Early-life stress is an established risk for the development of psychiatric disorders. Post-weaning isolation rearing of rats produces lasting developmental changes in behavior and brain function that may have translational pathophysiological relevance to alterations seen in schizophrenia, but the underlying mechanisms are unclear. Accumulating evidence supports the premise that gut microbiota influence brain development and function by affecting inflammatory mediators, the hypothalamic-pituitaryadrenal axis and neurotransmission, but there is little knowledge of whether the microbiota-gut-brain axis might contribute to the development of schizophrenia-related behaviors. To this end the effects of social isolation (SI; a well-validated animal model for schizophrenia)-induced changes in rat behavior were correlated with alterations in gut microbiota, hippocampal neurogenesis and brain cytokine levels. Twenty-four male Lister hooded rats were housed in social groups (group-housed, GH, 3 littermates per cage) or alone (SI) from weaning (post-natal day 24) for four weeks before recording open field exploration, locomotor activity/novel object discrimination (NOD), elevated plus maze, conditioned freezing response (CFR) and restraint stress at one week intervals. Post-mortem caecal microbiota composition, cortical and hippocampal cytokines and neurogenesis were correlated to indices of behavioral changes. SI rats were hyperactive in the open field and locomotor activity chambers traveling further than GH controls in the less aversive peripheral zone. While SI rats showed few alterations in plus maze or NOD they froze for significantly less time than GH following conditioning in the CFR paradigm, consistent with impaired associative learning and memory. SI rats had significantly fewer BrdU/NeuN positive cells in the dentate gyrus than GH controls. SI rats had altered microbiota composition with increases in Actinobacteria and decreases in the class Clostridia compared to GH controls. Differences were also noted at genus level. Positive correlations were seen between microbiota, hippocampal IL-6 and IL-10, conditioned freezing and open field exploration. Adverse early-life stress resulting from continuous SI increased several indices of 'anxiety-like' behavior and impaired associative learning and memory accompanied by changes to gut microbiota, reduced hippocampal IL-6, IL-10 and neurogenesis. This study suggests that early-life stress may produce long-lasting changes in gut microbiota contributing to development of abnormal neuronal and endocrine function and behavior which could play a pivotal role in the aetiology of psychiatric illness.

Major depressive disorder (MDD) is the leading cause of disability worldwide. The majority of antidepressant drugs require several weeks or months of treatment to demonstrate efficacy and a subset of patients are resistant to such interventions. Ketamine demonstrates rapid and long-lasting antidepressant effects in treatment resistant patients; however, side effects may limit its widespread clinical utility. The pharmaceutical industry is engaged in developing novel rapid-acting antidepressant drugs and the establishment of clinically relevant assays are needed to advance this process. Wistar Kyoto (WKY) rats are a valuable model of many of the characteristics of MDD and their resistance to selective serotonin reuptake inhibitors (SSRIs) in several behavioral paradigms emulates treatment resistance in clinical populations. Here, we confirmed the depressive-like phenotype of WKY rats in comparison to Sprague Dawley rats, characterized by increased immobility in the forced swim test, decreased locomotor activity and entries to the centre in the open field test, anhedonia in the female urine sniffing test and working memory deficits in the delayed non-match to position task. Single subcutaneous administration of 5 mg/kg ketamine in WKY rats mirrored the plasma exposure produced by the antidepressant dose in the clinic and rescued depressive-like behaviors. The same dose induced transient side effects, including decreased locomotor activity and reduced positive affect-associated vocalizations. Furthermore, ketamine acutely impaired working memory but induced pro-cognitive effects at a later time point. These data confirm the WKY rat as a preclinical model of depression. Ketamine's efficacy in recovering this depressive-like phenotype while inducing transient dissociative-like effects supports this as a translational model suitable for investigating novel antidepressant drugs.

Background Cognitive ability declines with age, ranging from normal age‐related decline (Craik and Bialystok, 2006), to mild cognitive impairment (Gauthier et al., 2006), and to dementias like Alzheimer’s disease (Perry and Hodges, 1999). One domain which is particularly affected is executive function (Lien et al., 2008). Attentional set‐shifting and reversal learning tasks have been widely used to quantify executive dysfunction in older humans (Robbins et al., 1998) and rats (Schoenbaum et al., 2006). Here, we describe the establishment of an operant conditioning task to assess reversal learning in rats. We investigated a series of pharmacological interventions, including drugs affecting cholinergic and serotonergic transmission, previously shown to have pro‐cognitive effects in animal models and humans. Method The reversal learning task utilises a rule learning (non‐match response) protocol with a reversal (match response) component. After a week’s habituation to the operant chambers and the task, male Sprague Dawley rats (n = 10 per group) were trained to a criteria of above 90% correct on the non‐match response (approximately 10 days). Following reversal of the correct response to the match response, rats received daily drug administration prior to the task. The reversal learning phase of the task continued until rats again achieved criteria (90% correct response). Result A number of compounds have been assessed in this reversal paradigm. Pro‐cognitive effects have been observed both using nicotine (acetylcholine receptor agonist; P<0.05 on sessions 5‐8 of reversal compared to control) and SB‐399885 (5‐HT6 antagonist; P<0.05 on session 7 of reversal compared to control). A breakdown of test sessions into smaller trial bins has yielded a better temporal resolution of the data to assess changes within as well as between testing sessions. Conclusion These data demonstrate the successful establishment of an operant reversal learning task in rats. The task is sensitive to pharmacological intervention and therefore can be used to investigate the potential pro‐cognitive effects of drugs under development for treatment of cognitive dysfunction associated with psychiatric and neurodegenerative disease. Future studies in aged animals and disease models will explore the possibility of employing the task to assess disease specific deficits in executive functioning.