University of Alberta

Year: 2012

State-dependent modulation of breathing in urethane-anesthetized rats

PMID: 22895710

Pagliardini S, Greer JJ, Funk GD, Dickson CT

J. Neurosci. 2012 Aug;32(33):11259-70


Respiratory activity is most fragile during sleep, in particular during paradoxical [or rapid eye movement (REM)] sleep and sleep state transitions. Rats are commonly used to study respiratory neuromodulation, but rodent sleep is characterized by a highly fragmented sleep pattern, thus making it very challenging to examine different sleep states and potential pharmacological manipulations within them. Sleep-like brain-state alternations occur in rats under urethane anesthesia and may be an effective and efficient model for sleep itself. The present study assessed state-dependent changes in breathing and respiratory muscle modulation under urethane anesthesia to determine their similarity to those occurring during natural sleep. Rats were anesthetized with urethane and respiratory airflow, as well as electromyographic activity in respiratory muscles were recorded in combination with local field potentials in neocortex and hippocampus to determine how breathing pattern and muscle activity are modulated with brain state. Measurements were made in normoxic, hypoxic, and hypercapnic conditions. Results were compared with recordings made from rats during natural sleep. Brain-state alternations under urethane anesthesia were closely correlated with changes in breathing rate and variability and with modulation of respiratory muscle tone. These changes closely mimicked those observed in natural sleep. Of great interest was that, during both REM and REM-like states, genioglossus muscle activity was strongly depressed and abdominal muscle activity showed potent expiratory modulation. We demonstrate that, in urethane-anesthetized rats, respiratory airflow and muscle activity are closely correlated with brain-state transitions and parallel those shown in natural sleep, providing a useful model to systematically study sleep-related changes in respiratory control.

BOSC: a better oscillation detection method, extracts both sustained and transient rhythms from rat hippocampal recordings

PMID: 21997899

Hughes AM, Whitten TA, Caplan JB, Dickson CT

Hippocampus 2012 Jun;22(6):1417-28


Neuronal population oscillations at a variety of frequencies can be readily seen in electroencephalographic (EEG) as well as local field potential recordings in many different species. Although these brain rhythms have been studied for many years, the methods for identifying discrete oscillatory epochs are still widely variable across studies. The “better oscillation detection” (BOSC) method applies standardized criteria to detect runs of “true” oscillatory activity and rejects transient events that do not reflect actual rhythms. It does so by estimating the background spectrum of the actual signal to derive detection criteria that include both power and duration thresholds. This method has not yet been applied to nonhuman data. Here, we test the BOSC method on two important rat hippocampal oscillatory signals, the theta rhythm and slow oscillation (SO), two large amplitude and mutually exclusive states. The BOSC method detected both the relatively sustained theta rhythm and the relatively transient SO apparent under urethane anesthesia and was relatively resilient to spectral features that changed across states, complementing previous findings for human EEG. Detection of oscillatory activity using the BOSC method (but not more traditional Fourier transform-based power analysis) corresponded well with human expert ratings. Moreover, for near-continuous theta, BOSC proved useful for detecting discrete disruptions that were associated with sudden and large amplitude phase shifts of the ongoing rhythm. Thus, the BOSC method accurately extracts oscillatory and nonoscillatory episodes from field potential recordings and produces systematic, objective, and consistent results-not only across frequencies, brain regions, tasks, and waking states, as shown previously, but also across species and for both sustained and transient rhythms. Thus, the BOSC method will facilitate more direct comparisons of oscillatory brain activity across all types of experimental paradigms.

Neurosilence: profound suppression of neural activity following intracerebral administration of the protein synthesis inhibitor anisomycin

PMID: 22396412

Sharma AV, Nargang FE, Dickson CT

J. Neurosci. 2012 Feb;32(7):2377-87


Early in their formation, memories are thought to be labile, requiring a process called consolidation to give them near-permanent stability. Evidence for consolidation as an active and biologically separate mnemonic process has been established through posttraining manipulations of the brain that promote or disrupt subsequent retrieval. Consolidation is thought to be ultimately mediated via protein synthesis since translational inhibitors such as anisomycin disrupt subsequent memory when administered in a critical time window just following initial learning. However, when applied intracerebrally, they may induce additional neural disturbances. Here, we report that intrahippocampal microinfusions of anisomycin in urethane-anesthetized rats at dosages previously used in memory consolidation studies strongly suppressed (and in some cases abolished) spontaneous and evoked local field potentials (and associated extracellular current flow) as well as multiunit activity. These effects were not coupled to the production of pathological electrographic activity nor were they due to cell death. However, the amount of suppression was correlated with the degree of protein synthesis inhibition as measured by autoradiography and was also observed with cycloheximide, another translational inhibitor. Our results suggest that (1) the amnestic effects of protein synthesis inhibitors are confounded by neural silencing and that (2) intact protein synthesis is crucial for neural signaling itself.

A critical test of the hippocampal theta model of anxiolytic drug action

PMID: 21723303

Yeung M, Treit D, Dickson CT

Neuropharmacology 2012 Jan;62(1):155-60


Hippocampal theta rhythms have been associated with a number of behavioural processes, including learning, memory and arousal. Recently it has been argued that the suppression of hippocampal theta is a valid indicator of anxiolytic drug action. Like all such models, however, it has relied almost exclusively on the experimental effects of well-known, clinically proven anxiolytic compounds for validation. The actual predictive validity of putative models of anxiolytic drug action, however, cannot be rigorously tested with this approach alone. The present study provides a stringent test of the predictive validity of the theta suppression model, using the drug phenytoin (50 mg/kg and 10 mg/kg), and a positive comparison compound, diazepam (2 mg/kg). Phenytoin has two important properties that are advantageous for assessing the validity of the theta suppression model: 1) it is a standard antiepileptic drug with no known anxiolytic effects, and 2) its primary mechanism of action is through suppression of the persistent sodium current, an effect that should also suppress hippocampal theta. Because of the latter property, we also directly compared the effects of phenytoin in the theta suppression model with its effects in the most widely tested behavioural model of anxiolytic drug action, the elevated plus-maze. While an anxiolytic-like effect of phenytoin in the theta suppression model might be expected simply due to its suppressive effects on sodium channel currents, anxiolytic effects in both tests would provide strong support for the predictive validity of the theta suppression model. Surprisingly, phenytoin produced clear anxiolytic-like effects in both neurophysiological and behavioural models, thus providing strong evidence of the predictive validity of the theta suppression model. This article is part of a Special Issue entitled ‘Anxiety and Depression’.

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