A mixed fixed ratio/progressive ratio procedure reveals an apathy phenotype in the BAC HD and the z_Q175 KI mouse models of Huntington’s disease

Abstract

Apathy, characterized by generally reduced interest in and likelihood to perform goal-directed actions, is a recognized symptom of Huntington’s disease (HD), a devastating neurological disorder caused by a CAG repeat expansion of the Htt gene located on chromosome 4. The present experiments used a modified progressive ratio task that incorporated a fixed-ratio schedule of reinforcement component to assess consummatory behavior, and a progressive-ratio schedule component that required increasing numbers of lever-presses for successive reinforcers (0.01 ml of evaporated milk). The studies revealed an apathetic phenotype in two mouse models of HD, with decreased response rates either overall or only at higher ratio requirements in the progressive-ratio component relative to wild-type controls. Based on the procedure used (within-session fixed- and progressive-ratio components), it is proposed that an observed phenotype can be ascribed either specifically to reduced motivation to work for food reinforcement or more generally to deficits in consummatory behavior. This procedure provides a simple means to assess this type of phenotype in rodents, with issues in consummatory vs. incentive motivation reflected in general alterations in fixed- versus progressive alterations on an escalating-ratio schedules respectively, providing translational measures of the amotivation/apathy construct of the human realm to the homologous construct of incentive motivation in preclinical models of human disease.

Large-scale phenome analysis defines a behavioral signature for Huntington's disease genotype in mice

“…Furthermore, this system could be used to estimate a drug's ability to rescue a disease phenotype while assessing its side effects 10 , or to discover new and unexpected animal model phenotypes 30 . One limitation of the approach is that it excludes tests of higher cognitive functions (e.g., learning and memory) that require training in multiple sessions over time but may be important for translation to the clinic 31 .…”

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

“…This term is most frequently used to refer to motivational deficits in schizophrenia, dysthymia, depression, stroke, progressive supranuclear palsy, and neurodegeneration, particularly in Huntington’s disease (Ishizaki and Mimura, 2011; van Reekum et al, 2005). Apathy is defined as “diminished goal-oriented behavior and cognition, and a diminished emotional connection to goal-directed behavior” (Marin, 1991); thus, this term describes a type of motivational dysfunction relevant to the focus of this review (Clarke et al, 2011; Oakeshott et al, 2012). …”

“…These activational aspects of motivation are widely studied in behavioral neuroscience, and they are clinically relevant also. As discussed above, clinicians have come to emphasize the importance of motivational symptoms related to effort expenditure, such as psychomotor slowing, apathy, and anergia in major depression, fatigue in parkinsonism and multiple sclerosis, and avolition in schizophrenia (Demyttenaere et al, 2005; Oakeshott et al, 2012; Salamone et al, 2006, 2010; Ward et al, 2011; Treadway and Zald, 2011). Moreover, it has been argued that many people with psychopathologies have fundamental deficits in reward seeking, exertion of effort, and effort-related decision making that do not simply depend on any problems that they may have with experiencing pleasure (Treadway and Zald, 2011).…”

Further investigation of phenotypes and confounding factors of progressive ratio performance and feeding behavior in the BACHD rat model of Huntington disease

“…The protocol for this test has been described in our initial study of the BACHD rats’ food consumption rates [18], and similar protocols have been described by others [28–33]. The aim of the test is to acquire a basic measurement of the rats’ apparent interest in food, i.e.…”