Animal models of attention-deficit hyperactivity disorder

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 α(2)-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

Cross-fostering does not alter the neurochemistry or behavior of spontaneously hypertensive rats

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

Effects of early life trauma are dependent on genetic predisposition: a rat study

<p>Abstract</p> <p>Background</p> <p>Trauma experienced early in life increases the risk of developing a number of psychological and/or behavioural disorders. It is unclear, however, how genetic predisposition to a behavioural disorder, such as attention-deficit/hyperactivity disorder (ADHD), modifies the long-term effects of early life trauma. There is substantial evidence from family and twin studies for susceptibility to ADHD being inherited, implying a strong genetic component to the disorder. In the present study we used an inbred animal model of ADHD, the spontaneously hypertensive rat (SHR), to investigate the long-term consequences of early life trauma on emotional behaviour in individuals predisposed to developing ADHD-like behaviour.</p> <p>Methods</p> <p>We applied a rodent model of early life trauma, maternal separation, to SHR and Wistar-Kyoto rats (WKY), the normotensive control strain from which SHR were originally derived. The effects of maternal separation (removal of pups from dam for 3 h/day during the first 2 weeks of life) on anxiety-like behaviour (elevated-plus maze) and depressive-like behaviour (forced swim test) were assessed in prepubescent rats (postnatal day 28 and 31). Basal levels of plasma corticosterone were measured using radioimmunoassay.</p> <p>Results</p> <p>The effect of maternal separation on SHR and WKY differed in a number of behavioural measures. Similar to its reported effect in other rat strains, maternal separation increased the anxiety-like behaviour of WKY (decreased open arm entries) but not SHR. Maternal separation increased the activity of SHR in the novel environment of the elevated plus-maze, while it decreased that of WKY. Overall, SHR showed a more active response in the elevated plus-maze and forced swim test than WKY, regardless of treatment, and were also found to have higher basal plasma corticosterone compared to WKY. Maternal separation increased basal levels of plasma corticosterone in SHR females only, possibly through adaptive mechanisms involved in maintaining their active response in behavioural tests. Basal plasma corticosterone was found to correlate positively with an active response to a novel environment and inescapable stress across all rats.</p> <p>Conclusion</p> <p>SHR are resilient to the anxiogenic effects of maternal separation, and develop a non-anxious, active response to a novel environment following chronic mild stress during the early stages of development. Our findings highlight the importance of genetic predisposition in determining the outcome of early life adversity. SHR may provide a model of early life trauma leading to the development of hyperactivity rather than anxiety and depression. Basal levels of corticosterone correlate with the behavioural response to early life trauma, and may therefore provide a useful marker for susceptibility to a certain behavioural temperament.</p

Perceived mental effort correlates with changes in tonic arousal during attentional tasks

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Maternal separation affects dopamine transporter function in the Spontaneously Hypertensive Rat: An in vivo electrochemical study

<p>Abstract</p> <p>Background</p> <p>Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterised by symptoms of inattention, impulsivity and hyperactivity. The spontaneously hypertensive rat (SHR) is a well-characterised model of this disorder and has been shown to exhibit dopamine dysregulation, one of the hypothesised causes of ADHD. Since stress experienced in the early stages of life can have long-lasting effects on behaviour, it was considered that early life stress may alter development of the dopaminergic system and thereby contribute to the behavioural characteristics of SHR. It was hypothesized that maternal separation would alter dopamine regulation by the transporter (DAT) in ways that distinguish SHR from control rat strains.</p> <p>Methods</p> <p>SHR and control Wistar-Kyoto (WKY) rats were subjected to maternal separation for 3 hours per day from postnatal day 2 to 14. Rats were tested for separation-induced anxiety-like behaviour followed by <it>in vivo </it>chronoamperometry to determine whether changes had occurred in striatal clearance of dopamine by DAT. The rate of disappearance of ejected dopamine was used as a measure of DAT function.</p> <p>Results</p> <p>Consistent with a model for ADHD, SHR were more active than WKY in the open field. SHR entered the inner zone more frequently and covered a significantly greater distance than WKY. Maternal separation increased the time that WKY spent in the closed arms and latency to enter the open arms of the elevated plus maze, consistent with other rat strains. Of note is that, maternal separation failed to produce anxiety-like behaviour in SHR. Analysis of the chronoamperometric data revealed that there was no difference in DAT function in the striatum of non-separated SHR and WKY. Maternal separation decreased the rate of dopamine clearance (k_-1) in SHR striatum. Consistent with this observation, the dopamine clearance time (T100) was increased in SHR. These results suggest that the chronic mild stress of maternal separation impaired the function of striatal DAT in SHR.</p> <p>Conclusions</p> <p>The present findings suggest that maternal separation failed to alter the behaviour of SHR in the open field and elevated plus maze. However, maternal separation altered the dopaminergic system by decreasing surface expression of DAT and/or the affinity of DAT for dopamine, increasing the time to clear dopamine from the extracellular fluid in the striatum of SHR.</p

