Browsing by Author "Russell, Vivienne"

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    Animal models of attention-deficit hyperactivity disorder
    (BioMed Central Ltd, 2005) Russell, Vivienne; Sagvolden, Terje; Johansen, Espen
    Although animals cannot be used to study complex human behaviour such as language, they do have similar basic functions. In fact, human disorders that have animal models are better understood than disorders that do not. ADHD is a heterogeneous disorder. The relatively simple nervous systems of rodent models have enabled identification of neurobiological changes that underlie certain aspects of ADHD behaviour. Several animal models of ADHD suggest that the dopaminergic system is functionally impaired. Some animal models have decreased extracellular dopamine concentrations and upregulated postsynaptic dopamine D1 receptors (DRD1) while others have increased extracellular dopamine concentrations. In the latter case, dopamine pathways are suggested to be hyperactive. However, stimulus-evoked release of dopamine is often decreased in these models, which is consistent with impaired dopamine transmission. It is possible that the behavioural characteristics of ADHD result from impaired dopamine modulation of neurotransmission in cortico-striato-thalamo-cortical circuits. There is considerable evidence to suggest that the noradrenergic system is poorly controlled by hypofunctional alpha2-autoreceptors in some models, giving rise to inappropriately increased release of norepinephrine. Aspects of ADHD behaviour may result from an imbalance between increased noradrenergic and decreased dopaminergic regulation of neural circuits that involve the prefrontal cortex. Animal models of ADHD also suggest that neural circuits may be altered in the brains of children with ADHD. It is therefore of particular importance to study animal models of the disorder and not normal animals. Evidence obtained from animal models suggests that psychostimulants may not be acting on the dopamine transporter to produce the expected increase in extracellular dopamine concentration in ADHD. There is evidence to suggest that psychostimulants may decrease motor activity by increasing serotonin levels. In addition to providing unique insights into the neurobiology of ADHD, animal models are also being used to test new drugs that can be used to alleviate the symptoms of ADHD.
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    Cross-fostering does not alter the neurochemistry or behavior of spontaneously hypertensive rats
    (BioMed Central Ltd, 2009) Howells, Fleur M; Bindewald, Leander; Russell, Vivienne
    BACKGROUND:Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable developmental disorder resulting from complex gene-gene and gene-environment interactions. The most widely used animal model, the spontaneously hypertensive rat (SHR), displays the major symptoms of ADHD (deficits in attention, impulsivity and hyperactivity) and has a disturbance in the noradrenergic system when compared to control Wistar-Kyoto rats (WKY). The aim of the present study was to determine whether the ADHD-like characteristics of SHR were purely genetically determined or dependent on the gene-environment interaction provided by the SHR dam. METHODS: SHR/NCrl (Charles River, USA), WKY/NCrl (Charles River, USA) and Sprague Dawley rats (SD/Hsd, Harlan, UK) were bred at the University of Cape Town. Rat pups were cross-fostered on postnatal day 2 (PND 2). Control rats remained with their birth mothers to serve as a reference for their particular strain phenotype. Behavior in the open-field and the elevated-plus maze was assessed between PND 29 and 33. Two days later, rats were decapitated and glutamate-stimulated release of [3H]norepinephrine was determined in prefrontal cortex and hippocampal slices. RESULTS: There was no significant effect of "strain of dam" but there was a significant effect of "pup strain" on all parameters investigated. SHR pups travelled a greater distance in the open field, spent a longer period of time in the inner zone and entered the inner zone of the open-field more frequently than SD or WKY. SD were more active than WKY in the open-field. WKY took longer to enter the inner zone than SHR or SD. In the elevated-plus maze, SHR spent less time in the closed arms, more time in the open arms and entered the open arms more frequently than SD or WKY. There was no difference between WKY and SD behavior in the elevated-plus maze. SHR released significantly more [3H]norepinephrine in response to glutamate than SD or WKY in both hippocampus and prefrontal cortex while SD prefrontal cortex released more [3H]norepinephrine than WKY. SHR were resilient, cross-fostering did not reduce their ADHD-like behavior or change their neurochemistry. Cross-fostering of SD pups onto SHR or WKY dams increased their exploratory behavior without altering their anxiety-like behavior. CONCLUSION: The ADHD-like behavior of SHR and their neurochemistry is genetically determined and not dependent on nurturing by SHR dams. The similarity between WKY and SD supports the continued use of WKY as a control for SHR and suggests that SD may be a useful additional reference strain for SHR. The fact that SD behaved similarly to WKY in the elevated-plus maze argues against the use of WKY as a model for anxiety-like disorders.
