Cognitive performance and response inhibition in developmentally vitamin D (DVD)-deficient rats

Evidence from epidemiological studies suggest that low levels of vitamin D during early life alter brain development and may increase the risk of various adverse health outcomes, including schizophrenia. The aim of this experiment was to examine the effect of developmental vitamin D (DVD) deficiency on attentional processing using the 5-choice serial reaction time task (5C-SRT) and the 5-choice continuous performance test (5C-CPT), which specifically assesses sustained attention and vigilance in rodents. DVD-deficient and control rats were exposed to a series of target and non-target trials within each operant testing session. A number of measures were recorded including hit, miss, false alarm and correct rejection, as well as premature and perseverative responses. Performance on 5C-CPT was also assessed after administration of the atypical antipsychotic, clozapine. The adult offspring of DVD-deficient rats had higher levels of impulsivity, as demonstrated by a significant increase in premature responses. On the 5C-SRT and target trials of the 5C-CPT, accuracy was not significantly affected by prenatal diet; however DVD-deficient rats made 50% fewer correct rejections compared to controls on non-target trials of the 5C-CPT. Thus, control rats were able to discriminate between target and non-target trials, whereas DVD-deficient rats were unable to make this discrimination. Clozapine reduced the occurrence of false alarms in DVD-deficient rats to a level comparable to control values. Taken together these data suggest DVD-deficient rats have increased impulsivity as well as a lack of inhibitory control, and these features may be informative in terms of modeling the cognitive deficits observed in schizophrenia

Attentional Processing in C57BL/6J Mice Exposed to Developmental Vitamin D Deficiency

Epidemiological evidence suggests that Developmental Vitamin D (DVD) deficiency is associated with an increased risk of schizophrenia. DVD deficiency in mice is associated with altered behaviour, however there has been no detailed investigation of cognitive behaviours in DVD-deficient mice. The aim of this study was to determine the effect of DVD deficiency on a range of cognitive tasks assessing attentional processing in C57BL/6J mice. DVD deficiency was established by feeding female C57BL/6J mice a vitamin D-deficient diet from four weeks of age. After six weeks on the diet, vitamin D-deficient and control females were mated with vitamin D-normal males and upon birth of the pups, all dams were returned to a diet containing vitamin D. The adult offspring were tested on a range of cognitive behavioural tests, including the five-choice serial reaction task (5C-SRT) and five-choice continuous performance test (5C-CPT), as well as latent inhibition using a fear conditioning paradigm. DVD deficiency was not associated with altered attentional performance on the 5C-SRT. In the 5C-CPT DVD-deficient male mice exhibited an impairment in inhibiting repetitive responses by making more perseverative responses, with no changes in premature or false alarm responding. DVD deficiency did not affect the acquisition or retention of cued fear conditioning, nor did it affect the expression of latent inhibition using a fear conditioning paradigm. DVD-deficient mice exhibited no major impairments in any of the cognitive domains tested. However, impairments in perseverative responding in DVD-deficient mice may indicate that these animals have specific alterations in systems governing compulsive or reward-seeking behaviour

Interaction of genotype and environment: effect of strain and housing conditions on cognitive behavior in rodent models of schizophrenia

Schizophrenia is associated with many genetic and environmental risk factors and there is growing evidence that the interactions between genetic and environmental "hits" are critical for disease onset. Animal models of schizophrenia have traditionally used specific strain and housing conditions to test potential risk factors. As the field moves towards testing gene (G) x environment (E) interactions the impact of these choices should be considered. Given the surge of research focused on cognitive deficits, we have examined studies of cognition in rodents from the perspective of GxE interactions, in which strain or housing manipulations have been varied. Behavior is clearly altered by these factors, yet few animal models of schizophrenia have investigated cognitive deficits using different strain and housing conditions. It is important to recognise the large variation in behavior observed when using different strain and housing combinations because GxE interactions may mask or exacerbate cognitive outcomes. Further consideration will improve our understanding of GxE interactions and the underlying neurobiology of cognitive impairments in neuropsychiatric disorders

