Five-choice Serial Reaction Time Task Research Articles

1-aminocyclopropanecarboxylic acid (ACPC) produces procognitive but not antipsychotic-like effects in rats.

RationaleIn addition to the negative and positive symptoms of schizophrenia, cognitive deficits, including prefrontal cortical dysfunction, are now recognized as core features of this disorder. Compounds increasing the NMDA receptor function via the strychnine-insensitive glycine receptors have been proposed as potential antipsychotics. Depending on the ambient concentrations of glutamate and glycine, 1-aminocyclopropanecarboxylic acid (ACPC) behaves as either a partial agonist or a functional antagonist at the strychnine-insensitive glycine receptors.ObjectivesWe investigated the procognitive and antipsychotic-like effects of ACPC in rats treated with phencyclidine (PCP) or ketamine (KET), compounds that produce psychotic-like symptoms in humans and laboratory animals.MethodsCognitive effects were investigated in the novel object recognition (NOR) and attentional set-shifting tests (ASST). In addition, the effects of ACPC were investigated in PCP-induced hyperactivity, conditioned avoidance response (CAR), and prepulse inhibition (PPI) tests. The effects on attention and impulsivity were measured in the five-choice serial reaction time task (5-CSRTT).ResultsACPC (200–400 mg/kg) inhibited memory fading in naive rats and like clozapine prevented PCP- and KET-induced amnesia in the NOR. In naive animals, ACPC at 400 but not 200 mg/kg enhanced cognitive flexibility in the ASST, as the animals required fewer trials to reach the criteria during the extra-dimensional phase. In contrast, ACPC did not affect PCP-induced hyperactivity, CAR, and PPI as well as attention and impulsivity in the 5-CSRTT.ConclusionThe present study demonstrates that ACPC enhanced both object recognition memory and cognitive flexibility dependent on the prefrontal cortex, but did not affect impulsivity nor exhibit an antipsychotic-like profile.

The behavioural response of mice lacking NK₁ receptors to guanfacine resembles its clinical profile in treatment of ADHD.

Background and PurposeMice with functional ablation of substance P-preferring neurokinin-1 receptors (NK1R−/− mice) display behavioural abnormalities resembling those in attention deficit hyperactivity disorder (ADHD). Here, we investigated whether the ADHD treatment, guanfacine, alleviated the hyperactivity and impulsivity/inattention displayed by NK1R−/− mice in the light/dark exploration box (LDEB) and 5-choice serial reaction–time task (5-CSRTT), respectively. Following reports of co-morbid anxiety in ADHD, we also investigated effects of guanfacine on anxiety-like behaviour displayed by NK1R−/− and wild-type (WT) mice in the elevated plus maze (EPM).Experimental ApproachMice were treated with guanfacine (0.1, 0.3 or 1.0 mg·kg−1, i.p.), vehicle or no injection and tested in the 5-CSRTT or the LDEB. Only the lowest dose of guanfacine was used in the EPM assays.Key ResultsIn the 5-CSRTT, a low dose of guanfacine (0.1 mg·kg−1) increased attention in NK1R−/− mice, but not in WT mice. This dose did not affect the total number of trials completed, latencies to respond or locomotor activity in the LDEB. Impulsivity was decreased by the high dose (1.0 mg·kg−1) of guanfacine, but this was evident in both genotypes and is likely to be secondary to a generalized blunting of behaviour. Although the NK1R−/− mice displayed marked anxiety-like behaviour, guanfacine did not affect the behaviour of either genotype in the EPM.Conclusions and ImplicationsThis evidence that guanfacine improves attention at a dose that did not affect arousal or emotionality supports our proposal that NK1R−/− mice express an attention deficit resembling that of ADHD patients.Linked ArticlesThis article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20

Deficit in sustained attention following selective cholinergic lesion of the pedunculopontine tegmental nucleus in rat, as measured with both post-mortem immunocytochemistry and in vivo PET imaging with [18F]fluoroethoxybenzovesamicol

