Thalamic inputs to dorsomedial striatum are involved in inhibitory control: evidence from the five-choice serial reaction time task in rats

Rationale Corticostriatal circuits are widely implicated in the top-down control of attention including inhibitory control and behavioural flexibility. However, recent neurophysiological evidence also suggests a role for thalamic inputs to striatum in behaviours related to salient, reward-paired cues. Objectives Here, we used designer receptors exclusively activated by designer drugs (DREADDs) to investigate the role of parafascicular (Pf) thalamic inputs to the dorsomedial striatum (DMS) using the five-choice serial reaction time task (5CSRTT) in rats. Methods The 5CSRTT requires sustained attention in order to detect spatially and temporally distributed visual cues and provides measures of inhibitory control related to impulsivity (premature responses) and compulsivity (perseverative responses). Rats underwent bilateral Pf injections of the DREADD vector, AAV2-CaMKIIa-HA-hM4D(Gi)-IRES-mCitrine. The DREADD agonist, clozapine N-oxide (CNO; 1 μl bilateral; 3 μM) or vehicle, was injected into DMS 1 h before behavioural testing. Task parameters were manipulated to increase attention load or reduce stimulus predictability respectively. Results We found that inhibition of the Pf-DMS projection significantly increased perseverative responses when stimulus predictability was reduced but had no effect on premature responses or response accuracy, even under increased attentional load. Control experiments showed no effects on locomotor activity in an open field. Conclusions These results complement previous lesion work in which the DMS and orbitofrontal cortex were similarly implicated in perseverative responses and suggest a specific role for thalamostriatal inputs in inhibitory control

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

Mice haploinsufficient for Map2k7, a gene involved in neurodevelopment and risk for schizophrenia, show impaired attention, a vigilance decrement deficit and unstable cognitive processing in an attentional task: impact of minocycline

Rationale: Members of the c-Jun N-terminal kinase (JNK) family of mitogen-activated protein (MAP) kinases, and the upstream kinase MKK7, have all been strongly linked with synaptic plasticity and with the development of the neocortex. However, the impact of disruption of this pathway on cognitive function is unclear. Objective: In the current study, we test the hypothesis that reduced MKK7 expression is sufficient to cause cognitive impairment. Methods: Attentional function in mice haploinsufficient for Map2k7 (Map2k7+/− mice) was investigated using the five-choice serial reaction time task (5-CSRTT). Results: Once stable performance had been achieved, Map2k7+/− mice showed a distinctive attentional deficit, in the form of an increased number of missed responses, accompanied by a more pronounced decrement in performance over time and elevated intra-individual reaction time variability. When performance was reassessed after administration of minocycline—a tetracycline antibiotic currently showing promise for the improvement of attentional deficits in patients with schizophrenia—signs of improvement in attentional performance were detected. Conclusions: Overall, Map2k7 haploinsufficiency causes a distinctive pattern of cognitive impairment strongly suggestive of an inability to sustain attention, in accordance with those seen in psychiatric patients carrying out similar tasks. This may be important for understanding the mechanisms of cognitive dysfunction in clinical populations and highlights the possibility of treating some of these deficits with minocycline

Impaired performance of alpha7 nicotinic receptor knockout mice in the five-choice serial reaction time task

Rationale Nicotinic receptors have been implicated in attentional performance. Nicotine can improve attention in animals and humans, but knowledge about relevant receptor subtypes is very limited. Objectives The aim was to examine the role of alpha 7 receptors in attentional performance of mice and in effects of nicotine. Materials and methods Mice with targeted deletion of the gene coding for the alpha 7 subunit of nicotinic receptors and wild-type controls were trained on a five-choice serial reaction time task with food reinforcers presented under varying parametric conditions. Nicotine was administered in a range of doses (0.001-1.0 mg/kg sc), including those reported to enhance attentional performance. Results Initially the alpha 7(-/-) (knockout) mice responded less accurately and made more anticipatory responses. After task parameters were altered so that the time allowed for responding was reduced and anticipatory (impulsive) responses were punished by a time-out, the pattern of performance deficits changed; there were increased omission errors in alpha 7(-/-) mice but normal levels of accuracy and anticipatory responding. Nicotine did not improve any measure of performance, either with the original training parameters or after retraining; the largest dose used (1.0 mg/kg) produced a general impairment of responding in alpha 7(-/-) and wild-type mice. Conclusions alpha 7 nicotinic receptor knockout mice are impaired in performance of the 5-CSRTT, suggesting a possible role for alpha 7 receptors in attentional processing. However, identification of a protocol for assessing attention-enhancing effects of nicotine in mice may require further modifications of test procedures or the use of different strains of anima