Baseline-dependent effects of amphetamine on attention are associated with striatal dopamine metabolism

Psychostimulants, such as amphetamine, are widely used to treat attentional deficits. In humans, response to dopaminergic medications is complex with improvement often dependent on baseline performance. Our goal was to determine if attention in rats could be improved by low dose amphetamine in a baseline-dependent manner by examining the relationship between task performance, drug response and monoamine levels in corticostriatal tissue. Firstly, rats performed a signal detection task with varying signal durations before administration of saline, 0.1 or 0.25 mg/kg amphetamine. Following 0.1 mg/kg amphetamine, accuracy in poor performing individuals increased to that of high performing rats. Furthermore, baseline accuracy correlated with the magnitude of improvement after amphetamine. Secondly, neurochemical analysis of monoamine content and gene expression levels in the prefrontal cortex (PFC) and dorsal striatum (CPU) was conducted. CPU homovanillic acid and 5-hydroxyindoleacetic acid levels were increased in poor performers with a significant correlation between the expression of the dopamine transporter gene and baseline accuracy. No changes were found in the PFC. These results indicated poor performance was associated with greater response to amphetamine and altered DA and 5-HT neurotransmitter systems in CPU. These results suggest striatal monoamine function may be fundamental to explaining individual differences in psychostimulant response

Measuring attention in rodents: comparison of a modified signal detection task and the 5-choice serial reaction time task

Neuropsychiatric research has utilized cognitive testing in rodents to improve our understanding of cognitive deficits and for preclinical drug development. However, more sophisticated cognitive tasks have not been as widely exploited due to low throughput and the extensive training time required. We developed a modified signal detection task (SDT) based on the growing body of literature aimed at improving cognitive testing in rodents. This study directly compares performance on the modified SDT with a traditional test for measuring attention, the 5-choice serial reaction time task (5CSRTT). Adult male Sprague-Dawley rats were trained on either the 5CSRTT or the SDT. Briefly, the 5CSRTT required rodents to pay attention to a spatial array of five apertures and respond with a nose poke when an aperture was illuminated. The SDT required the rat to attend to a light panel and respond either left or right to indicate the presence of a signal. In addition, modifications were made to the reward delivery, timing, control of body positioning, and the self-initiation of trials. It was found that less training time was required for the SDT, with both sessions to criteria and daily session duration significantly reduced. Rats performed with a high level of accuracy (>87%) on both tasks, however omissions were far more frequent on the 5CSRTT. The signal duration was reduced on both tasks as a manipulation of task difficulty relevant to attention and a similar pattern of decreasing accuracy was observed on both tasks. These results demonstrate some of the advantages of the SDT over the traditional 5CSRTT as being higher throughput with reduced training time, fewer omission responses and their body position was controlled at stimulus onset. In addition, rats performing the SDT had comparable high levels of accuracy. These results highlight the differences and similarities between the 5CSRTT and a modified SDT as tools for assessing attention in preclinical animal models

Pre-pulse Inhibition.

<p>(A,B) Acoustic startle response in SD (left panels) and LE (right panels) rats demonstrating increasing startle amplitude with louder acoustic pulses. (C,D) Habituation of the startle response to 110 db pulses presented at the start, middle and end of the session showing a clear within-session reduction in LE rats compared to SD rats, such that there was a main effect of strain at the end of the session (<i>F</i>_(1,30) = 7.96, <i>p</i> = .009). (E,F) %PPI is presented as each intensity (74, 78 and 86 dB) averaged across different six pre-pulse intervals. %PPI at 74 dB was significantly reduced in SD rats housed in enrichment compared to standard housed rats (<i>t</i>₍₁₃₎ = −2.31, <i>p</i> = .038). Variability of PPI within LE rats was noticeably greater than in SD rats and no significant effect of housing was found. (G,H) %PPI for each pre-pulse interval (averages across the three intensities) shows reduced PPI at 64 ms in SD rats from enriched cages compared to standard housed SD rats (<i>t</i>_(8.27) = −2.40, <i>p</i> = .042) while LE rats from both housing conditions did not differ. Standard housing (open), enriched housing (closed). Data presented as mean ± S.E.M.*p<0.05.</p

