reward-stay and reversals completed are unaffected but response-shift following punished correct response trials, referred to as negative feedback sensitivity (NFS), is increased. The aims of this study were to: establish an operant spatial PRL test appropriate for mice; obtain evidence for the processes mediating reward-stay and punishment-shift responding; and assess effects thereon of genetically- and pharmacologically-altered serotonin (5-HT) function. The study was conducted with wildtype (WT) and heterozygous mutant (HET) mice from a 5-HT transporter (5-HTT) null mutant strain. Mice were mildly food deprived and reward was sugar pellet and punishment was 5-s time out. Mice exhibited high motivation and adaptive reversal performance. Increased probability of punished correct response (PCR) trials per session (p = 0.1, 0.2 or 0.3) led to monotonic decrease in reward-stay and reversals completed, suggesting accurate reward prediction. NFS differed from chance-level at p PCR = 0.1, suggesting accurate punishment prediction, whereas NFS was at chance-level at p = 0.2-0.3. At p PCR = 0.1, HET mice exhibited lower NFS than WT mice. The 5-HTT blocker escitalopram was studied acutely at p PCR = 0.2: a low dose (0.5-1.5 mg/kg) resulted in decreased NFS, increased reward-stay and increased reversals completed, and similarly in WT and HET mice. This study demonstrates that testing PRL in mice can provide evidence on the regulation of reward and punishment processing that is, albeit within certain limits, of relevance to human emotional-cognitive processing, its dysfunction and treatment.

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Section: Discussionmentioning

confidence: 99%

Establishing a probabilistic reversal learning test in mice: Evidence for the processes mediating reward-stay and punishment-shift behaviour and for their modulation by serotonin

Ineichen¹,

Sigrist²,

Spinelli³

et al. 2012

Neuropharmacology

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“…Behavioural testing (Expt A, D) was conducted under dim lighting in a room adjacent to the mouse holding room, between 09:00-12:00 h (early dark phase), using a Multi-Conditioning System in which activity was monitored continuously using an infrared movement-detection system (TSE Systems GmbH, Bad Homburg, Germany) (Cathomas et al, 2015;Pryce et al, 2012 Neutral arena tests. The mouse was placed on the grid floor in an arena (context) for 15 min, and activity and % time freezing were recorded continuously.…”

Section: Pavlovian Fear Learning and Memorymentioning

confidence: 99%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

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125

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Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immuneinflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-, IFN-, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, higher KYN and 3-HK in amygdala and hippocampus. However, CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders. ABSTRACTPsychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyperactivity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.3

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“…On the other hand, SERT +/− rodents show enhanced reversal learning and impaired object recognition after 8 h (Olivier et al, 2009; Brigman et al, 2010). In response to a stressor such as an inescapable foot shocks male SERT +/− mice, but not rats (van der Doelen et al, 2013) showed increased helplessness compared to SERT +/+ mice, indicated by a higher escape latency (Muller et al, 2011) or less escapes (Pryce et al, 2012) during the test session where they could actually escape the foot shock. However, basal behavioral differences between SERT +/− and SERT +/+ mice were not observed in fear conditioning or in anxiety and depressive-like behavior, including the open field, novelty suppressed feeding, and forced swim test (Muller et al, 2011).…”

Section: Rodent Models Of Sert Gene Variationmentioning

confidence: 99%

The Serotonin Transporter and Early Life Stress: Translational Perspectives

Houwing

Buwalda

Zee

et al. 2017

Front. Cell. Neurosci.

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The interaction between the serotonin transporter (SERT) linked polymorphic region (5-HTTLPR) and adverse early life stressing (ELS) events is associated with enhanced stress susceptibility and risk to develop mental disorders like major depression, anxiety, and aggressiveness. In particular, human short allele carriers are at increased risk. This 5-HTTLPR polymorphism is absent in the rodent SERT gene, but heterozygous SERT knockout rodents (SERT+/−) show several similarities to the human S-allele carrier, therefore creating an animal model of the human situation. Many rodent studies investigated ELS interactions in SERT knockout rodents combined with ELS. However, underlying neuromolecular mechanisms of the (mal)adaptive responses to adversity displayed by SERT rodents remain to be elucidated. Here, we provide a comprehensive review including studies describing mechanisms underlying SERT variation × ELS interactions in rodents. Alterations at the level of translation and transcription but also epigenetic alterations considerably contribute to underlying mechanisms of SERT variation × ELS interactions. In particular, SERT+/− rodents exposed to adverse early rearing environment may be of high translational and predictive value to the more stress sensitive human short-allele carrier, considering the similarity in neurochemical alterations. Therefore, SERT+/− rodents are highly relevant in research that aims to unravel the complex psychopathology of mental disorders. So far, most studies fail to show solid evidence for increased vulnerability to develop affective-like behavior after ELS in SERT+/− rodents. Several reasons may underlie these failures, e.g., (1) stressors used might not be optimal or severe enough to induce maladaptations, (2) effects in females are not sufficiently studied, and (3) few studies include both behavioral manifestations and molecular correlates of ELS-induced effects in SERT+/− rodents. Of course, one should not exclude the (although unlikely) possibility of SERT+/− rodents not being sensitive to ELS. In conclusion, future studies addressing ELS-induced effects in the SERT+/− rodents should extensively study both long-term behavioral and (epi)genetic aspects in both sexes. Finally, further research is warranted using more severe stressors in animal models. From there on, we should be able to draw solid conclusions whether the SERT+/− exposed to ELS is a suitable translational animal model for studying 5-HTTLPR polymorphism and stress interactions.

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Establishing a learned-helplessness effect paradigm in C57BL/6 mice: Behavioural evidence for emotional, motivational and cognitive effects of aversive uncontrollability per se

Cited by 40 publications

References 39 publications

Establishing a probabilistic reversal learning test in mice: Evidence for the processes mediating reward-stay and punishment-shift behaviour and for their modulation by serotonin

Establishing a probabilistic reversal learning test in mice: Evidence for the processes mediating reward-stay and punishment-shift behaviour and for their modulation by serotonin

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

The Serotonin Transporter and Early Life Stress: Translational Perspectives

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