Cholinergic neurons of the pedunculopontine tegmental nucleus (PPTg) are thought to be involved in cognitive functions such as sustained attention, and lesions of these cells have been documented in patients showing fluctuations of attention such as in Parkinson's disease or dementia with Lewy Body. Animal studies have been conducted to support the role of these cells in attention, but the lesions induced in these animals were not specific to the cholinergic PPTg system, and were assessed by post-mortem methods remotely performed from the in vivo behavioral assessments. Moreover, sustained attention have not been directly assessed in these studies, but rather deduced from indirect measurements. In the present study, rats were assessed on the 5-Choice Serial Reaction Time Task (5-CSRTT), and a specific measure of variability in response latency was created. Animals were observed both before and after selective lesion of the PPTg cholinergic neurons. Brain cholinergic denervation was assessed both in vivo and ex vivo, using PET imaging with [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) and immunocytochemistry respectively. Results showed that the number of correct responses and variability in response latency in the 5-CSRTT were the only behavioral measures affected following the lesions. These measures were found to correlate significantly with the number of PPTg cholinergic cells, as measured with both [18F]FEOBV and immunocytochemistry. This suggests the primary role of the PPTg cholinergic cells in sustained attention. It also allows to reliably use the PET imaging with [18F]FEOBV for the purpose of assessing the relationship between behavior and cholinergic innervation in living animals.

Alpha 2A adrenergic receptor agonist, guanfacine, attenuates cocaine-related impairments of inhibitory response control and working memory in animal models

There is considerable evidence that centrally acting α2A adrenergic receptor agonists can attenuate impairments in executive function that result from dysfunction of the prefrontal cortex. Such positive effects resulted in the recent approval by the United States Food and Drug Administration (FDA) of the α2A agonists clonidine and guanfacine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), but also suggest that they could have beneficial effects in substance abuse disorders and other neuropsychiatric conditions. The purpose of this study was to evaluate guanfacine for its ability to attenuate behavioral alterations associated with acute cocaine exposure in rats trained to perform a task of sustained attention, the five choice serial reaction time task (5C-SRTT) and monkeys trained to perform a task of working/short term memory, the delayed match to sample (DMTS) task. In the rodent 5C-SRTT acute intraperitoneal (i.p.) administration of cocaine (3.5–15.0mg/kg) did not affect accuracy, but was associated with dose-dependent increases in premature responses and timeout responses. Guanfacine (0.1–1.0mg/kgi.p.) dose-dependently decreased premature responses and timeout responses associated with cocaine and it attenuated similar deficits in inhibitory response control observed in a variable ITI version of the 5C-SRTT. In the DMTS task in monkeys, acute intramuscular (i.m.) administration of cocaine (4.0mg/kg) was associated with impairments in accuracy at long delay intervals, an effect that was attenuated by guanfacine (0.4mg/kg). These animal studies suggest that guanfacine may have therapeutic potential for treating impairments of executive function that are associated with the abuse of cocaine.

Effects of atomoxetine on attention and impulsivity in the five-choice serial reaction time task in rats with lesions of dorsal noradrenergic ascending bundle.

Atomoxetine, a noradrenaline reuptake inhibitor (NRI), which is a non-stimulating medicine that is used for the treatment of patients with attention deficit hyperactivity disorder (ADHD), has been found to be effective in reducing behavioral impulsivity in rodents, but its efficacy in a dorsal noradrenergic ascending bundle (DNAB)-lesioned condition has not been examined. The present study aimed to investigate the effects of DNAB lesions on attention and impulsive control in the five-choice serial reaction time task (5-CSRTT) in rats treated with atomoxetine. The drug-induced changes in noradrenaline efflux in the medial prefrontal cortex were also measured. 5-CSRTT-trained rats were included in one of the following groups: N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)/Atomoxetine, Sham/Atomoxetine, DSP-4/Saline, or Sham/Saline. Acute atomoxetine (0.3 mg/kg) was administered 14 days after the DSP-4 regime. The behavioral testing included manipulations of the inter-trial interval (ITI), stimulation duration and food satiety. In vivo microdialysis of the noradrenaline efflux in the medial prefrontal cortex and the expression of the noradrenaline transporter (NAT) in the DNAB areas were examined. Atomoxetine reduced impulsivity and perseveration in the long-ITI condition with no effects on any other variables. This phenomenon was not influenced by DSP-4 pre-treatment. The DNAB-lesioned rats had lower noradrenaline efflux in the medial prefrontal cortex. DSP-4 caused no change in NAT expression in the DNAB areas. These findings suggested that noradrenaline reuptake may not be exclusively responsible for the atomoxetine effects in adjusting impulsivity. The role of DNAB should also be considered, particularly in conditions requiring greater behavioral inhibition.

