Category: Uncategorized (Page 3 of 5)

PMID: 19553480

Nazer F, Dickson CT

J. Neurophysiol. 2009 Sep;102(3):1880-9

Abstract

In mesial temporal lobe (MTL) epilepsy, which typically involves the hippocampus (HPC), epileptiform events are enhanced during slow wave sleep (SWS). It remains unclear how and why the electroencephalographic (EEG) states that constitute SWS might predispose the HPC to this type of pathological activity. Recently our laboratory has described a novel state of deactivated hippocampal EEG activity that occurs during both SWS and urethan anesthesia: the slow oscillation (SO). This activity is characterized by a high-amplitude approximately 1-Hz signal, high synchrony within the hippocampus, and a dynamic coordination with neocortical SO. To assess how this activity state might influence epileptiform discharges, we studied the properties of stimulation-evoked and spontaneous epileptiform events elicited in the HPC of urethan-anesthetized rats. We compared those elicited during the SO to those occurring during the theta rhythm. The average duration but not the amplitude of evoked afterdischarges (ADs) was consistently larger during the SO. In addition, spontaneous epileptiform events were more frequent and of higher amplitude during the SO. Last, the bilateral propagation of both ADs and spontaneous events in the hippocampus was enhanced during the SO. These results imply that the threshold for the generation and propagation of epileptiform activity in the hippocampus is lowered during the SO and that this state may be a seed for the initiation, maintenance, and generalization of MTL epilepsy. Further examination of the pathophysiology of sleep-epilepsy interactions in the HPC will be of benefit for an understanding of the mechanisms, prognosis, and therapy for this form of epilepsy.

PMID: 19587317

Whitten TA, Martz LJ, Guico A, Gervais N, Dickson CT

J. Neurophysiol. 2009 Sep;102(3):1647-56

Abstract

During sleep, warm-blooded animals exhibit cyclic alternations between rapid-eye-movement (REM) and nonrapid-eye-movement (non-REM) states, characterized by distinct patterns of brain activity apparent in electroencephalographic (EEG) recordings coupled with corresponding changes in physiological measures, including body temperature. Recently we have shown that urethane-anesthetized rats display cyclic alternations between an activated state and a deactivated state that are highly similar in both EEG and physiological characteristics to REM and non-REM sleep states, respectively. Here, using intracranial local field potential recordings from urethane-anesthetized rats, we show that brain-state alternations were correlated to core temperature fluctuations induced using a feedback-controlled heating system. Activated (REM-like) states predominated during the rising phase of the temperature cycle, whereas deactivated (non-REM-like) states predominated during the falling phase. Brain-state alternations persisted following the elimination of core temperature fluctuations by the use of a constant heating protocol, but the timing and rhythmicity of state alternations were altered. In contrast, thermal fluctuations applied to the ventral surface (and especially the scrotum) of rats in the absence or independently of core temperature fluctuations appeared to induce brain-state alternations. Heating brought about activated patterns, whereas cooling produced deactivated patterns. This shows that although alternations of sleeplike brain states under urethane anesthesia can be independent of imposed temperature variations, they can also be entrained through the activation of peripheral thermoreceptors. Overall, these results imply that brain state and bodily metabolism are highly related during unconsciousness and that the brain mechanisms underlying sleep cycling and thermoregulation likely represent independent, yet coupled oscillators.

PMID: 19321151

Engin E, Treit D, Dickson CT

Neuroscience 2009 Jun;161(2):359-69

Abstract

Ketamine, a dissociative anesthetic agent, appears to have rapid antidepressant effects at sub-anesthetic doses in clinically depressed patients. Although promising, these results need to be replicated in double-blind placebo-controlled studies, a strategy thwarted by the psychoactive effects of ketamine, which are obvious to both patients and clinicians. Alternatively, demonstrations of the psychotherapeutic effects of ketamine in animal models are also complicated by ketamine’s side-effects on general activity, which have not been routinely measured or taken into account in experimental studies. In this study we found that ketamine decreased “behavioral despair” in the forced swim test, a widely used rats model of antidepressant drug action. This effect was not confounded by side-effects on general activity, and was comparable to that of a standard antidepressant drug, fluoxetine. Interestingly, ketamine also produced anxiolytic-like effects in the elevated-plus-maze. Importantly, the effective dose of ketamine in the plus-maze did not affect general locomotion measures, in either the plus-maze or in the open field test. While the selective N-methyl-d-aspartic acid (NMDA) receptor antagonist MK-801 also produced antidepressant-like and anxiolytic-like effects, these were mostly confounded by changes in general activity. Finally, in a neurophysiological model of anxiolytic drug action, ketamine reduced the frequency of reticularly-activated theta oscillations in the hippocampus, similar to the proven anxiolytic drug diazepam. This particular neurophysiological signature is common to all known classes of anxiolytic drugs (i.e. benzodiazepines, 5-HT1A agonists, antidepressants) and provides strong converging evidence for the anxiolytic-like effects of ketamine. Further studies are needed to understand the underlying pharmacological mechanisms of ketamine’s effects in these experiments, since it is not clear they were mimicked by the selective NMDA antagonist MK-801.