Comprehensive Behavioural Analysis of Long Evans and Sprague-Dawley Rats Reveals Differential Effects of Housing Conditions on Tests Relevant to Neuropsychiatric Disorders

<div><p>Genetic (G) and environmental (E) manipulations are known to alter behavioural outcomes in rodents, however many animal models of neuropsychiatric disorders only use a restricted selection of strain and housing conditions. The aim of this study was to examine GxE interactions comparing two outbred rat strains, which were housed in either standard or enriched cages. The strains selected were the albino Sprague-Dawley rat, commonly used for animal models, and the other was the pigmented Long Evans rat, which is frequently used in cognitive studies. Rats were assessed using a comprehensive behavioural test battery and included well-established tests frequently employed to examine animal models of neuropsychiatric diseases, measuring aspects of anxiety, exploration, sensorimotor gating and cognition. Selective strain and housing effects were observed on a number of tests. These included increased locomotion and reduced pre-pulse inhibition in Long Evans rats compared to Sprague Dawley rats; and rats housed in enriched cages had reduced anxiety-like behaviour compared to standard housed rats. Long Evans rats required fewer sessions than Sprague Dawley rats to learn operant tasks, including a signal detection task and reversal learning. Furthermore, Long Evans rats housed in enriched cages acquired simple operant tasks faster than standard housed Long Evans rats. Cognitive phenotypes in animal models of neuropsychiatric disorders would benefit from using strain and housing conditions where there is greater potential for both enhancement and deficits in performance.</p></div

Operant training.

<p>(A) Fixed ratio (FR1) training in LE rats, showing the number of trials completed was greater in enriched rats compared to those from standard housing conditions after 3 days of training (<i>t₍₁₃₎</i> = 2.41, <i>p</i> = .032). (B) On the first session of learning to nose poke to receive a food reward, LE rats completed more trials than SD rats (<i>F</i>_(1,31) = 26.3, <i>p</i><0.001). Additionally, LE rats from enriched housing successfully performed more trials compared to those from standard housing (t(13) = 2.41, p = .032). (C) The number of sessions required to reach criteria on a signal detection task (SDT) was greater in SD rats compared to LE (F(1,31) = 6.47; p = .017). (D) LE rats were able to acquire the reversed contingency on SDT in fewer sessions than SD rats (F(1,31) = 21.21, p<0.001). Standard housing (open), enriched housing (closed). Data presented as mean ± S.E.M.*p<0.05.</p

Behavioural Test Battery. Key behavioural parameters from each test in the behaviour screen for Sprague Dawley and Long Evans rats housed in standard or enriched conditions.

<p>Data are presented as mean ± SEM and statistical results for strain comparison. Main effect of Strain and Housing was assessed by ANOVA and independent-samples <i>t</i>-tests were then performed if a significant Strain*Housing interaction was detected; *p<0.05, **p<0.01.</p

Growth Curve.

<p>The body weight of Sprague Dawley (SD, circles) and Long Evans (LE, squares) rats from 3–16 weeks of age housed in either standard (SH, open) or enriched (EE, closed) housing. Overall, there was a main effect of strain (<i>F</i>_(1,28) = 54.75, <i>p</i><0.001), but not housing (<i>F</i>_(1,28) = 0.24, <i>p</i> = 0.625). LE rats tended to separate more towards the end of the experiment, however this was not significant even at 16 weeks (<i>t</i>_(10.85) = 2.18, <i>p</i> = 0.052).</p