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    The impact of voluntary exercise on relative telomere length in a rat model of developmental stress
    (BioMed Central Ltd, 2012) Botha, Martmari; Grace, Laurian; Bugarith, Kishor; Russell, Vivienne; Kidd, Martin; Seedat, Soraya; Hemmings, Sian
    BACKGROUND: Exposure to early adverse events can result in the development of later psychopathology, and is often associated with cognitive impairment. This may be due to accelerated cell aging, which can be catalogued by attritioned telomeres. Exercise enhances neurogenesis and has been proposed to buffer the effect of psychological stress on telomere length. This study aimed to investigate the impact of early developmental stress and voluntary exercise on telomere length in the ventral hippocampus (VH) and prefrontal cortex (PFC) of the rat. Forty-five male Sprague-Dawley rats were categorised into four groups: maternally separated runners (MSR), maternally separated non-runners (MSnR), non-maternally separated runners (nMSR) and non-maternally separated non-runners (nMSnR). Behavioural analyses were conducted to assess anxiety-like behaviour and memory performance in the rats, after which relative telomere length was measured using qPCR. RESULTS: Maternally separated (MS) rats exhibited no significant differences in either anxiety levels or memory performance on the elevated-plus maze and the open field compared to non-maternally separated rats at 49 days of age. Exercised rats displayed increased levels of anxiety on the day that they were removed from the cages with attached running wheels, as well as improved spatial learning and temporal recognition memory compared to non-exercised rats. Exploratory post-hoc analyses revealed that maternally separated non-exercised rats exhibited significantly longer telomere length in the VH compared to those who were not maternally separated; however, exercise appeared to cancel this effect since there was no difference in VH telomere length between maternally separated and non-maternally separated runners. CONCLUSIONS: The increased telomere length in the VH of maternally separated non-exercised rats may be indicative of reduced cellular proliferation, which could, in turn, indicate hippocampal dysfunction. This effect on telomere length was not observed in exercised rats, indicating that voluntary exercise may buffer against the progressive changes in telomere length caused by alterations in maternal care early in life. In future, larger sample sizes will be needed to validate results obtained in the present study and obtain a more accurate representation of the effect that psychological stress and voluntary exercise have on telomere length.
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    In Memoriam Terje Sagvolden
    (2011-03-17) Sergeant, Joseph; Aase, Heidi; Faraone, Stephen V; Johansen, Espen; Kalaria, Raj; Meyer, Anneke; Russell, Vivienne; Sadile, Adolfo; Sonuga-Barke, Edmund; Tannock, Rosemary
    It is with great sadness that we note the sudden passing of our colleague and friend Professor Terje Sagvolden, a highly accomplished neuroscientist, well known across the world for his contribution to our understanding of the neurobiology of attention deficit hyperactivity disorder (ADHD). Here we pay tribute to this magnificent man and scientist in an intercontinental recognition of his contribution to science. Terje was a wonderful caring person, a kind considerate friend and a brilliant researcher. Terje was inspiring and creative, as well as a visionary. He pioneered collaborative research and forged links between basic and clinical researchers in different disciplines, across different countries. With Terje’s help, the European Network for Hyperkinetic Disorders (Eunethydis), of which he was a founding member, obtained a major EU grant in 1993 that enabled the then participating centres to work on the same ADHD project cross-nationally. The effect of this was to harmonize research efforts in several European groups. This forged the basis for the later projects on genetics and intervention evaluation. In the discussions held at Eunethydis meetings, Terje took up the challenge with his characteristic enthusiasm to demonstrate that the animal model he was using had considerable clinical relevance to ADHD.
