The role of norepinephrine in arousal and attention: a human and rat study

Howells, Fleur Margaret

The role of norepinephrine in arousal and attention: a human and rat study

Thesis / Dissertation

2009

Abstract

Background The locus coeruleus-norepinephrine (LC-NE) system is known to play an integral role in attention and arousal. The LC fires both tonically and phasically. We propose that tonic firing of the LC-NE system needs to be maintained in a critical range for phasic activity of the LCNE system to enhance the signal-to-noise ratio in stimulus-related neural networks. In addition terminal release of NE from LC neurons responds synergistically with glutamate release from glutamatergic neurons, thereby potentiating its signal. The Yerkes and Dodson (1908) theory of arousal and performance can be represented by an inverted-U shaped curve which serves to relate the proposed functioning of the LC-NE system role (level of arousal) to attentional performance. In the present study we performed both non-invasive human studies (Part A) and invasive rat studies (Part B) to test this hypothesis and elaborate its parameters. Part A The first aim of the human study was to determine whether perceived mental effort during performance of an attentional task was reflected by physiological arousal. The second aim was to determine whether healthy individuals with high levels of behavioral impulsivity were physiologically hypo-aroused. The third aim was to determine whether healthy individuals with high levels of anxiety were physiologically hyper-aroused, and whether smoking (nicotine) was used as a form of self-medication. The fourth aim was to determine whether healthy individuals who had experienced childhood traumatic events showed physiological correlates during attentional task performance that were related to arousal and the LC-NE system activity. Healthy participants were recruited voluntarily, they completed three attentional tasks designed to test different aspect of attention and impulsivity: (1) a continuous performance task, (2) a Go/No-Go task, and (3) a cued target detection task. During completion of the attentional tasks, the participants' arousal levels were continuously recorded: ( 1) electroencephalogram (EEG), (2) electrocardiogram (ECG), and (3) skin conductance responses. Prior(± 5min) to commencement of the attentional tasks participants supplied a saliva sample for cortisol measurement and a second sample was collected immediately after the attentional tasks. Participants also gave blood for future genetic analysis; these samples were obtained on a separate day to that of the attentional tasks. Participants also completed a battery of neuropsychological questionnaires/inventories with respect to their day to day behaviors that were used to relate perceived mental effort, impulsivity, anxiety, and childhood trauma to the physiological measures recorded. Our results indicate healthy participants' perceived mental effort was related to aspects of physiological arousal, left parietal relative beta power was found to be associated with perceived mental effort during each of the three attentional tasks. In addition each of the tasks, due to their different parameters showed associations with several other relative cortical frequency bands. Only the Go/No-Go task showed associations with peripheral physiological arousal. We suggested that mental effort in a 'healthy' cohort of participants could be used as a measure of tonic arousal afforded by the LC-NE system, we found several cortical associations. This finding needs to be extended to see if reported mental effort may serve to measure functional LC-NE systems and highlight dysfunction in the LC-NE systems tonic activities in human disorders of 'hypoarousal' such as individuals with ADHD and of 'hyperarousal' such as individuals with anxiety related disorders. We proposed that organisms that were 'hypoaroused' present with decreased tonic activity. Individuals with ADHD have been reported to make increased errors and have short response times. Impulsivity was effectively shown in the present study in the Go/No-Go task response times and self-reported impulsive behavior. Impulsivity within our cohort was measured as short response times in the Go/No-Go task which was reflected by increased relative beta power over both frontal and parietal lobes. These associations dissipated with the progression of the task suggesting that healthy participants with impulsive behaviors were able to improve cortical arousal levels. This finding needs to be extended to include human disorders of 'hypoarousal' such as ADHD to ascertain whether 'hypoaroused' individuals are unable to reduce these associations as the present 'healthy' cohort of participants were able to do, this would further support the present hypothesis. We proposed that organisms that were 'hyperaroused' would present with increased tonic activity. Individuals with anxiety related disorders are reported to be distracted and attempt to passively avoid environmental cues. Anxiety levels were reflected in the present cohort of 'healthy' participants' cortical activities related to the LC-NE system activity tonically by relative frequency power and phasically by the short latency in P300. This finding needs to be extended to ascertain whether 'hyperaroused' individuals with disorders such as anxiety related disorders and depression show a similar pattern of activation of tonic and phasic firing of the LC that would further support the present hypothesis. Interestingly nicotine use showed a similar association, suggesting that nicotine users improved their functional information processing shown by their reduced P300 latency. Experiences of childhood trauma led to several cortical associations with physical neglect, abuse and emotional abuse, there were no associations with emotional neglect and sexual abuse. For emotional abuse relative right frontal alpha power was negatively associated across all three attentional tasks. The majority of the associations