C8 - Analysis of higher cognitive functions in rodent models of schizophrenia and depression
Prof. Dr. med. Peter Gass
Zentralinstitut für Seelische Gesundheit
PD. Dr. Barbara Vollmayr
Institut für Psychiatrie und Psychotherapie
AG Psychiatrische Tiermodelle
Zentralinstitut für Seelische Gesundheit (ZI)
J5, D-68159 Mannheim
Projects within the BCCN:
This project aimed to establish a bridge from rodent to human studies and computational modeling by testing behavioral model predictions, compare cross-species behavior and generating behavioral data for informing computational models. To this end, we streamlined the animal models and behavioral paradigms across the different projects.
Higher cognitive functions were first analyzed in rats bred for learned helplessness, an animal model derived from the cognitive theory of depression (Vollmayr & Gass 2013). Introducing the analysis of the time course into the test for learned helplessness refined the paradigm and reduced the experimental burden for the animals (Richter et al. 2014). Using behavioral paradigms established in the lab, we demonstrated that the negative cognitive bias and anhedonia associated with learned helplessness are modulated by environmental enrichment (Richter et al. 2012, Richter et al. 2013a). In analogy to C7 and in cooperation with B5, we tested the rats bred for learned helplessness in a radial arm maze with a temporal delay. In helpless rats we found impaired performance after a 30 sec but not after a 15 min delay, indicating stress-related attentional deficits in the depressive-like strain (Richter et al. 2013b). Furthermore, we demonstrated increased mGluR5-signalling in these animals, but MPEP-treatment unfortunately did not reverse learned helplessness (Pignatelli et al. 2013).
The abilities to either flexibly adjust behavior according to changing demands (cognitive flexibility) or to maintain it in the face of potential distractors (cognitive stability) are part of executive control. The main goal of our project was to translate a novel human paradigm (C4) to mice and to test conceptual predictions of the Dual State Theory assuming an antagonistic relation between cognitive flexibility and stability. Using touchscreen chambers, we established and confirmed a novel test paradigm for assessing cognitive flexibility versus cognitive stability in mice. On the basis of a simple discriminative task, we combined four task conditions with different degrees of difficulty, and introduced an ‘ambiguous’ condition for the assessment of an ‘individual spontaneous switching score’, reflecting the probability of spontaneously switching between two responses without explicit external cues. The results thus support a cross-species dichotomy of cognitive flexibility and stability and confirm behavioural predictions derived from the Dual State Theory (Richter et al. 2014). Stress and satiation-related consequences of food-restriction and touchscreen training were published in a second article (Mallien et al. 2016). Subsequently, we started the analysis of a transgenic mouse strain (A3) with a brain-specific deletion of a schizophrenia risk gene, CAGNA 1C. Interestingly, model- based data analysis supported by B5 and D2 revealed that CACNA1C knockout mice do not exhibit general learning deficits, as previously proposed, but rather apply different (but sub-optimal) behavioral strategies to improve on a task (Koppe et al., in revision).
Prof. (apl.) Dr.med., Dipl. Phys. Alexander Sartorius
Mallien AS, Palme R, Richetto J, Muzzillo C, Richter SH, Vogt MA, Riva MA, Vollmayr B, Gass P (2016) Daily exposure to a touchscreen-paradigm and associated food restriction evokes an increase in adrenocortical and neural activity in mice.
Hormones and Behavior 81: 97-105
Weber T, Vogt MA, Gartside SE, Berger S, Lujan R, Lau T, Herrmann E, Sprengel R, Bartsch D, Gass P (2015) Adult AMPA GLUA1 receptor subunit loss in 5-HT neurons results in a specific anxiety-phenotype with evidence for dysregulation of 5-HT neuronal activity.
Richter SH, Vogel AS, Ueltzhöffer K, Muzzillo C, Vogt MA, Lankisch K, Armbruster-Genç DJN, Riva MA, Fiebach CJ, Gass P, Vollmayr B (2014) Touchscreen-paradigm for mice reveals cross-species evidence for an antagonistic relationship of cognitive flexibility and stability
Frontiers in Behavioral Neuroscience 8: 154
Richter SH, Sartorius A, Gass P, Vollmayr B (2014) A matter of timing: harm reduction in learned helplessness
Behavioral and Brain Functions 10: 41 (2014), eCollection
Richter SH, Zeuch B, Riva MA, Gass P, Vollmayr B (2013) Environmental enrichment ameliorates depressive-like symptoms in young rats bred for learned helplessness.
Behavioural Brain Research 252: 287-292
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Bernstein Center Heidelberg / Mannheim