The 5-choice serial reaction time task: a task of attention and impulse control for rodents.

This protocol describes the 5-choice serial reaction time task, which is an operant based task used to study attention and impulse control in rodents. Test day challenges, modifications to the standard task, can be used to systematically tax the neural systems controlling either attention or impulse control. Importantly, these challenges have consistent effects on behavior across laboratories in intact animals and can reveal either enhancements or deficits in cognitive function that are not apparent when rats are only tested on the standard task. The variety of behavioral measures that are collected can be used to determine if other factors (i.e., sedation, motivation deficits, locomotor impairments) are contributing to changes in performance. The versatility of the 5CSRTT is further enhanced because it is amenable to combination with pharmacological, molecular, and genetic techniques.

The 5-Choice Serial Reaction Time Task: A Task of Attention and Impulse Control for Rodents

This protocol describes the 5-choice serial reaction time task, which is an operant based task used to study attention and impulse control in rodents. Test day challenges, modifications to the standard task, can be used to systematically tax the neural systems controlling either attention or impulse control. Importantly, these challenges have consistent effects on behavior across laboratories in intact animals and can reveal either enhancements or deficits in cognitive function that are not apparent when rats are only tested on the standard task. The variety of behavioral measures that are collected can be used to determine if other factors (i.e., sedation, motivation deficits, locomotor impairments) are contributing to changes in performance. The versatility of the 5CSRTT is further enhanced because it is amenable to combination with pharmacological, molecular, and genetic techniques.

Prenatal alcohol exposure and adolescent stress - unmasking persistent attentional deficits in rats.

Prenatal alcohol exposure (PAE) can produce a myriad of deficits. Unfortunately, affected individuals may also be exposed to the stress of an adverse home environment, contributing to deficits of attentional processes that are the hallmark of optimal executive function. Male offspring of ad-libitum-fed Control (Con), Pairfed (PF), and PAE dams were randomly assigned to either a 5-day period of variable chronic mild stress (CMS) or no CMS in adolescence. In adulthood, rats were trained in a non-match to sample task (T-maze), followed by extensive assessment in the five-choice serial reaction time task. Once rats acquired the five-choice serial reaction time task (stable accuracy), they were tested in three challenge conditions: (i) increased sustained attention, (ii) selective attention and, (iii) varying doses of d-amphetamine, an indirect dopamine and norepinephrine agonist. At birth and throughout the study, PAE offspring showed reduced body weight. Moreover, although PAE animals were similar to Con animals in task acquisition, they were progressively less proficient with transitions to shorter stimulus durations (decreased accuracy and increased omissions). Five days of adolescent CMS increased basal corticosterone levels in adolescence and disrupted cognitive performance in adulthood. Further, CMS augmented PAE-related disturbances in acquisition and, to a lesser extent, also disrupted attentional processes in Con and PF animals. Following task acquisition, challenges unmasked persistent attentional difficulties resulting from both PAE and adolescent CMS. In conclusion, PAE, adolescent CMS, and their interaction produced unique behavioural profiles that suggest vulnerability in select neurobiological processes at different stages of development.

Exaggerated waiting impulsivity associated with human binge drinking, and high alcohol consumption in mice.

There are well-established links between impulsivity and alcohol use in humans and animal models; however, whether exaggerated impulsivity is a premorbid risk factor or a consequence of alcohol intake remains unclear. In a first approach, human young (18-25 years) social binge and non-binge drinkers were tested for motor impulsivity and attentional abilities in a human version of the Five-Choice Serial Reaction Time Task (Sx-5CSRTT), modeled on the rodent 5CSRTT. Participants completed four variants of the Sx-5CSRT, in addition to being screened for impulsive traits (BIS-11 questionnaire) and impulsive behavior (by means of the Delay Discounting Questionnaire, Two-Choice Impulsivity Paradigm (TCIP), Stop Signal Reaction Time, and Time Estimation Task). Using a second approach, we compared one of these impulsivity measures, 5CSRTT performance, in two inbred strains of mice known to differ in alcohol intake. Compared with non-bingers (NBD; n=22), binge drinkers (BD, n=22) showed robust impairments in attention and premature responding when evaluated under increased attentional load, in addition to presenting deficits in decision making using the TCIP. The best predictors for high binge drinking score were premature responding in the Sx-5CSRTT, trait impulsivity in the BIS-11, and decision making in the TCIP. Alcohol-naïve C57BL/6J (B6) mice (alcohol preferring) were more impulsive in the 5CSRTT than DBA2/J (D2) mice (alcohol averse); the degree of impulsivity correlated with subsequent alcohol consumption. Homologous measures in animal and human studies indicate increased premature responding in young social BD and in the ethanol-preferring B6 strain of mice.

