Opposing Roles of the Dorsolateral and Dorsomedial Striatum in the Acquisition of Skilled Action Sequencing in Rats.

The shift in control from dorsomedial to dorsolateral striatum during skill and habit formation has been well established, but whether striatal subregions orchestrate this shift cooperatively or competitively remains unclear. Cortical inputs have also been implicated in the shift toward automaticity, but it is unknown whether they mirror their downstream striatal targets across this transition. We addressed these questions using a five step heterogeneous action sequencing task in male rats that is optimally performed by automated chains of actions. By optimizing automatic habitual responding, we discovered that loss of function in the dorsomedial striatum accelerated sequence acquisition. In contrast, loss of function in the dorsolateral striatum impeded acquisition of sequencing, demonstrating functional opposition within the striatum. Unexpectedly, the mPFC was not involved; however, the lateral orbitofrontal cortex was critical. These results shift current theories about striatal control of behavior to a model of competitive opposition, where the dorsomedial striatum interferes with the development of dorsolateral-striatum dependent behavior.SIGNIFICANCE STATEMENT We provide the most direct evidence to date that the dorsomedial and dorsolateral striatum compete for control in the acquisition of habitual action sequences. The dorsolateral striatum was critical for sequencing behavior, but loss of dorsomedial striatum function enhanced acquisition. In addition, we found that the mPFC was not required for the formation of automated actions. Using a task that optimizes habitual responding, we demonstrate that the arbitration of dorsomedial and dorsolateral control is not modulated by medial prefrontal cortical activity. However, we find evidence for the role of the lateral orbitofrontal cortex in action sequencing. These results have implications for our understanding of how habits and skills form.

Developmentally vitamin D-deficient rats show enhanced prepulse inhibition after acute Δ9-tetrahydrocannabinol.

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD-deficient rats show selective cognitive deficits and novelty-induced hyperlocomotion and enhanced locomotor responses from acute treatment with psychomimetic drugs, such as amphetamine and MK-801. Here we aimed to examine the effect of a drug from a different class of psychomimetic/psychoactive compounds, Δ9-tetrahydrocannabinol (THC), on tasks of relevance to the cognitive and positive symptoms of schizophrenia. The aim of this study was to investigate whether DVD deficiency modulates the behavioural effects of THC on tests of delay-dependent memory, sensorimotor gating and locomotion. Adult control and DVD-deficient rats were injected with THC (0, 0.3, 0.6, 1.25, 2.5 mg/kg) 15 min before a delay match to sample (DMTS) task using variable delays (0-24 s). A separate group of rats was injected with either 2.5 mg/kg THC or vehicle before tests of either prepulse inhibition (PPI) of the acoustic startle response or in the open field. Control and DVD-deficient rats showed a similar dose-dependent impairment in performance on the DMTS. The greatest impairment was observed at 2.5 mg/kg for all delays (0-24 s). DVD-deficient rats showed THC-induced enhancement of PPI, which was not observed in control rats. There was no effect of maternal diet on acoustic startle response or locomotor responses in the open field. This study reports the novel findings that DVD-deficient rats were more sensitive to the acute effects of THC on PPI. It appears that prenatal vitamin D deficiency has long-term effects on sensitivity to the behavioural effects of cannabinoids.

Does disrupting the orbitofrontal cortex alter sensitivity to punishment? A potential mechanism of compulsivity.

Abnormal orbitofrontal cortex (OFC) activity is one of the most common findings from neuroimaging studies of individuals with compulsive disorders such as substance use disorder and obsessive-compulsive disorder. The nature of this abnormality is complex, however, with some studies reporting the OFC to be over-active in compulsive individuals relative to controls, whereas other studies report it being under-active, and a further set of studies reporting OFC abnormality in both directions within the same individuals. The OFC has been implicated in a broad range of cognitive processes such as decision-making and goal-directed action. OFC dysfunction could thus impair decision-making and goal-directed action, leading to the kinds of cognitive/behavioral deficits observed in individuals with compulsive disorders. One such deficit that could arise as a result of OFC dysfunction is an altered sensitivity to punishment, which is one of the core characteristics displayed by individuals across multiple types of compulsive disorders. It is, therefore, the aim of the current review to assess the evidence implicating the OFC in adaptation to punishment and to attempt to identify the critical factors that determine this relationship. We distill from this analysis some guidelines for future studies attempting to determine the precise role of the OFC in punishment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Prefrontal regulation of behavioural control: Evidence from learning theory and translational approaches in rodents.

