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Principal Investigator:
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Gary Aston-Jones, Ph.D.
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Organization:
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University of Pennsylvania
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Project Ended:
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2004
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Astronauts' execution of complex tasks is dependent on their attention level during stressful space flight conditions. Attention level has been associated with the rate of electrical impulses in the locus coeruleus neurons, and Dr. Gary Aston-Jones is exploring whether the activity of these neurons is affected by stress, explaining stress's disruptive effects on attention. Through this research, he will look at pharmaceutical countermeasures that could help combat stress's negative effects on attention.
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Principal Investigator:
|
Gary Aston-Jones, Ph.D.
|
|
Organization:
|
University of Pennsylvania
|
|
Project Ended:
|
2004
|
Original Aims The original aims of this project were: 1. Analyze the activity of brain stem noradrenergic locus coeruleus (LC) neurons during a continuous performance task, 2. Determine the effects of acute and repeated stress on changes in LC function and performance, and 3. Identify pharmacological countermeasures to mitigate stress effects on LC activity and attentional function.
Key Findings
- Development of a continuous performance task for the rat. We developed a target detection continuous performance task that rats can learn rapidly. This task mimics many of the attributes of the target detection task in our previous studies in monkeys in which LC activity appears to play a major role. Rats initiate each trial by pressing one lever, and then must discriminate between two signal lights to determine if the one illuminated is a target or non-target. If the target signal light is illuminated the rat must press a second lever to obtain food reward. If the nontarget is illuminated he must withhold responding with no reward and await the next trial. Targets occur randomly on 20% of the trials. This task will be the means by which we measure performance abilities and changes therein induced by stress and pharmacologic treatments.
- Effects of stress on performance in the target detection task. To date we have tested only acute noise stress on performance of this task. Results indicate that white noise during task performance at 90 db significantly increased responding to the non-target stimulus (false alarm (FA) errors) in this task. Interestingly, this effect habituated rapidly, so that subsequent administration of 105 db did not influence performance. Chronic stress (planned for this year) may be needed to see continued performance deficits. The alpha2 adrenoceptor agonist clonidine (which decreases LC-NE neurotransmission) at 8 mg/kg reduced the FA error rate seen with 90 db noise stress. Higher doses of clonidine (25 mg/kg) produced sedation. These preliminary experiments require confirmation with additional studies, but they suggest that the NE system may be involved in stress effects on performance in this task.
- Effects of idazoxan on performance in the target detection task. The alpha2 adrenoceptor antagonist idazoxan increases firing of LC neurons and release of NE from LC terminals. Our view of LC's role in performance predicts that this agent should worsen performance on this task, with increased FA errors (as observed in monkey LC neurons during periods of high tonic LC activity). Systemic idazoxan had no effect on two rats that were performing marginally in the task (i.e. a 30% false alarm rate). However, this compound markedly increased false alarms in both of the rats that were performing exceptionally well and had low baseline false alarm rates in the absence of the drug. Although preliminary, these results are consistent with the view that moderate levels of tonic LC activity are critical for maintaining focused attentiveness to task stimuli and performing optimally, and that behavioral performance declines when tonic LC firing rates are increased. We speculate that the lack of an effect of idazoxan in rats with marginal baseline performance reflects the inverted U relationship described by the PI for the relationship between LC activity and performance on such a task. Thus, in these rats the poor performance pre-drug may have been due to a high level of baseline tonic LC activity, placing them at the right of the inverted U relationship. This pre-existing heightened LC activity could have created a ceiling effect that prevented idazoxan from further increasing LC firing rates and disrupting responses.
- Role of the LC in circadian regulation of sleep and waking. We expanded our program to include analysis of the role of LC in effects of sleep deprivation on performance. We took this step because sleep deprivation is one of the largest stresses affecting the astronaut, and there are well-established effects of sleep deprivation on performance. For this, considerable technological development has occurred. We implemented a telemetry system for recording EEG, EMG, body temperature and locomotor activity in freely moving, untethered rats. This system produces robust sleep measures over long periods of time. We have also developed a mechanism for producing sleep deprivation, consisting of a slowly rotating wheel that the rat is within. This device allows access to food and water and also contains levers and stimuli to allow task performance during the sleep deprivation period. We will use this system to deprive rats of sleep at different times of their circadian rhythm and examine effects on performance. We will then analyze effects of manipulating the LC system on the performance deficits produced by sleep deprivation.
Impact of these findings The development of a target detection task for the rat now allows us to test the effects of stressors on a type of performance important in space missions. This model will also allow analysis of the effects of manipulations of the brain NE system of the LC in these stress effects to facilitate development of countermeasures that should facilitate performance in the face of stress. We found that acute stress increases FA errors in this task, and that decreasing neurotransmission in the LC system with clonidine may offset this effect. Accordingly, we also found that increased NE neurotransmission (with idazoxan) in non-stressed animals worsens performance on this task by producing the same type of errors (FAs). These results indicate that the LC-NE system may be a valid target for development of countermeasures to the effects of stress on performance. Finally, we have developed a device to sleep-deprive rats and measure effects on performance in this task. This will allow analysis of this important stressor on performance, and the ability of manipulations of the LC system to offset such stress effects on performance.
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