Measuring reinforcement learning and motivation constructs in experimental animals: Relevance to the negative symptoms of schizophrenia

Abstract

The present review article summarizes and expands upon the discussions that were initiated during a meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS; http://cntrics.ucdavis.edu). A major goal of the CNTRICS meeting was to identify experimental procedures and measures that can be used in laboratory animals to assess psychological constructs that are related to the psychopathology of schizophrenia. The issues discussed in this review reflect the deliberations of the Motivation Working Group of the CNTRICS meeting, which included most of the authors of this article as well as additional participants. After receiving task nominations from the general research community, this working group was asked to identify experimental procedures in laboratory animals that can assess aspects of reinforcement learning and motivation that may be relevant for research on the negative symptoms of schizophrenia, as well as other disorders characterized by deficits in reinforcement learning and motivation. The tasks described here that assess reinforcement learning are the Autoshaping Task, Probabilistic Reward Learning Tasks, and the Response Bias Probabilistic Reward Task. The tasks described here that assess motivation are Outcome Devaluation and Contingency Degradation Tasks and Effort-Based Tasks. In addition to describing such methods and procedures, the present article provides a working vocabulary for research and theory in this field, as well as an industry perspective about how such tasks may be used in drug discovery. It is hoped that this review can aid investigators who are conducting research in this complex area, promote translational studies by highlighting shared research goals and fostering a common vocabulary across basic and clinical fields, and facilitate the development of medications for the treatment of symptoms mediated by reinforcement learning and motivational deficits.

GlyT-1 Inhibition Attenuates Attentional But Not Learning or Motivational Deficits of the Sp4 Hypomorphic Mouse Model Relevant to Psychiatric Disorders

“…Reduced breakpoint in a progressive ratio setting has often been suggested as a measure of reduced motivation in mice that is relevant to negative symptoms in schizophrenia (Barnes et al, 2014;Ellenbroek and Cools, 2000;Markou et al, 2013;. Support for these assertions comes from recent evidence of reduced breakpoint in patients with schizophrenia that negatively correlated with negative symptom scale ratings (Wolf et al, 2014).…”

“…Once trained to respond in lit apertures (experiment 1), the Sp4 mice were tested in the progressive ratio breakpoint procedure (experiment 2) in order to gauge the motivation of mice to work for a single reward (Barnes et al, 2014;Markou et al, 2013), as described previously (Bensadoun et al, 2004;. The mice were then trained in the 5C-CPT and stable baseline performance recorded (experiment 3).…”

Effort-Based Decision-Making Paradigms for Clinical Trials in Schizophrenia: Part 1—Psychometric Characteristics of 5 Paradigms

“…Effort-based decision making has been investigated in preclinical models of motivational negative symptoms, as well as healthy and clinical samples. [1][2][3] Animal studies demonstrate a general "law of least effort" in which organisms choose to exert the least amount of physical or cognitive effort necessary to obtain a given level of reward, 4 but when reward levels increase, the animal is typically willing to exert more effort. Decisions about whether to exert more effort for higher levels of reward depend on factors such as perceived effort required to complete the associated task, subjective valuation of potential rewards, and likelihood that the reward will actually be received if the task is successfully completed.…”

The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia

“…Motivation and reinforcement learning was highlighted by a CNTRICS working group (Markou et al 2013) as a reflection of extensive evidence of impairments in patients with schizophrenia (e.g. Gard et al 2007Gard et al , 2014Gold et al 2008Gold et al , 2013Weiler et al 2009;Barch and Dowd 2010;Kasanova et al 2011;Dowd and Barch 2012;Yılmaz et al 2012;Barch et al 2014;Griffiths et al 2014).…”

“…Some of the tasks proposed by the working group are already established in the touchscreen, such as autoshaping, which has been successfully used in both rat and mouse models (Bussey et al 1997b;Parkinson et al 2000a, b;Dalley et al 2005;Ito et al 2005;DePoy et al 2013;Horner et al 2013). Others, such as progressive ratio , probabilistic (selection) learning task (rPST; Mar et al unpublished;Trecker et al 2012 poster;Markou et al 2013), and notionally a version of an operant probabilistic reversal paradigm that can assess bias to negative and positive feedback (Bari et al 2010) are the focus of current development and validation and will together form a battery to screen for motivational and reinforcement Fig. 10 A schematic of four trials of the paired-associate learning task.…”