Everyday activities require adaptive decision-making and control over our actions to achieve our goals. Sub-regions within the cortex are widely reported to regulate these choices. Here we review rodent studies from two disparate fields of instrumental action control - goal-directed and habitual responding, and impulsive and compulsive behaviour. Our aim was to compare findings across the spectrum, from precision associative learning to translational studies of action control. The evidence suggests that each cortical sub-region performs different roles depending on task requirements and, within tasks, clear dissociations exist between regions. Rather than synthesizing a single role or function for a given region, we should consider regions to be capable of many different functions. Further investigation of cortico-cortical connections and the pattern of input and output circuitry within each region may be needed to identify unique process-specific pathways. Despite differences in the scope and purpose of these two fields, integrating evidence across tasks provides a broader context for testing hypotheses about the role of cortical regions in adaptive actions and decision-making.

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.

BALB/c Mice Can Learn Touchscreen Visual Discrimination and Reversal Tasks Faster than C57BL/6 Mice.

Touchscreen technology is increasingly being used to characterize cognitive performance in rodent models of neuropsychiatric disorders. Researchers are attracted to the automated system and translational potential for touchscreen-based tasks. However, training time is extensive and some mouse strains have struggled to learn touchscreen tasks. Here we compared the performance of commonly used C57BL/6 mice against the BALB/c mice, which are considered a poor performing strain, using a touchscreen task. BALB/c and C57BL/6 mice were trained to operate the touchscreens before learning a visual discrimination (VD) and reversal task. Following touchscreen testing, these strains were assessed for differences in locomotion and learned helplessness. BALB/c mice finished training in nearly half the number of sessions taken by C57BL/6 mice. Following training, mice learned a VD task where BALB/c mice again reached criteria in fewer than half the sessions required for C57BL/6 mice. Once acquired, there were no strain differences in % correct responses, correction trials or response latency. BALB/c mice also learnt the reversal task in significantly fewer sessions than C57BL/6 mice. On the open field test C57BL/6 mice traveled further and spent more time in the center, and spent less time immobile than BALB/c mice on the forced swim test (FST). After touchscreen testing, strains exhibited well-established behavioral traits demonstrating the extensive training and handling from touchscreen testing did not alter their behavioral phenotype. These results suggest that BALB/c mice can be examined using touchscreen tasks and that task adaptations may improve feasibility for researchers using different strains.

Touchscreen-based Visual Discrimination and Reversal Tasks for Mice to Test Cognitive Flexibility.

Reversal learning can be used to examine deficits in cognitive flexibility, which have been linked to a number of neuropsychiatric disorders including schizophrenia and addiction. However, methods of examining reversal learning have varied substantially between species. Touchscreen technology has allowed researchers to explore cognitive deficits with a platform that is translatable across rodents, non-human primates and human subjects. Here we describe a method for measuring visual discrimination and reversal learning in mice using automated touchscreen-based operant chambers.

Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain.

BACKGROUND: Epidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. METHODS: Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue. RESULTS: Ubiquitous reductions in the levels of glutamine (12-24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. CONCLUSIONS: Our results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat brain.

Improvement of attention with amphetamine in low- and high-performing rats.

RATIONALE: Attentional deficits occur in a range of neuropsychiatric disorders, such as schizophrenia and attention deficit hyperactivity disorder. Psychostimulants are one of the main treatments for attentional deficits, yet there are limited reports of procognitive effects of amphetamine in preclinical studies. Therefore, task development may be needed to improve predictive validity when measuring attention in rodents. OBJECTIVES: This study aimed to use a modified signal detection task (SDT) to determine if and at what doses amphetamine could improve attention in rats. METHODS: Sprague-Dawley rats were trained on the SDT prior to amphetamine challenge (0.1, 0.25, 0.75 and 1.25 mg/kg). This dose range was predicted to enhance and disrupt cognition with the effect differing between individuals depending on baseline performance. RESULTS: Acute low dose amphetamine (0.1 and 0.25 mg/kg) improved accuracy, while the highest dose (1.25 mg/kg) significantly disrupted performance. The effects differed for low- and high-performing groups across these doses. The effect of amphetamine on accuracy was found to significantly correlate with baseline performance in rats. CONCLUSIONS: This study demonstrates that improvement in attentional performance with systemic amphetamine is dependent on baseline accuracy in rats. Indicative of the inverted U-shaped relationship between dopamine and cognition, there was a baseline-dependent shift in performance with increasing doses of amphetamine. The SDT may be a useful tool for investigating individual differences in attention and response to psychostimulants in rodents.

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.

MK-801-induced behavioural sensitisation alters dopamine release and turnover in rat prefrontal cortex.

