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

ABSTRACT: 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.The aim was to examine the role of alpha7 receptors in attentional performance of mice and in effects of nicotine.Mice with targeted deletion of the gene coding for the alpha7 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.Initially the alpha7(-/-) (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 alpha7(-/-) 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 alpha7(-/-) and wild-type mice.alpha7 nicotinic receptor knockout mice are impaired in performance of the 5-CSRTT, suggesting a possible role for alpha7 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 animal.

SUBMITTER: Hoyle E

PROVIDER: S-EPMC1705494 | biostudies-other | 2006 Dec

REPOSITORIES: biostudies-other

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Project description:BackgroundThe 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 resultsThe 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.ConclusionIn 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.

Project description:The subthalamic nucleus (STN), a key component of the basal ganglia circuitry, receives inputs from broad cerebral cortical areas and relays cortical activity to subcortical structures. Recent human and animal studies have suggested that executive function, which is assumed to consist of a set of different cognitive processes for controlling behavior, depends on precise information processing between the cerebral cortex and subcortical structures, leading to the idea that the STN contains neurons that transmit the information required for cognitive processing through their activity, and is involved in such cognitive control directly and dynamically. On the other hand, the STN activity also affects intracellular signal transduction and gene expression profiles influencing plasticity in other basal ganglia components. The STN may also indirectly contribute to information processing for cognitive control in other brain areas by regulating slower signaling mechanisms. However, the precise correspondence and causal relationship between the STN activity and cognitive processes are not fully understood. To address how the STN activity is involved in cognitive processes for controlling behavior, we applied Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic manipulation of neural activity to behavioral analysis using a touchscreen operant platform. We subjected mice selectively expressing DREADD receptors in the STN neurons to a five-choice serial reaction time task, which has been developed to quantitatively measure executive function. Chemogenetic suppression of the STN activity reversibly impaired attention, especially required under highly demanding conditions, and increased impulsivity but not compulsivity. These findings, taken together with the results of previous lesion studies, suggest that the STN activity, directly and indirectly, participates in cognitive processing for controlling behavior, and dynamically regulates specific types of subprocesses in cognitive control probably through fast synaptic transmission.

Project description:Uncontrollable binge drinking is becoming an increasingly prevalent issue in our society. This is a factor that plays a role in the development of alcohol use disorder (AUD). AUD impacts 15 million Americans annually, with approximately 88,000 dying from alcohol related deaths. There are several aspects of AUD that encourage a strong dependence on alcohol. Impulsivity, motivation, and attention are the primary behavioral facets we contribute to AUD. Many past studies have used the 5-Choice Serial Reaction Time Task (5-Choice) to analyze these types of behaviors using sugar as the reward. We have recently published a study where alcohol was used as a reward in the 5-Choice. 48 mice were trained to respond for alcohol in the 5-Choice, and the analyses for these animals were originally categorized by their alcohol preference and consumption. Upon looking at the data, we became more interested in a new way to classify these mice into groups. High engaged (HE) and low engaged (LE) mice were classified based on their number of correct responses in the last five late-stage sessions. During early-stage training, mice began to separate themselves into two groups based on their interaction with the task. The high-engaged (HE) mice were much more engaged with the task by having a high number of trials and correct responses, as well as a much lower percentage of omissions. The low engaged (LE) mice were not as engaged, this was apparent because of their lower number of trials and correct responses. They also had a much higher percentage of omissions in comparison to HE mice. LE mice presented no significant changes in late-stage training, while HE mice began responding and engaging more. These mice went through a period of intermittent access (IA), where they were allowed to drink alcohol in their cage for 3 weeks. After intermittent access, LE mice increased their responding which suggests an increase in motivation for alcohol as a reward. Engagement analysis presents two clearly different groups, one being motivated to work for alcohol and the other not wanting to work for this reward. These two distinct phenotypes in the 5-Choice could be used to model alcohol motivated behavior, which could help us further understand AUD.

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

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