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    Parallel changes in gene expression in peripheral blood mononuclear cells and the brain after maternal separation in the mouse
    (BioMed Central Ltd, 2009) van Heerden, Johan; Conesa, Ana; Stein, Dan J; Montaner, David; Russell, Vivienne; Illing, Nicola
    BACKGROUND: The functional integration of the neuro-, endocrine- and immune-systems suggests that the transcriptome of white blood cells may reflect neuropsychiatric states, and be used as a non-invasive diagnostic indicator. We used a mouse maternal separation model, a paradigm of early adversity, to test the hypothesis that transcriptional changes in peripheral blood mononuclear cells (PBMCs) are paralleled by specific gene expression changes in prefrontal cortex (PFC), hippocampus (Hic) and hypothalamus (Hyp). Furthermore, we evaluated whether gene expression profiles of PBMCs could be used to predict the separation status of individual animals.FINDINGS:Microarray gene expression profiles of all three brain regions provided substantial evidence of stress-related neural differences between maternally separated and control animals. For example, changes in expression of genes involved in the glutamatergic and GABAergic systems were identified in the PFC and Hic, supporting a stress-related hyperglutamatergic state within the separated group. The expression of 50 genes selected from the PBMC microarray data provided sufficient information to predict treatment classes with 95% accuracy. Importantly, stress-related transcriptome differences in PBMC populations were paralleled by stress-related gene expression changes in CNS target tissues. CONCLUSION: These results confirm that the transcriptional profiles of peripheral immune tissues occur in parallel to changes in the brain and contain sufficient information for the efficient diagnostic prediction of stress-related neural states in mice. Future studies will need to evaluate the relevance of the predictor set of 50 genes within clinical settings, specifically within a context of stress-related disorders.
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    Research perceived mental effort correlates with changes in tonic arousal during attentional tasks
    (BioMed Central Ltd, 2010) Howells, Fleur; Stein, Dan; Russell, Vivienne
    BACKGROUND: It has been suggested that perceived mental effort reflects changes in arousal during tasks of attention. Such changes in arousal may be tonic or phasic, and may be mediated by the locus-coeruleus norepinephrine (LC-NE) system. We hypothesized that perceived mental effort during attentional tasks would correlate with tonic changes in cortical arousal, as assessed by relative electroencephalogram (EEG) band power and theta/beta ratio, and not with phasic changes in cortical arousal, assessed by P300 amplitude and latency. METHODS: Forty-six healthy individuals completed tasks that engage the anterior and posterior attention networks (continuous performance task, go/no-go task, and cued target detection task). During completion of the three attentional tasks a continuous record of tonic and phasic arousal was taken. Cortical measures of arousal included frequency band power, theta/beta ratios over frontal and parietal cortices, and P300 amplitude and latency over parietal cortices. Peripheral measures of arousal included skin conductance responses, heart rate and heart rate variance. Participants reported their perceived mental effort during each of the three attentional tasks. RESULTS: First, changes in arousal were seen from rest to completion of the three attentional tasks and between the attentional tasks. Changes seen between the attentional tasks being related to the task design and the attentional network activated. Second, perceived mental effort increased when demands of the task increased and correlated with left parietal beta band power during the three tasks of attention. Third, increased mental effort during the go/no-go task and the cued target detection task was inversely related to theta/beta ratios. CONCLUSION: These results indicate that perceived mental effort reflects tonic rather than phasic changes in arousal during tasks of attention. We suggest that perceived mental effort may reflect in part tonic activity of the LC-NE system in healthy individuals.
