The instrumental role of operant paradigms in translational psychiatric research: Insights from a maternal immune activation model of schizophrenia risk

Abstract

Rigorous behavioral analysis is essential to the translation of research conducted using animal models of neuropsychiatric disease. Here we discuss the use of operant paradigms within our lab as a powerful approach for exploring the biobehavioral bases of disease in the maternal immune activation rat model of schizophrenia. We have investigated a range of disease features in schizophrenia including abnormal perception of time, cognition, learning, motivation, and internal state (psychosis), providing complex insights into brain and behavior. Beyond simple phenotyping, implementing sophisticated operant procedures has been effective in delineating aspects of pathological behavior, identifying interacting pathologies, and isolating contributing mechanisms of disease. We provide comment on the strengths of operant techniques to support high-quality behavioral investigations in fundamental neuropsychiatric research.

Keywords: animal model; maternal immune activation; operant; rat; schizophrenia.

Figure 1

Key Outcomes of Operant Experiments Note. (A) MIA rats exhibit abnormal perception of time (a subjective quickening of the passage of time relative to control animals). (B) Association of temporal accuracy (PSE = point of subjective equality) with sustained attention. Higher PSEs (indicative of impaired timing) corresponded with poorer sustained attention capacity (a greater value on the y axis). (C) MIA rats exhibit reduced sensitivity to action–outcome contingencies. When the probability of reward was increased to 0.10 for withholding lever presses, MIA rats continued to respond at a high rate relative to the notable reduction exhibited by control animals. (D) MIA rats show impaired discrimination of ketamine only at psychotomimetic doses.

Figure 2

(A) Schematic of the Signaled Probability Sustained Attention Task, Adapted from Ward et al.,  Note. Trials were initiated with both levers retracted. (1) During a variable pre‐cue interval, the houselight state (on or off) cued either a high or low reward probability for making a correct choice. (2) The cue light indicates which lever will be rewarded at the choice point. (3) Levers extend, requiring animals to make a choice. (4) Reward delivery is dependent on the animal selecting the cued lever. (B) Representative signaled probability sustained attention (SPSA) performance during acquisition for MIA and control rats.

Figure 3

Schematic and Results of Reversal Task Note. (A) Schematic showing light and lever associations used in the reversal task (Fisken & Ward, 2019). MIA rats exhibit impaired reversal learning. Average learning trends can be observed for animals who started with (B) the Same discrimination rule, and (C) the Opposite discrimination rule.