Invited ReviewEffects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: Towards translational challenge models for drug discovery in Alzheimer’s disease
Highlights
► Analysis of electroencephalographic (EEG) rhythms in animal models of deficit and drug-induced EEG normalisation provides a useful approach to drug discovery. ► Effects on EEG rhythms of challenges represented by administration of pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation provide a knowledge platform for preclinical investigation in Alzheimer’s disease. ► Expected changes of EEG rhythms due to experimental manipulations can promote preclinical innovative translational models fitting dynamics in humans.
Introduction
It is well known that Alzheimer’s disease (AD) is a progressive, neurodegenerative disease of the elderly, characterised by memory loss as well as additional cognitive and behavioural abnormalities. Early AD is associated with pathological changes in the basal forebrain cholinergic system, thalamocortical system, associative parietal–temporal areas and the complex of inter-related brain regions formed by the entorhinal cortex, hippocampus and amygdala (Daulatzai, 2010). Cholinergic neurotransmission protects neurons from amyloid beta (Abeta) production and its toxicity, which are enhanced by cholinergic depletion (Mohamed et al., 2011, Schliebs and Arendt, 2011). Symptomatic therapies target the cholinergic and glutamatergic systems, but no approved therapy is currently available to slow down or halt the neurodegenerative process.
A key objective of AD research is to develop and validate procedures for effective early proof-of-concept studies to evaluate novel symptomatic and disease-modifying agents in humans. The European Innovative Medicines Initiative project, PharmaCog, (IMI Undertaking on Neurodegenerative disorders, 2008) has adopted a strategy of parallel preclinical and human research for this purpose. In particular, procedures transiently interfering with cortical activity and cognitive processes in healthy volunteers and normal animals, that is, challenge models, are evaluated in this project. Such deficit models overcome the inherent difficulty of detecting significant improvements in cognitive performance in normal subjects. Pharmacological challenges include systemic administration of cholinergic or glutamatergic antagonists such as scopolamine and ketamine, hypoxia, sleep deprivation (SD) and transcranial magnetic stimulation (TMS). Validation of these models in drug discovery requires that potential symptomatic drugs normalise deficits or pathological alteration induced by challenge models in key neurophysiological mechanisms and cognitive processes.
In this article, the literature on animal models is reviewed in order to weigh the relative value of resting state or spontaneous ongoing electroencephalographic (EEG) patterns as putative ‘end’ points for an understanding of neurodegenerative processes. The aim is also to review drug effects in relevant animal models. The interest in these markers stems from the fact that recording of EEG activity is relatively inexpensive and able to probe the brain key features of oscillatory nature (Berger, 1929, Nunez, 2000, Michel et al., 2004, Rossini et al., 2007, Rossini, 2009, Babiloni et al., 2009a). Furthermore, spontaneous ongoing EEG rhythms in the resting state seem to reflect, at least at group level, preclinical and clinical stages of AD in humans (Babiloni et al., 2004, Babiloni et al., 2006a). From a translational point of view, spontaneous ongoing EEG rhythms show some similarities in humans and rodents. For example, alertness in humans and rodents is associated with enhanced power of low-voltage fast frequencies in EEG rhythms (i.e., beta rhythms spanning about 14–30 Hz), whereas non-rapid eye movement (REM) sleep and drowsiness are characterised by the enhanced power of high-voltage slow frequencies in EEG rhythms (i.e., delta and theta rhythms spanning about 1–7 Hz; Marshall and Born, 2002, Vyazovskiy et al., 2005). Anxiety has been shown to increase the power of low-voltage high frequencies in the resting-state EEG rhythms in both humans and rodents (Sviderskaia et al., 2001, Oathes et al., 2008). Finally, there is converging evidence that cholinergic and monoaminergic drugs have similar effects on spontaneous ongoing EEG rhythms in humans and rodents (Dimpfel et al., 1992, Jongsma et al., 1998, Jongsma et al., 2000, Coenen and Van Luijtelaar, 2003, Dimpfel, 2005). In the following sections, basic concepts about EEG techniques and markers are introduced.
