Preclinical Models to Investigate Mechanisms of Negative Symptoms in Schizophrenia

Barnes, Sarah; Der-Avakian, Andre; Young, Jared W.

doi:10.1093/schbul/sbx065

Cited by 14 publications

(10 citation statements)

References 72 publications

(77 reference statements)

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“…Nevertheless, the mouse model is a well-vetted compromise between sufficient complexity for behavioral analogy to schizophrenia, genetic tractability, and feasibility for high-throughput molecular studies (94,95). Dozens of genetically altered mouse lines model one or more intermediate phenotypes (96,97); here we restrict evidence to the most wellstudied models demonstrating glutamatergic and dopaminergic synergistic molecular and behavioral phenotypes.…”

Section: Preclinical Studies Relating To Schizophrenia Etiologymentioning

confidence: 99%

Cognition and Reward Circuits in Schizophrenia: Synergistic, Not Separate

Robison

Thakkar

Diwadkar

2020

Biological Psychiatry

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Schizophrenia has been studied from the perspective of cognitive-or reward-related impairments, yet it cannot be wholly related to one or the other process and corresponding neural circuits. We posit a comprehensive circuit-based model proposing that dysfunctional interactions between the brain's cognitive and reward circuits underlie schizophrenia. The model is underpinned by how the relationship between glutamatergic and dopaminergic dysfunction in schizophrenia drives interactions between cognition and reward circuits. We argue that this interaction is synergistic: that is, deficits of cognition and reward processing interact, and this interaction is a core feature of schizophrenia. In adopting this position, we undertake a focused review of animal physiology and human clinical data, and in proposing this synergistic model, we highlight dopaminergic afferents from the ventral tegmental area to nucleus accumbens (mesolimbic circuit) and frontal cortex (mesocortical circuit). We then expand on the role of glutamatergic inputs to these dopamine circuits, and dopaminergic modulation of critical excitatory pathways, with attention given to the role of glutamatergic hippocampal outputs onto nucleus accumbens. Finally, we present evidence for how in schizophrenia, dysfunction in the mesolimbic and mesocortical circuits, and their corresponding glutamatergic inputs gives rise to clinical and cognitive phenotypes, and is associated with positive and negative symptom dimensions. The synthesis attempted here provides an impetus for a conceptual shift that links cognitive and motivational aspects of schizophrenia and which can lead to treatment approaches that seek to harmonize network interactions between the brain's cognition and reward circuits with ameliorative effects in each behavioral domain.

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Section: Preclinical Studies Relating To Schizophrenia Etiologymentioning

confidence: 99%

Cognition and Reward Circuits in Schizophrenia: Synergistic, Not Separate

Robison

Thakkar

Diwadkar

2020

Biological Psychiatry

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“…These findings led the field to shift away from a unidimensional conceptualization, in favor of a 2-dimensional conceptualization of negative symptoms. 19 EFA studies supporting the 2 factors have been influential, informing how researchers search for pathophysiological mechanisms of negative symptoms [20][21][22][23][24] and how pharmaceutical companies approach targeted treatment development. 25 However, conclusions about the latent structure of negative symptoms based on EFAs alone are insufficient.…”

mentioning

confidence: 99%

Reconsidering the Latent Structure of Negative Symptoms in Schizophrenia: A Review of Evidence Supporting the 5 Consensus Domains

Strauss

Ahmed

Young

et al. 2018

Schizophrenia Bulletin

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“…Motivation is often defined as an organism's willingness to expend effort for a particular reinforcer, often a reward. This conceptualization is based on effort‐based decision making where reward valuation and an effort calculation are integrated to produce a cost–benefit construct (Barnes et al, 2017; Chong et al, 2016; Der‐Avakian et al, 2016; Epstein & Silbersweig, 2015; Hamill et al, 1999; Randall et al, 2012; Randall, Lee, Nunes, et al, 2014; Randall, Lee, Podurgiel, et al, 2014; Rotolo et al, 2019, 2020, 2021; Stewart et al, 1974; Yohn et al, 2018). Willingness to overcome physical effort (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Willingness to overcome physical effort (i.e. pressing a lever) that is required to receive a particular reinforcer provides a quantifiable approach for studying motivation in preclinical models (Barnes et al, 2017; Chong et al, 2016; Hamill et al, 1999; Mingote et al, 2005; Salamone & Correa, 2002). Motivation and reward‐value are often quantified by the number of reinforcers an animal earns, also known as break‐point, and the highest ratio completed in a progressive ratio task (Chong et al, 2016; Pipkin & Vollmer, 2009).…”

Section: Discussionmentioning

confidence: 99%

The influence of reinforcement schedule on experience‐dependent changes in motivation

Johnson¹,

Christensen

Kelly³

et al. 2022

J Exper Analysis Behavior

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The progressive ratio procedure is used across fields to assess motivation for different reinforcers, define the effects of experimental interventions on motivation, and determine experience‐dependent changes in motivation. However, less is known about how operant training schedules affect performance on this widely utilized task. Here we designed an experiment to examine the effect of variable ratio versus fixed ratio training schedules of reinforcement on progressive ratio performance while holding other performance variables constant between groups. We found a robust increase in maximum ratio completed between the pretest and posttraining test highlighting a robust training effect on progressive ratio performance. However, it did not matter if the training was under a fixed or variable ratio schedule. Additionally, we show that neither individual rates during training nor extinction responding correlated with maximum ratio achieved during the sessions. Finally, we show that rates during the training sessions do correlate with extinction performance, suggesting that these variables measure a different aspect of performance that does not predict motivation.

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Preclinical Models to Investigate Mechanisms of Negative Symptoms in Schizophrenia

Cited by 14 publications

References 72 publications

Cognition and Reward Circuits in Schizophrenia: Synergistic, Not Separate

Cognition and Reward Circuits in Schizophrenia: Synergistic, Not Separate

Reconsidering the Latent Structure of Negative Symptoms in Schizophrenia: A Review of Evidence Supporting the 5 Consensus Domains

The influence of reinforcement schedule on experience‐dependent changes in motivation

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