Flintoff Jonathan Martin, Alexander Suzy, Kesby James Paul, Burne Thomas Henry
Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia.
Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, QLD, Australia.
Front Psychiatry. 2024 Jun 28;15:1303728. doi: 10.3389/fpsyt.2024.1303728. eCollection 2024.
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.
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.
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.
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.>.
尽管精神分裂症与包括幻觉、妄想和动机减退在内的广泛症状相关，但认知功能障碍的指标，包括认知灵活性和执行功能，是功能预后的最强预测因素。抗精神病药物有助于减轻精神病症状，但对改善认知缺陷无效。尽管业界投入巨大，但针对精神分裂症患者开发认知前药物从临床前试验到临床试验的转化并不成功。在此，我们描述了一种新型动态策略转换任务（DSST）的优化，该任务使用标准操作箱来研究限制先前任务所需大量训练时间所需的最佳刺激。
我们确定，雄性和雌性斯普拉格-道利大鼠在灵活性任务中的最佳学习包括在空间规则（如遵循视觉线索或在一个位置做出反应）和非空间规则（如对中央视觉或听觉线索做出反应）之间进行动态策略转换。在行为策略上进行会话内改变需要至少连续6次正确反应。作为概念验证，我们在DSST上训练并测试了84只斯普拉格-道利大鼠，然后在急性给予氯胺酮（0、3、10mg/kg）后，使用受试者内设计评估它们的认知灵活性。氯胺酮给药后，大鼠开始试验时的过早反应减少，持续反应增多。氯胺酮对达到标准试验次数的影响取决于规则。
氯胺酮显著改善了非空间视觉辨别规则的反转。氯胺酮对空间视觉或反应辨别规则没有显著影响。
DSST是一种用于研究不同形式认知灵活性的新型检测方法，为评估在日益具有挑战性的规则条件之间转换的能力提供了一种快速且适应性强的手段。DSST在推进我们对认知过程以及与执行功能障碍发生的神经精神和神经疾病中的灵活性相关的潜在神经生物学机制的理解方面具有潜在效用。