RATIONALE: Repeated exposure to psychostimulants that either increase dopamine (DA) release or target N-methyl-D-aspartate (NMDA) receptors can induce behavioural sensitisation, a phenomenon that may be important for the processes of addiction and even psychosis. A critical component of behavioural sensitisation is an increase in DA release within mesocorticolimbic circuits. In particular, sensitisation to amphetamine leads to increased DA release within well-known sub-cortical brain regions and also regulatory regions such as prefrontal cortex (PFC). However, it is unknown how DA release within the PFC of animals is altered by sensitisation to NMDA receptor antagonists. OBJECTIVES: The aims of the present study were twofold, firstly to examine whether a single dose of dizocilpine maleate (MK-801) could induce long-term behavioural sensitisation and secondly to examine DA release in the PFC of sensitised rats. MATERIALS AND METHODS: Behavioural sensitisation was assessed by measuring locomotion after drug exposure. DA release in the PFC was measured using freely moving microdialysis. RESULTS: We show that a single dose of MK-801 can induce sensitisation to subsequent MK-801 exposure in a high percentage of rats (66 %). Furthermore, rats sensitised to MK-801 have altered DA release and turnover in the PFC compared with non-sensitised rats. CONCLUSION: Schizophrenia patients have been postulated to have 'endogenous sensitisation' to psychostimulants. MK-801-induced sensitised rats, in particular when compared with non-sensitised rats, provide a useful model for studying PFC dysfunction in schizophrenia.

Comprehensive behavioural analysis of Long Evans and Sprague-Dawley rats reveals differential effects of housing conditions on tests relevant to neuropsychiatric disorders.

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.

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.

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.

The impact of adult vitamin D deficiency on behaviour and brain function in male Sprague-Dawley rats.

BACKGROUND: Vitamin D deficiency is common in the adult population, and this has been linked to depression and cognitive outcomes in clinical populations. The aim of this study was to investigate the effects of adult vitamin D (AVD) deficiency on behavioural tasks of relevance to neuropsychiatric disorders in male Sprague-Dawley rats. METHODS: Ten-week old male Sprague-Dawley rats were fed a control or vitamin D deficient diet for 6 weeks prior to, and during behavioural testing. We first examined a range of behavioural domains including locomotion, exploration, anxiety, social behaviour, learned helplessness, sensorimotor gating, and nociception. We then assessed locomotor response to the psychomimetic drugs, amphetamine and MK-801. Attention and vigilance were assessed using the 5 choice serial reaction time task (5C-SRT) and the 5 choice continuous performance task (5C-CPT) and, in a separate cohort, working memory was assessed using the delay match to sample (DMTS) task. We also examined excitatory and inhibitory neurotransmitters in prefrontal cortex and striatum. RESULTS: AVD-deficient rats were deficient in vitamin D3 (<10 nM) and had normal calcium and phosphate levels after 8-10 weeks on the diet. Overall, AVD deficiency was not associated with an altered phenotype across the range of behavioural domains tested. On the 5C-SRT AVD-deficient rats made more premature responses and more head entries during longer inter-trial intervals (ITI) than control rats. On the 5C-CPT AVD-deficient rats took longer to make false alarm (FA) responses than control rats. AVD-deficient rats had increases in baseline GABA levels and the ratio of DOPAC/HVA within the striatum. CONCLUSIONS: AVD-deficient rats exhibited no major impairments in any of the behavioural domains tested. Impairments in premature responses in AVD-deficient rats may indicate that these animals have specific alterations in striatal systems governing compulsive or reward-seeking behaviour.

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.

Transient knockdown of tyrosine hydroxylase during development has persistent effects on behaviour in adult zebrafish (Danio rerio).

Abnormal dopamine (DA) signaling is often suggested as causative in schizophrenia. The other prominent hypothesis for this disorder, largely driven by epidemiological data, is that certain adverse events during the early stages of brain development increase an individual's risk of developing schizophrenia later in life. However, the clinical and preclinical literature consistently implicates behavioural, cognitive, and pharmacological abnormalities, implying that DA signaling is abnormal in the adult brain. How can we reconcile these two major hypotheses underlying much of the clinical and basic research into schizophrenia? In this study we have transiently knocked down tyrosine hydroxylase (TH, the rate limiting enzyme in DA synthesis) gene expression in the early stages of brain development in zebrafish using morpholinos. We show that by adulthood, TH and DA levels have returned to normal and basic DA-mediated behaviours, such as locomotion, are also normal. However, when they were exposed to a novel environment the levels of freezing and immediate positioning in deeper zones were significantly reduced in these adult fish. The neurochemistry underlying these behaviours is complex, and the exact mechanisms for these abnormal behaviours remains unknown. This study demonstrates that early transient alterations in DA ontogeny can produce persistent alterations in adult brain function and suggests that the zebrafish may be a promising model animal for future studies directed at clarifying the basic neurodevelopmental mechanisms behind complex psychiatric disease.