Implicit cognition is impaired and dissociable in a head-injured group with executive deficits

Implicit or non-conscious cognition is traditionally assumed to be robust to pathology but Gomez-Beldarrain et al (1999, 2002) recently showed deficits on a single implicit task after head injury. Laboratory research suggests that implicit processes dissociate. This study therefore examined implicit cognition in 20 head-injured patients and age- and I.Q.-matched controls using a battery of four implicit cognition tasks: a Serial Reaction Time task (SRT), mere exposure effect task, automatic stereotype activation and hidden co-variation detection. Patients were assessed on an extensive neuropsychological battery, and MRI scanned. Inclusion criteria included impairment on at least one measure of executive function. The patient group was impaired relative to the control group on all the implicit cognition tasks except automatic stereotype activation. Effect size analyses using the control mean and standard deviation for reference showed further dissociations across patients and across implicit tasks. Patients impaired on implicit tasks had more cognitive deficits overall than those unimpaired, and a larger Dysexecutive Self/Other discrepancy (DEX) score suggesting greater behavioural problems. Performance on the SRT task correlated with a composite measure of executive function. Head-injury thus produced heterogeneous impairments in the implicit acquisition of new information. Implicit activation of existing knowledge structures appeared intact. Impairments in implicit cognition and executive function may interact to produce dysfunctional behaviour after head-injury. Future comparisons of implicit and explicit cognition should use several measures of each function, to ensure that they measure the latent variable of interest

Neural Dynamics of Learning and Performance of Fixed Sequences: Latency Pattern Reorganizations and the N-STREAMS Model

Fixed sequences performed from memory play a key role in human cultural behavior, especially in music and in rapid communication through speaking, handwriting, and typing. Upon first performance, fixed sequences are often produced slowly, but extensive practice leads to performance that is both fluid and as rapid as allowed by constraints inherent in the task or the performer. The experimental study of fixed sequence learning and production has generated a large database with some challenging findings, including practice-related reorganizations of temporal properties of performance. In this paper, we analyze this literature and identify a coherent set of robust experimental effects. Among these are both the sequence length effect on latency, a dependence of reaction time on sequence length, and practice-dependent lost of the lengths effect on latency. We then introduce a neural network architecture capable of explaining these effects. Called the NSTREAMS model, this multi-module architecture embodies the hypothesis that the brain uses several substrates for serial order representation and learning. The theory describes three such substrates and how learning autonomously modifies their interaction over the course of practice. A key feature of the architecture is the co-operation of a 'competitive queuing' performance mechanism with both fundamentally parallel ('priority-tagged') and fundamentally sequential ('chain-like') representations of serial order. A neurobiological interpretation of the architecture suggests how different parts of the brain divide the labor for serial learning and performance. Rhodes (1999) presents a complete mathematical model as implementation of the architecture, and reports successful simulations of the major experimental effects. It also highlights how the network mechanisms incorporated in the architecture compare and contrast with earlier substrates proposed for competitive queuing, priority tagging and response chaining.Defense Advanced Research Projects Agency and the Office of Naval Research (N00014-92-J-1309, N00014-93-1-1364, N00014-95-1-0409); National Institute of Health (RO1 DC02852

Interference during the implicit learning of two different motor sequences

It has been demonstrated that learning a second motor task after having learned a first task may interfere with the long-term consolidation of the first task. However, little is known about immediate changes in the representation of the motor memory in the early acquisition phase within the first minutes of the learning process. Therefore, we investigated such early interference effects with an implicit serial reaction time task in 55 healthy subjects. Each subject performed either a sequence learning task involving two different sequences, or a random control task. The results showed that learning the first sequence led to only a slight, short-lived interference effect in the early acquisition phase of the second sequence. Overall, learning of neither sequence was impaired. Furthermore, the two processes, sequence-unrelated task learning (i.e. general motor training) and the sequence learning itself did not appear to interfere with each other. In conclusion, although the long-term consolidation of a motor memory has been shown to be sensitive to other interfering memories, the present study suggests that the brain is initially able to acquire more than one new motor sequence within a short space of time without significant interferenc