Using the five-choice serial reaction time task to examine the effects of atomoxetine and methylphenidate in the male spontaneously hypertensive rat

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder and is normally treated with either stimulant or non-stimulant medication such as methylphenidate and atomoxetine respectively. The impact of these drugs on attention and impulsivity has been explored extensively in healthy animals but there is little research into their effects in an animal model of ADHD. In the present study we investigated the effects of both drugs on the spontaneously hypertensive rat (SHR) model of ADHD using the five-choice serial reaction time task (5CSRTT). We found a number of difficulties associated with training this vulnerable strain on such a complex task. However, where rats were able to learn the task we found very small effects of methylphenidate; increased incorrect responding and therefore decreased accuracy, a marker of attention at a single dose. There were no significant effects of atomoxetine on accuracy once multiple comparisons were taken into consideration. We found no effects of either drug on premature responding, a marker of impulsivity. These results indicate that the 5CSRTT may not be most sensitive to the impulsivity displayed in the SHR. Furthermore, they suggest that the SHR may lack predictive validity and further investigation is needed to optimise use of this model.

Serotoninergic and dopaminergic modulation of cortico-striatal circuit in executive and attention deficits induced by NMDA receptor hypofunction in the 5-choice serial reaction time task

Executive functions are an emerging propriety of neuronal processing in circuits encompassing frontal cortex and other cortical and subcortical brain regions such as basal ganglia and thalamus. Glutamate serves as the major neurotrasmitter in these circuits where glutamate receptors of NMDA type play key role. Serotonin and dopamine afferents are in position to modulate intrinsic glutamate neurotransmission along these circuits and in turn to optimize circuit performance for specific aspects of executive control over behavior. In this review, we focus on the 5-choice serial reaction time task which is able to provide various measures of attention and executive control over performance in rodents and the ability of prefrontocortical and striatal serotonin 5-HT1A, 5-HT2A, and 5-HT2C as well as dopamine D1- and D2-like receptors to modulate different aspects of executive and attention disturbances induced by NMDA receptor hypofunction in the prefrontal cortex. These behavioral studies are integrated with findings from microdialysis studies. These studies illustrate the control of attention selectivity by serotonin 5-HT1A, 5-HT2A, 5-HT2C, and dopamine D1- but not D2-like receptors and a distinct contribution of these cortical and striatal serotonin and dopamine receptors to the control of different aspects of executive control over performance such as impulsivity and compulsivity. An association between NMDA antagonist-induced increase in glutamate release in the prefrontal cortex and attention is suggested. Collectively, this review highlights the functional interaction of serotonin and dopamine with NMDA dependent glutamate neurotransmission in the cortico-striatal circuitry for specific cognitive demands and may shed some light on how dysregulation of neuronal processing in these circuits may be implicated in specific neuropsychiatric disorders.

Repeated exposures to diisopropylfluorophosphate result in impairments of sustained attention and persistent alterations of inhibitory response control in rats

Organophosphate (OP)-based chemicals are used worldwide for many purposes and they have likely saved millions of people from starvation and disease. However, due to their toxicity they can also pose a significant environmental risk. While considerable research has focused on the acute symptoms and long-term consequences of overtly toxic exposures to OPs, less attention has been given to the subject of repeated exposures to levels that are not associated with acute symptoms (subthreshold exposures). There is clinical evidence indicating that this type of OP exposure can lead to prolonged deficits in cognition; however only a few studies have addressed this issue prospectively in animal models. In this study, repeated subthreshold exposures to the OP nerve agent diisopropylfluorophosphate (DFP) were evaluated in a 5-Choice Serial Reaction Time Task (5C-SRTT), an animal model of sustained attention. Adult rats were trained to stably perform the 5C-SRTT and then injected subcutaneously with vehicle or DFP of 0.5mg/kg every other day for 30days. Behavioral testing occurred daily during the DFP-exposure period and throughout a 45day (OP-free) washout period. Compared to vehicle-treated controls, DFP-treated rats exhibited deficits in accuracy, increases in omissions and timeout responses during the OP exposure period, while no significant effects on premature responses, perseverative responses, or response latencies were noted. While the increase in timeout responses remained detectible during washout, all other DFP-related alterations in 5C-SRTT performance abated. When the demands of the task were increased by the presentation of variable intertrial intervals, premature responses were also elevated in DFP-treated rats during the washout period. These results indicate that repeated exposures to subthreshold doses of DFP lead to reversible impairments in sustained attention as well as persistent impairments of inhibitory response control in rats.