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    Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis
    (BioMed Central Ltd, 2006) Russell, Vivienne; Oades, Robert; Tannock, Rosemary; Killeen, Peter; Auerbach, Judith; Johansen, Espen; Sagvolden, Terje
    1. ABSTRACT:BACKGROUND:Current concepts of Attention-Deficit/Hyperactivity Disorder (ADHD) emphasize the role of higher-order cognitive functions and reinforcement processes attributed to structural and biochemical anomalies in cortical and limbic neural networks innervated by the monoamines, dopamine, noradrenaline and serotonin. However, these explanations do not account for the ubiquitous findings in ADHD of intra-individual performance variability, particularly on tasks that require continual responses to rapid, externally-paced stimuli. Nor do they consider attention as a temporal process dependent upon a continuous energy supply for efficient and consistent function. A consideration of this feature of intra-individual response variability, which is not unique to ADHD but is also found in other disorders, leads to a new perspective on the causes and potential remedies of specific aspects of ADHD.THE HYPOTHESIS:We propose that in ADHD, astrocyte function is insufficient, particularly in terms of its formation and supply of lactate. This insufficiency has implications both for performance and development: H1) In rapidly firing neurons there is deficient ATP production, slow restoration of ionic gradients across neuronal membranes and delayed neuronal firing; H2) In oligodendrocytes insufficient lactate supply impairs fatty acid synthesis and myelination of axons during development. These effects occur over vastly different time scales: those due to deficient ATP (H1) occur over milliseconds, whereas those due to deficient myelination (H2) occur over months and years. Collectively the neural outcomes of impaired astrocytic release of lactate manifest behaviourally as inefficient and inconsistent performance (variable response times across the lifespan, especially during activities that require sustained speeded responses and complex information processing).TESTING THE HYPOTHESIS:Multi-level and multi-method approaches are required. These include: 1) Use of dynamic strategies to evaluate cognitive performance under conditions that vary in duration, complexity, speed, and reinforcement; 2) Use of sensitive neuroimaging techniques such as diffusion tensor imaging, magnetic resonance spectroscopy, electroencephalography or magnetoencephalopathy to quantify developmental changes in myelination in ADHD as a potential basis for the delayed maturation of brain function and coordination, and 3) Investigation of the prevalence of genetic markers for factors that regulate energy metabolism (lactate, glutamate, glucose transporters, glycogen synthase, glycogen phosphorylase, glycolytic enzymes), release of glutamate from synaptic terminals and glutamate-stimulated lactate production (SNAP25, glutamate receptors, adenosine receptors, neurexins, intracellular Ca2+), as well as astrocyte function (alpha1, alpha2 and beta-adrenoceptors, dopamine D1 receptors) and myelin synthesis (lactate transporter, Lingo-1, Quaking homolog, leukemia inhibitory factor, and Transferrin).IMPLICATIONS OF THE HYPOTHESIS:The hypothesis extends existing theories of ADHD by proposing a physiological basis for specific aspects of the ADHD phenotype - namely frequent, transient and impairing fluctuations in functioning, particularly during performance of speeded, effortful tasks. The immediate effects of deficient ATP production and slow restoration of ionic gradients across membranes of rapidly firing neurons have implications for daily functioning: For individuals with ADHD, performance efficacy would be enhanced if repetitive and lengthy effortful tasks were segmented to reduce concurrent demands for speed and accuracy of response (introduction of breaks into lengthy/effortful activities such as examinations, motorway driving, assembly-line production). Also, variations in task or modality and the use of self- rather than system-paced schedules would be helpful. This would enable energetic demands to be distributed to alternate neural resources, and energy reserves to be re-established. Longer-term effects may manifest as reduction in regional brain volumes since brain areas with the highest energy demand will be most affected by a restricted energy supply and may be reduced in size. Novel forms of therapeutic agent and delivery system could be based on factors that regulate energy production and myelin synthesis. Since the phenomena and our proposed basis for it are not unique to ADHD but also manifests in other disorders, the implications of our hypotheses may be relevant to understanding and remediating these other conditions as well.
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    The role of norepinephrine in arousal and attention: a human and rat study
    (2009) Howells, Fleur Margaret; Russell, Vivienne; Vaughan, Christopher
    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.