Section snippets
Electroencephalographic techniques for translational research on AD
In humans, spontaneous ongoing scalp EEG rhythms reflect extracellular ion flow due to excitatory and inhibitory postsynaptic potentials in large populations of cortical pyramidal neurons (Nunez, 2000). There is a consensus that scalp EEG voltages mainly correspond to the local field potentials generated in superficial cortical layers, as local field potentials deriving from deeper cortical layers are attenuated by resistance of the head as a volume conductor. Specifically, the synaptic
Physiological generation of ongoing EEG rhythms
EEG activity characterised by slow-frequency oscillation and large-voltage amplitude can be observed in large slabs of neocortical tissue after an isolation procedure, suggesting that intrinsic cortical networks can sustain this type of slow, deactivated cortical oscillations (Timofeev et al., 2000). The presence of two distinct types of synchronised high-voltage, low-frequency rhythms has been suggested by the EEG recordings in cats and humans, namely one ensemble of slow-frequency rhythms in
Pharmacological modulation of ongoing EEG rhythms in animal models: the effects of cholinergic agonists and antagonists
Cholinergic therapies have been the mainstay of symptomatic therapeutic approaches in the treatment of AD for over 20 years. Acetylcholinesterase inhibitors sustain the availability of the natural transmitter by limiting its removal from the synapse. Alternatively, direct exogenous agonists or positive allosteric modulators of both nicotinic and muscarinic receptors still represent important therapeutic targets. For example, postsynaptic muscarinic M1 receptors are expressed in brain areas that
Pharmacological modulation of spontaneous ongoing EEG rhythms in animal models: interaction between cholinergic agents and other neuromodulatory agents
The interaction between cholinergic agents and other neuromodulatory (noradrenergic, dopaminergic, serotonergic and histaminergic) agents has contributed to the understanding of the physiology of spontaneous ongoing EEG rhythms and cortical arousal (Vertes, 1988, Jones and Cuello, 1989, Semba and Fibiger, 1989, Zaborszky, 1989). The available evidence suggests that these transmitters can indirectly modulate spontaneous ongoing cortical EEG rhythms by an action in the basal forebrain that
Effects of SD on EEG rhythms in animal models
Three sets of data are briefly discussed in this section: (1) the physiological model of the generation of EEG rhythms during sleep stages, (2) the main caveats of the experiments on SD in animal models and (3) the main effects of drug treatments on sleep.
A widely accepted model of sleep regulation postulates that sleep is under the control of two fundamental processes, the circadian and homeostatic processes (Daan et al., 1984). The circadian process governs the timing of virtually all 24 h
Effects of hypoxia on EEG rhythms recorded in animal models
Hypoxia is caused by a reduction in blood supply due to a variety of pathophysiological or traumatic insults to the brain. It is hypothesised to induce glucose hypometabolism in the hippocampus and other key brain areas subserving cognitive functions including memory. During sleep, repeated hypoxic events may affect respiratory cholinergic mechanism, respiratory regulation, upper airway patency and cerebral oxygenation (Peers et al., 2009, Scragg et al., 2005, Daulatzai, 2010). Diurnally,
Effects of TMS on EEG rhythms recorded in animal models
TMS enables the quantification of motor system excitability and transient ‘virtual’ functional lesions of cortical networks subserving cognitive functions including attention and episodic memory. Although this approach is routinely used in humans, its application to laboratory animal species is rare and little is known about the characteristics of animal TMS. Of note, TMS is non-invasive and produces predominantly interneuronal stimulation at low intensity, enabling its use in evaluating
Cortical spontaneous ongoing EEG rhythms in transgenic animal models of AD
Many laboratories have produced transgenic mice that recapitulate certain features of AD pathology, for example, mice which over-express the amyloid precursor protein (APP), which is associated with familial forms of AD (Howlett and Richardson, 2009). Histopathological assessment shows that APP transgenic mice demonstrate an accumulation of Abeta in plaques from an early age; these plaques are invariably surrounded by activated inflammatory cells such as astrocytes and microglia, as is common
Conclusions
We here reviewed the literature on spontaneous, ongoing, resting-state EEG rhythms as potential biomarkers for preclinical research in AD. Antagonists of cholinergic neurotransmission can synchronise spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs can restore a normal pattern of EEG desynchronisation. SD and hypoxia challenges also produce abnormal
Acknowledgements
The activity leading to the present review has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) for the Innovative Medicine Initiative under Grant Agreement No. 115009 (Prediction of cognitive properties of new drug candidates for neurodegenerative diseases in early clinical development, PharmaCog). For further information on the PharmaCog project, please refer to http://www.alzheimer-europe.org. We thank the staff of University of Foggia for its help
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