Nucleus accumbens core and shell inactivation differentially affects impulsive behaviours in rats.

Impulsivity is a multifactorial phenomenon, determined by deficits in decision-making (impulsive choice) and impulse control (impulsive action). Recent findings indicate that impulsive behaviour is not only top-down controlled by cortical areas, but also modulated at subcortical level. The nucleus accumbens (NAc) might be a key substrate in cortico-limbic-striatal circuits involved in impulsive behaviour. Dissociable effects of the NAc subregions in various behavioural paradigms point to a potential functional distinction between NAc core and shell concerning different types of impulsivity. The present study used reversible inactivation of the rats' NAc core and shell via bilateral microinfusion of the GABAA receptor agonist muscimol (0.05μg/0.3μl) and fluorophore-conjugated muscimol (FCM, 0.27μg/0.3μl) in order to study their contribution to different aspects of impulse control in a 5-choice serial reaction time task (5-CSRTT) and impulsive choice in a delay-based decision-making T-maze task. Acute inactivation of NAc core as well as shell by muscimol increased impulsive choice, with higher impairments of the rats' waiting capacity in the T-maze following core injections compared to shell. Intra-NAc shell infusion of muscimol also induced specific impulse control deficits in the 5-CSRTT, while deactivation of the core caused severe general impairments in task performance. FCM did not affect animal behaviour. Our findings reveal clear involvement of NAc shell in both forms of impulsivity. Both subareas play a key role in the regulation of impulsive decision-making, but show functional dichotomy regarding impulse control with the core being more implicated in motivational and motor aspects.

The effects of acute and repeated administration of ketamine on attentional performance in the five-choice serial reaction time task in rats

Ketamine, the non-competitive antagonist of the N-methyl-d-aspartate receptors, is used in clinical and preclinical studies to produce schizophrenia-like cognitive impairments. However, the impact of ketamine on attentional functions remains poorly characterised. In the present study, we further examine the effects of ketamine on attentional processes assessed in the five-choice serial reaction time task (5-CSRTT) in rats. The applied schedules of ketamine administration have been previously demonstrated to evoke frontal-dependent set-shifting impairments. Rats were trained to reach a stable baseline performance. Afterwards, animals received a single injection of ketamine (0, 3 and 10mg/kg, IP) 45min before the 5-CSRTT session (experiment 1). In experiment 2, ketamine (0 and 30mg/kg, IP) was administered after the daily test session for 10 consecutive days. The rats׳ performance was assessed at 22h following ketamine administration and for 4 days after the last dose. Acute and repeated administration of ketamine disrupted rats׳ performance on the 5-CSRTT. Reduced speed of responding and an increased number of omissions were noted in the absence of reduced food motivation. The within-session pattern of responding differed between rats treated acutely and repeatedly with ketamine. Specifically, repeated drug administration evoked an increase in omissions toward the end of the session, and this effect was not secondary to the reduced motivation. Ketamine affected performance during the withdrawal period only when testing with variable inter-trial intervals. The repeated administration of ketamine can impair rats׳ ability to sustain attention over the course of session, suggesting some utility for modelling attentional disturbances.