were found during the Go/No-Go task. Childhood trauma reflected increased recruitment of mental resources as seen by reduced alpha activity, how this is related to the functioning of the LC-NE system needs further interrogation. Part B The first aim was to determine whether the relationship (or synergism) between LC-NE terminals and glutamate in hippocampal slices was different in a strain of rat that shows 'hypoarousal' and a rat strain that shows 'hyperarousal'. The second aim was to determine which glutamate receptors played a role in LC-NE terminal release in these two rat strains. The third aim was to determine whether LC-NE terminals responded differentially in several rat strains. The fourth aim was to determine whether the differential release of NE form LCNE terminals extended to other brain areas that are known to receive NE input from the LC. The fifth aim was to determine whether a change in maternal environment to that of 'hypoaroused' or 'hyperaroused' dam would lead to changes in behaviors related to arousal and whether the synergistic interaction between glutamate and LC-NE terminals was affected by the different rearing conditions. The sixth aim was to determine whether maternal separation affected glutamate stimulated release of NE in hippocampal and prefrontal cortical brain slices. The seventh aim was to determine whether an acute nicotine dose reduced anxiety-like and depressive-like behaviors in several rat strains and to relate it to the effects of acetylcholine on the LC-NE system. Several strains of rat were used for the animal studies including the spontaneously hypertensive rat (SHR), the Wistar-Kyoto rat (WKY), Sprague-Dawley (SD), Long-Evans hooded-rat, and Wistar rat. The open-field and the elevated-plus maze were used to assess exploratory behaviors and anxiety-like behavior between P29 and P33. Glutamate-stimulated release of NE from LC-NE terminals was achieved by a superfusion technique. The 'hyporaroused' rats (SHR) showed exaggerated release of NE from LC-NE hippocampal terminals when stimulated with glutamate as compared to the 'hyperaroused' rats (WKY). Glutamate ionotropic receptor antagonism yielded differential release of NE from LC-NE hippocampal terminals when stimulated with glutamate. WKY rats depended more heavily on AMPA receptor activation for the release of NE, while SHR released greater amounts of NE when the NMDA receptors were antagonized. The exaggeration of NE release in the 'hypoaroused' rats and decrease of NE release in the 'hyperaroused' rats was explained by assessing glutamate stimulated release of NE in hippocampal slices in several strains of rat. Change in maternal environment through cross-fostering of several rat strains showed enhanced anxiety-like behaviors in the 'hyperaroused' rat model when fostered by the 'hyporaroused' dams, while fostering of the 'hyperaroused' rat model onto a reference strain showed reduction in anxiety-like behaviors. When the reference strain was fostered onto the 'hyperaroused' rat strain their anxiety-like behaviors increased. Glutamate stimulated release of NE from the hippocampus and prefrontal cortices were not associated with the changes in behavior. Maternal separation of Sprague-Dawley rats did not affect glutamate stimulated release of NE release from LC-NE terminals of the hippocampus and prefrontal cortex. Acute nicotine led to increased activity in the references strain, however did not affect the behavior of the 'hypoaroused' and 'hyperaroused' rat strains. Acute nicotine did not lead to a change in glutamate stimulated release of NE from hippocampal or prefrontal cortical brain slices. The exaggerated release of NE from the 'hypoaroused' rat model suggested that there may be reduced synergistic action between the NEergic and glutamatergic terminals. We suggest that this may be a result of increased GABAergic inhibition, resulting in reduced levels of NE at LC-NE terminals. This suggestion supports the present hypothesis as reduced tonic activity leads to increased terminal release of NE from LC-NE terminals. The reduced response of NE release from the "hyperaroused' rat model LC-NE terminals suggests a down regulation of glutamate receptors that may result from the increased tonic firing of the LC thereby reducing the synergistic activation between the NEergic and glutamatergic terminals. This suggestion supports the present hypothesis as increased tonic activity would enhance the release of NE, without clearance of NE as the present hypothesis suggests there may be down-regulation of AMPA receptors in vivo. We suggest that the 'hyperaroused' rat model is susceptible to environmental manipulations, while the 'hypoaroused' rat model was resilient to environmental manipulations. These findings led us to suggest that organisms that are 'hypoaroused' may be more resilient to external environmental inputs as a result of increased GABAergic function as changes in glutamate-stimulated release was not affected. This suggestion is complimented by the finding that glutamate-stimulated release of NE was not altered in the maternally separated Sprague-Dawley rats. Interestingly acute nicotine decreased anxiety-like behavior in Sprague-Dawley rats, however no change was seen in either the 'hypoaroused' or the 'hyperaroused' rat models employed. Conclusions Cortical arousal as seen by relative frequencies from EEG recordings does serve to assess tonic activity of the LC-NE system. P300 amplitude and latency provides a measure of the phasic activity of the LC-NE system. The relationship between noradrenergic and glutamatergic neurons at terminal loci of the LC-NE system serve to highlight the dysfunction of the LC-NE system in 'hypoaroused' and 'hyperaroused' organisms. Nicotine use does serve as a form of self-medication in the reduction of anxiety. Childhood trauma and environmental manipulations affect arousal regulation.

Keywords

Human Biology

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PhD / Doctoral

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