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Project 14: Expectation maintenance vs. change in animal models: Serotonin-orchestrating, associative learning and neuronal plasticity processes

Dr. Markus Wöhr & Dr. Metin Üngör 

PhD Student: Maria Willadsen

Applying a translational approach to rats and humans, we plan to investigate neurobiological mechanisms underlying psychological processes involved in expectation change vs. maintenance after expectation violations by means of a translational approach including rats and humans. The serotonergic (5-HT) system has been repeatedly implicated in cognitive flexibility, with alterations in its components resulting in exaggerated persistence of expectations, as reflected by impairments in extinction and/or reversal learning. Brain 5-HT synthesis depends on the rate limiting enzyme tryptophan hydroxylase 2 (gene: TPH2), with extracellular levels of 5-HT being primarily regulated by reuptake through the 5-HT transporter (SERT; gene: SLC6A4). SLC6A4 is thought to function as a plasticity gene, increasing sensitivity to environmental changes by promoting neuronal plasticity processes, such as neurogenesis. In humans and other primates, genetic alterations in both the TPH2 and the SLC6A4 gene (e.g. 5-HTTLPR) have been associated with impairments in extinction and/or reversal learning. Their crucial role was confirmed by means of genetic rodent models, yet little is known about underlying behavioral and neurobiological mechanisms. Here, we therefore plan to study underlying mechanisms that result in exaggerated persistence of expectations by means of TPH2 and SLC6A4 knockout rats at the behavioral and neurobiological level. Specifically, we plan to test (1) the hypothesis that the impairment in extinction learning in the two genetic models reflecting extreme personality traits is due to impaired inhibitory learning, but not impaired learning per se, yet associated with a lack of relevant neuronal plasticity processes; (2) whether environmental enrichment promoting neuronal plasticity processes leads to a concomitant improvement in extinction learning; and (3) whether deficits in extinction learning are specific for aversive situations or whether they occur in appetitive situations as well. To this aim, we will perform our established fear conditioning paradigm during which we focus on extinction learning as a measure for persistence of expectations, testing the hypothesis that the impairment in extinction learning seen in TPH2 and SLC6A4 knockout rats is due to impaired inhibitory learning, but not impaired learning per se. Inhibitory learning plays a central role in current theories of extinction and its importance is indicated by several recovery phenomena, such as the renewal effect. The conditioned emotional response will be assessed by means of freezing behavior and aversive 22-kHz ultrasonic vocalizations (USV). As neuronal plasticity markers, neurogenesis and related measures will be determined. To support causality, we will further test whether environmental enrichment promoting neuronal plasticity processes leads to a concomitant improvement in extinction learning. Importantly, the genetic approach in rats will be paralleled by human studies focusing on inhibitory learning during extinction in a fear conditioning paradigm, in which 5-HT system polymorphisms will be determined.

Publications

Berz, A., Pasquini de Souza, C., Wöhr, M., & Schwarting, R. K. W. (in press). Limited generalizability, pharmacological modulation, and state-dependency of the habituation towards pro-social 50-kHz calls in rats. iScience.

Redecker, T. M., Kisko, T. M., Wöhr, M., & Schwarting, R. K. W. (2020). Cacna1c haploinsufficiency lacks effects on adult hippocampal neurogenesis and volumetric properties of prefrontal cortex and hippocampus in female rats. Physiology & Behaviour. 223:112974.

Sangarapillai, N., Ellenberger, M., Wöhr, M., & Schwarting, R.K.W. (2020). Ultrasonic vocalizations and individual differences in rats performing a Pavlovian conditioned approach task. Behavioural Brain Research, in press.

Uengoer, M., Thorwart, A., Lucke, S., Wöhr, M., & Lachnit, H. (2020). Adding or removing context components equally disrupts extinction in human predictive learning. Behavioural Processes, 179, 104216. https://doi.org/10.1016/j.beproc.2020.104216

Willadsen, M., Uengoer, M., Schwarting, R., Homberg, J. R., & Wöhr, M. (accepted, 2020). Reduced emission of alarm 22-kHz ultrasonic vocalizations during fear conditioning in rats lacking the serotonin transporter. Progress in Neuropsychopharmacology & Biological Psychiatry.

Wöhr, M., Willadsen, M., Kisko, T. M., Schwarting, R. K., & Fendt, M. (2020). Sex-dependent effects of Cacna1c haploinsufficiency on behavioral inhibition evoked by conspecific alarm signals in rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 99, 109849.

Redecker, T. M., Kisko, T. M., Schwarting, R. K., & Wöhr, M. (2019). Effects of Cacna1c haploinsufficiency on social interaction behavior and 50-kHz ultrasonic vocalizations in adult female rats. Behavioural Brain Research, 367, 35-52.

Fendt, M., Brosch, M., Wernecke, K. E., Willadsen, M., & Wöhr, M. (2018). Predator odour but not TMT induces 22-kHz ultrasonic vocalizations in rats that lead to defensive behaviours in conspecifics upon replay. Scientific reports, 8(1), 1-11.

Willadsen, M., Best, L. M., Wöhr, M., & Clarke, P. B. S. (2018). Effects of anxiogenic drugs on the emission of 22-kHz and 50-kHz ultrasonic vocalizations in adult rats. Psychopharmacology, 235(8), 2435-2445.

More information on Dr. Markus Wöhr and Dr. Metin Üngör 

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