Neuregulin-3 in the Mouse Medial Prefrontal Cortex Regulates Impulsive Action

A deficit in impulse control is a prominent, heritable symptom in several psychiatric disorders, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia. Here, we aimed to identify genes regulating impulsivity, specifically of impulsive action, in mice. Using the widely used 5-choice serial reaction time task, we measured impulsive action in 1) a panel of 41 BXD recombinant inbred strains of mice (n = 13.7 ± .8 per strain; n = 654 total) to detect underlying genetic loci; 2) congenic mice (n = 23) to replicate the identified locus; 3) mice overexpressing the Nrg3 candidate gene in the medial prefrontal cortex (n = 21); and 4) a Nrg3 loss-of-function mutant (n = 59) to functionally implicate the Nrg3 candidate gene in impulsivity. Genetic mapping of impulsive action in the BXD panel identified a locus on chromosome 14 (34.5-41.4 Mb), syntenic with the human 10q22-q23 schizophrenia-susceptibility locus. Congenic mice carrying the impulsivity locus (Impu1) confirmed its influence on impulsive action. Increased impulsivity was associated with increased Nrg3 gene expression in the medial prefrontal cortex (mPFC). Viral overexpression of Nrg3 in the mPFC increased impulsivity, whereas a constitutive Nrg3 loss-of-function mutation decreased it. The causal relation between Nrg3 expression in the mPFC and level of impulsive action shown here provides a mechanism by which polymorphism in NRG3 in humans contributes to a specific cognitive deficit seen in several psychiatric diseases, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia.

Attention and executive functions in a rat model of chronic epilepsy

Temporal lobe epilepsy is a relatively frequent, invalidating, and often refractory neurologic disorder. It is associated with cognitive impairments that affect memory and executive functions. In the rat lithium-pilocarpine temporal lobe epilepsy model, memory impairment and anxiety disorder are classically reported. Here we evaluated sustained visual attention in this model of epilepsy, a function not frequently explored. Thirty-five Sprague-Dawley rats were subjected to lithium-pilocarpine status epilepticus. Twenty of them received a carisbamate treatment for 7 days, starting 1 h after status epilepticus onset. Twelve controls received lithium and saline. Five months later, attention was assessed in the five-choice serial reaction time task, a task that tests visual attention and inhibitory control (impulsivity/compulsivity). Neuronal counting was performed in brain regions of interest to the functions studied (hippocampus, prefrontal cortex, nucleus basalis magnocellularis, and pedunculopontine tegmental nucleus). Lithium-pilocarpine rats developed motor seizures. When they were able to learn the task, they exhibited attention impairment and a tendency toward impulsivity and compulsivity. These disturbances occurred in the absence of neuronal loss in structures classically related to attentional performance, although they seemed to better correlate with neuronal loss in hippocampus. Globally, rats that received carisbamate and developed motor seizures were as impaired as untreated rats, whereas those that did not develop overt motor seizures performed like controls, despite evidence for hippocampal damage. This study shows that attention deficits reported by patients with temporal lobe epilepsy can be observed in the lithium-pilocarpine model. Carisbamate prevents the occurrence of motor seizures, attention impairment, impulsivity, and compulsivity in a subpopulation of neuroprotected rats.

Lewis rats have greater response impulsivity than Fischer rats

Impulsivity, a tendency toward immediate action without consideration of future consequences, is associated with a wide array of problematic behaviors. Response impulsivity, a type of behaviorally-assessed impulsivity characterized by behavioral disinhibition, is also associated with health risk behaviors. Response impulsivity is distinct from choice impulsivity, which is characterized by intolerance for delay. Lewis rats have higher levels of choice impulsivity than Fischer rats (Anderson & Woolverton, 2005; Madden et al., 2008; Stein et al., 2012). However, no studies have examined whether Lewis and Fischer rats have different levels of response impulsivity. The present research examined response impulsivity in the two rat strains. Subjects were 16 male Lewis and Fischer rats. Rats' response impulsivity was measured using the Five Choice Serial Reaction Time Task (5-CSRTT). In addition, their locomotor activity was measured in locomotor activity chambers. Lewis rats had more premature responses than Fischer rats during the 5-CSRTT assessment [F(1, 14)=5.34, p<0.05], indicating higher levels of response impulsivity. Locomotor activity did not differ between rat strain groups [F(1, 14)=3.05, p=.10], suggesting that overall movement did not account for group differences in response impulsivity on the 5-CSRTT. It can be concluded from this research that Lewis rats have higher levels of response impulsivity than Fischer rats, and therefore provide a valid rat model of individual differences in impulsivity.