Differential vulnerability of different forms of skill learning in Parkinson’s disease

The striatal dopaminergic dysfunction in Parkinson’s disease (PD) has been associated with deficits in skill learning in a number of studies, but the results are inconclusive so far. Motor sequence learning (especially sequence-specific learning) is found to be deficient in the majority of studies using the Serial Reaction Time Task (SRTT; Siegert, Taylor, Weatherall, & Abernethy, 2006; Jackson et al., 1995; Ferraro, Balota and Connor, 1993; Pascual-Leone et al., 1993, Muslimovic et al., 2007; Gobel et al., 2013; but see Kwak et al., 2012), although results are contradictory when verbal response is required instead of button presses (Westwater et al. 1998; Smith, Siegert and McDowall 2001). While problems with motor sequences seem to be prevalent, PD patients show intact performance on Artificial Grammar Learning (AGL) tasks, suggesting that the sequencing problem may be response type- or task type-dependent (Smith, Siegert and McDowall 2001; Witt, Nühsman and Deuschl, 2002) Acquisition of nonsequential probabilistic associations also seems to be vulnerable as evidenced by impaired PD performance on a probabilistic category learning task (Knowlton, Mangels et al., 1996; Shohamy, Myers, Onlaor, & Gluck, 2004). Our aim was to explore the nature of the skill learning deficit by testing different types of skill learning (sequential versus nonsequential, motor versus verbal) in the same group of Parkinson’s patients. 14 patients with PD (mean age: 59.77 range: 45.5-74) were compared to age-matched typical adults using 1) a Serial Reaction Time Task (SRTT) testing the learning of motor sequences, 2) an Artificial Grammar Learning (AGL) task testing the extraction of regularities from auditory sequences and 3) a Weather prediction task (PCL-WP), testing probabilistic category learning in a non-sequential task. In motor sequence learning on the SRTT task, the two groups did not differ in accuracy; PD patients were generally slower, and analysis of z-transformed reaction times showed no evidence of sequence learning in PD. A deficit in artificial grammar learning was present only as a tendency in the PD group. The PD group showed evidence of learning on the PCL task, and their learning performance was not statistically different from that of the control group. These results partly support and also extend previous findings suggesting that motor skill learning is vulnerable in PD, while other forms of skill learning are less prone to impairment. Results are also in line with previous assumptions that mechanisms underlying artificial grammar learning and probabilistic categorization do not depend on the striatum (Reber & Squire, 1999; Skosnik et al., 2002)

Acute effects of nicotine on visual search tasks in young adult smokers

Rationale Nicotine is known to improve performance on tests involving sustained attention and recent research suggests that nicotine may also improve performance on tests involving the strategic allocation of attention and working memory. Objectives We used measures of accuracy and response latency combined with eye-tracking techniques to examine the effects of nicotine on visual search tasks. Methods In experiment 1 smokers and non-smokers performed pop-out and serial search tasks. In experiment 2, we used a within-subject design and a more demanding search task for multiple targets. In both studies, 2-h abstinent smokers were asked to smoke one of their own cigarettes between baseline and tests. Results In experiment 1, pop-out search times were faster after nicotine, without a loss in accuracy. Similar effects were observed for serial searches, but these were significant only at a trend level. In experiment 2, nicotine facilitated a strategic change in eye movements resulting in a higher proportion of fixations on target letters. If the cigarette was smoked on the first trial (when the task was novel), nicotine additionally reduced the total number of fixations and refixations on all letters in the display. Conclusions Nicotine improves visual search performance by speeding up search time and enabling a better focus of attention on task relevant items. This appears to reflect more efficient inhibition of eye movements towards task irrelevant stimuli, and better active maintenance of task goals. When the task is novel, and therefore more difficult, nicotine lessens the need to refixate previously seen letters, suggesting an improvement in working memory