Response variability in Attention-Deficit/Hyperactivity Disorder: a neuronal and glial energetics hypothesis

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 Ca(2+)), as well as astrocyte function (α(1), α(2 )and β-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

Origins of altered reinforcement effects in ADHD

Attention-deficit/hyperactivity disorder (ADHD), characterized by hyperactivity, impulsiveness and deficient sustained attention, is one of the most common and persistent behavioral disorders of childhood. ADHD is associated with catecholamine dysfunction. The catecholamines are important for response selection and memory formation, and dopamine in particular is important for reinforcement of successful behavior. The convergence of dopaminergic mesolimbic and glutamatergic corticostriatal synapses upon individual neostriatal neurons provides a favorable substrate for a three-factor synaptic modification rule underlying acquisition of associations between stimuli in a particular context, responses, and reinforcers. The change in associative strength as a function of delay between key stimuli or responses, and reinforcement, is known as the delay of reinforcement gradient. The gradient is altered by vicissitudes of attention, intrusions of irrelevant events, lapses of memory, and fluctuations in dopamine function. Theoretical and experimental analyses of these moderating factors will help to determine just how reinforcement processes are altered in ADHD. Such analyses can only help to improve treatment strategies for ADHD

Developmental stress elicits preference for methamphetamine in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder

Background: Developmental stress has been hypothesised to interact with genetic predisposition to increase the risk of developing substance use disorders. Here we have investigated the effects of maternal separation-induced developmental stress using a behavioural proxy of methamphetamine preference in an animal model of attentiondeficit/hyperactivity disorder, the spontaneously hypertensive rat, versus Wistar Kyoto and Sprague–Dawley comparator strains. Results: Analysis of results obtained using a conditioned place preference paradigm revealed a significant strain × stress interaction with maternal separation inducing preference for the methamphetamine-associated compartment in spontaneously hypertensive rats. Maternal separation increased behavioural sensitization to the locomotor-stimulatory effects of methamphetamine in both spontaneously hypertensive and Sprague–Dawley strains but not in Wistar Kyoto rats. Conclusions: Our findings indicate that developmental stress in a genetic rat model of attention-deficit/hyperactivity disorder may foster a vulnerability to the development of substance use disorders

The 2dF Galaxy Redshift Survey: stochastic relative biasing between galaxy populations

It is well known that the clustering of galaxies depends on galaxy type. Such relative bias complicates the inference of cosmological parameters from galaxy redshift surveys, and is a challenge to theories of galaxy formation and evolution. In this paper we perform a joint counts-in-cells analysis on galaxies in the 2dF Galaxy Redshift Survey, classified by both colour and spectral type, η, as early- or late-type galaxies. We fit three different models of relative bias to the joint probability distribution of the cell counts, assuming Poisson sampling of the galaxy density field. We investigate the non-linearity and stochasticity of the relative bias, with cubic cells of side 10 =L = 45 Mpc (h = 0.7). Exact linear bias is ruled out with high significance on all scales. Power-law bias gives a better fit, but likelihood ratios prefer a bivariate lognormal distribution, with a non-zero ‘stochasticity', i.e. scatter that may result from physical effects on galaxy formation other than those from the local density field. Using this model, we measure a correlation coefficient in log-density space (rLN) of 0.958 for cells of length L = 10 Mpc, increasing to 0.970 by L = 45 Mpc. This corresponds to a stochasticity of 0.44 ± 0.02 and 0.27 ± 0.05, respectively. For smaller cells, the Poisson-sampled lognormal distribution presents an increasingly poor fit to the data, especially with regard to the fraction of completely empty cells. We compare these trends with the predictions of semi-analytic galaxy formation models: these match the data well in terms of the overall level of stochasticity, variation with scale and the fraction of empty cell