Ventral medial prefrontal cortex inactivation impairs impulse control but does not affect delay-discounting in rats

Maladaptive levels of impulsivity are found in several neuropsychiatric disorders, such as ADHD, addiction, aggression and schizophrenia. Intolerance to delay-of-gratification, or delay-discounting, and deficits in impulse control are dissociable forms of impulsivity top-down controlled by the prefrontal cortex, with the ventral medial prefrontal cortex (vmPFC) suggested to be critically involved. The present study used transient inactivation of the rats’ vmPFC via bilateral microinfusion of the GABAA receptor agonist muscimol (0.05, 0.5μg/0.3μl) to analyse its relevance for impulse control in a 5-choice serial reaction time task (5-CSRTT) and delay-discounting in a Skinner box. Intra-vmPFC injection of low-dose muscimol impaired impulse control indicated by enhanced premature responding in the 5-CSRTT, while flattening the delay-dependent shift in the preference of the large reward in the delay-discounting task. Likewise, high-dose muscimol did not affect delay-discounting, though raising the rate of omissions. On the contrary, 5-CSRTT performance was characterised by deficits in impulse and attentional control. These data support the behavioural distinction of delay-discounting and impulse control on the level of the vmPFC in rats. Reversible inactivation with muscimol revealed an obvious implication of the vmPFC in the modulation of impulse control in the 5-CSRTT. By contrast, delay-discounting processes seem to be regulated by other neuronal pathways, with the vmPFC playing, if at all, a minor role.

Cholinergic Contributions to Supramodal Attentional Processes in Rats

Cholinergic neurotransmission has been shown to play an important role in modulating attentional processing of visual stimuli. However, it is not yet clear whether the neurochemical acetylcholine (ACh) is necessary exclusively for visual attention, or if it also contributes to attentional functions through some modality-independent (supramodal) mechanism. To answer this question, we examined the effects of reduced cortical cholinergic afferentation on both a traditional visual and a novel olfactory five-choice serial reaction time task (5-CSRTT), the benchmark rodent test of sustained attention in rats. Following the successful acquisition of both modalities of the task, the rats underwent either a cholinergic immunotoxic- or sham-lesion surgery of the nucleus basalis magnocellularis (NBM), the basal forebrain nuclei that provide the majority of neocortical ACh. Reduced cholinergic afferentation to the neocortex was induced by bilaterally infusing the cholinergic immunotoxin 192 IgG-saporin into the NBM. After surgery, ACh-NBM-lesioned rats performed comparably to sham-lesioned rats under the conditions of low attentional demand, but displayed behavioral decrements relative to the sham-lesioned rats when the attentional demands of the task were increased. Moreover, this decrement in attentional functioning correlated significantly with the number of choline acetyltransferase-immunoreactive cells in the NBM. Importantly, the nature of this behavioral decrement was identical in the visual and olfactory 5-CSRTTs. Together, these data suggest the presence of a supramodal attentional modulatory cortical network whose activity is dependent on cholinergic innervation from the NBM.

Dissociable contributions of anterior cingulate cortex and basolateral amygdala on a rodent cost/benefit decision-making task of cognitive effort.

Personal success often requires the choice to expend greater effort for larger rewards, and deficits in such effortful decision making accompany a number of illnesses including depression, schizophrenia, and attention-deficit/hyperactivity disorder. Animal models have implicated brain regions such as the basolateral amygdala (BLA) and anterior cingulate cortex (ACC) in physical effort-based choice, but disentangling the unique contributions of these two regions has proven difficult, and effort demands in industrialized society are predominantly cognitive in nature. Here we utilize the rodent cognitive effort task (rCET), a modification of the five-choice serial reaction-time task, wherein animals can choose to expend greater visuospatial attention to obtain larger sucrose rewards. Temporary inactivation (via baclofen-muscimol) of BLA and ACC showed dissociable effects: BLA inactivation caused hard-working rats to 'slack off' and 'slacker' rats to work harder, whereas ACC inactivation caused all animals to reduce willingness to expend mental effort. Furthermore, BLA inactivation increased the time needed to make choices, whereas ACC inactivation increased motor impulsivity. These data illuminate unique contributions of BLA and ACC to effort-based decision making, and imply overlapping yet distinct circuitry for cognitive vs physical effort. Our understanding of effortful decision making may therefore require expanding our models beyond purely physical costs.