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      The dynamic strategy shifting task: Optimisation of an operant task for assessing cognitive flexibility in rats

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          Abstract

          Introduction

          Although schizophrenia is associated with a broad range of symptoms including hallucinations, delusions, and reduced motivation, measures of cognitive dysfunction, including cognitive flexibility and executive function, are the strongest predictors of functional outcomes. Antipsychotic medications are useful for reducing psychotic symptoms, but they are ineffective at improving cognitive deficits. Despite extensive investment by industry, the transition from preclinical to clinical trials has not been successful for developing precognitive medications for individuals with schizophrenia. Here, we describe the optimisation of a novel dynamic strategy shifting task (DSST) using standard operant chambers to investigate the optimal stimuli required to limit the extensive training times required in previous tasks.

          Methods

          We determined that optimal learning by male and female Sprague Dawley rats for the flexibility task incorporated dynamic strategy shifts between spatial rules, such as following a visual cue or responding at one location, and non-spatial rules, such as responding to a central visual or auditory cue. A minimum of 6 correct consecutive responses were required to make a within-session change in the behavioural strategies. As a proof of concept, we trained and tested 84 Sprague Dawley rats on the DSST, and then assessed their cognitive flexibility using a within-subject design after an acute dose of ketamine (0, 3, 10 mg/kg). Rats made fewer premature and more perseverant responses to initiate a trial following ketamine. The effects of ketamine on trials to criterion was dependent on the rule.

          Results

          Ketamine induced a significant improvement on the reversal of a non-spatial visual discrimination rule. There was no significant effect of ketamine on the spatial visual or response discrimination rules.

          Discussion

          The DSST is a novel assay for studying distinct forms of cognitive flexibility and offers a rapid and adaptable means of assessing the ability to shift between increasingly challenging rule conditions. The DSST has potential utility in advancing our understanding of cognitive processes and the underlying neurobiological mechanisms related to flexibility in neuropsychiatric and neurological conditions where executive dysfunctions occur.>

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          Most cited references61

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          Executive Functions

          Executive functions (EFs) make possible mentally playing with ideas; taking the time to think before acting; meeting novel, unanticipated challenges; resisting temptations; and staying focused. Core EFs are inhibition [response inhibition (self-control—resisting temptations and resisting acting impulsively) and interference control (selective attention and cognitive inhibition)], working memory, and cognitive flexibility (including creatively thinking “outside the box,” seeing anything from different perspectives, and quickly and flexibly adapting to changed circumstances). The developmental progression and representative measures of each are discussed. Controversies are addressed (e.g., the relation between EFs and fluid intelligence, self-regulation, executive attention, and effortful control, and the relation between working memory and inhibition and attention). The importance of social, emotional, and physical health for cognitive health is discussed because stress, lack of sleep, loneliness, or lack of exercise each impair EFs. That EFs are trainable and can be improved with practice is addressed, including diverse methods tried thus far.
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            Schizophrenia: a concise overview of incidence, prevalence, and mortality.

            Recent systematic reviews have encouraged the psychiatric research community to reevaluate the contours of schizophrenia epidemiology. This paper provides a concise overview of three related systematic reviews on the incidence, prevalence, and mortality associated with schizophrenia. The reviews shared key methodological features regarding search strategies, analysis of the distribution of the frequency estimates, and exploration of the influence of key variables (sex, migrant status, urbanicity, secular trend, economic status, and latitude). Contrary to previous interpretations, the incidence of schizophrenia shows prominent variation between sites. The median incidence of schizophrenia was 15.2/100,000 persons, and the central 80% of estimates varied over a fivefold range (7.7-43.0/100,000). The rate ratio for males:females was 1.4:1. Prevalence estimates also show prominent variation. The median lifetime morbid risk for schizophrenia was 7.2/1,000 persons. On the basis of the standardized mortality ratio, people with schizophrenia have a two- to threefold increased risk of dying (median standardized mortality ratio = 2.6 for all-cause mortality), and this differential gap in mortality has increased over recent decades. Compared with native-born individuals, migrants have an increased incidence and prevalence of schizophrenia. Exposures related to urbanicity, economic status, and latitude are also associated with various frequency measures. In conclusion, the epidemiology of schizophrenia is characterized by prominent variability and gradients that can help guide future research.
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              Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants.

              Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2599245Role: Role: Role: Role: Role: Role: Role: Role:
                Role: Role: Role: Role:
                URI : https://loop.frontiersin.org/people/97920Role: Role: Role:
                URI : https://loop.frontiersin.org/people/30985Role: Role: Role: Role: Role: Role: Role: Role:
                Journal
                Front Psychiatry
                Front Psychiatry
                Front. Psychiatry
                Frontiers in Psychiatry
                Frontiers Media S.A.
                1664-0640
                28 June 2024
                2024
                : 15
                : 1303728
                Affiliations
                [1] 1 Queensland Brain Institute, The University of Queensland , St Lucia, QLD, Australia
                [2] 2 Queensland Centre for Mental Health Research, The Park Centre for Mental Health , Wacol, QLD, Australia
                Author notes

                Edited by: Tertia Purves-Tyson, Neuroscience Research Australia, Australia

                Reviewed by: Sj Owens, University of New South Wales, Australia

                Lorenz S. Neuwirth, State University of New York at Old Westbury, United States

                *Correspondence: Thomas Henry Burne, t.burne@ 123456uq.edu.au
                Article
                10.3389/fpsyt.2024.1303728
                11240049
                1dba88e2-ba76-43e5-baf9-e0d776595d10
                Copyright © 2024 Flintoff, Alexander, Kesby and Burne

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 September 2023
                : 06 June 2024
                Page count
                Figures: 7, Tables: 2, Equations: 0, References: 61, Pages: 16, Words: 9524
                Funding
                Funded by: National Health and Medical Research Council , doi 10.13039/501100000925;
                Award ID: APP1078159, APP1099709
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. JF was supported by an Australian Government Research Training Program Scholarship, and top-up funding was provided through the Queensland Brain Institute, University of Queensland. This research was supported from core funding from the Queensland Centre for Mental Health Research and grants from National Health and Medical Research Council (APP1078159, APP1099709 and 2020567) awarded to TB.
                Categories
                Psychiatry
                Original Research
                Custom metadata
                Molecular Psychiatry

                Clinical Psychology & Psychiatry
                cognitive flexibility,strategy-shifting,operant tasks,neuropsychiatric disease,translational research

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