PMID: 18940236

Engin E, Stellbrink J, Treit D, Dickson CT

Neuroscience 2008 Dec;157(3):666-76

Abstract

Somatostatin (SST) is a cyclic polypeptide that inhibits the release of a variety of regulatory hormones (e.g. growth hormone, insulin, glucagon, thyrotropin). Moreover, SST is widely distributed within the CNS, acting both as a neurotransmitter and as a neuromodulator of other neurotransmitter systems. However, despite its extensive expression in limbic areas, and its co-localization with GABA, a neurotransmitter previously implicated in emotion, the effects of SST on anxiety and depression have not been investigated. By performing intraventricular infusions in rats we demonstrate, for the first time, that SST has anxiolytic- and antidepressant-like effects in the elevated plus-maze and forced swim test, respectively. In addition, by performing local field potential recordings of hippocampal theta activity evoked by reticular stimulation in urethane-anesthetized rats we also show that SST application suppresses the frequency of theta in a similar fashion to diazepam. This neurophysiological signature, common to all classes of anxiolytic drugs (i.e. benzodiazepines, selective 5-HT reuptake inhibitors, 5-HT1A agonists) provides strong converging evidence for the anxiolytic-like characteristics of SST. Our pharmacological antagonism experiments with bicuculline further suggest that the anxiolytic effect of SST may be attributable to the interaction of SST with GABA, whereas the antidepressant-like effect of SST may be GABA-independent. In addition to contributing to the current understanding of the role of neuropeptides in mood and emotion, these findings support a clinical role for SST (or its analogues) in the treatment of anxiety and depression.

PMID: 18562122

Saraga F, Balena T, Wolansky T, Dickson CT, Woodin MA

Neuroscience 2008 Jul;155(1):64-75

Abstract

Spike-timing modifies the efficacy of both excitatory and inhibitory synapses onto CA1 pyramidal neurons in the rodent hippocampus. Repetitively spiking the presynaptic neuron before the postsynaptic neuron induces inhibitory synaptic plasticity, which results in a depolarization of the reversal potential for GABA (E(GABA)). Our goal was to determine how inhibitory synaptic plasticity regulates CA1 pyramidal neuron spiking in the rat hippocampus. We demonstrate electrophysiologically that depolarizing E(GABA) by 24.7 mV increased the spontaneous action potential firing frequency of cultured hippocampal neurons 254% from 0.12+/-0.07 Hz to 0.44+/-0.13 Hz (n=11; P<0.05). Next we used a single compartment model of a CA1 pyramidal neuron to explore in detail how inhibitory synaptic plasticity of feedforward and feedback inhibition regulates the generation of action potentials, spike latency, and the minimum excitatory conductance required to generate an action potential; plasticity was modeled as a depolarization of E(GABA), which effectively weakens inhibition. Depolarization of E(GABA) at feedforward and feedback inhibitory synapses decreased the latency to the 1st spike by 2.27 ms, which was greater that the sum of the decreases produced by depolarizing E(GABA) at feedforward (0.85 ms) or feedback inhibitory synapses (0.02 ms) alone. In response to a train of synaptic inputs, depolarizing E(GABA) decreased the inter-spike interval and increased the number of output spikes in a frequency dependent manner, improving the reliability of input-output transmission. Moreover, a depolarizing shift in E(GABA) at feedforward and feedback synapses triggered by spike trains recorded from CA1 pyramidal layer neurons during field theta from anesthetized rats, significantly increased spiking on the up- and down-strokes of the first half of the theta rhythm (P<0.05), without changing the preferred phase of firing (P=0.783). This study provides the first explanation of how depolarizing E(GABA) affects pyramidal cell output within the hippocampus.

PMID: 18436639

Jackson J, Dickson CT, Bland BH

J. Neurophysiol. 2008 Jun;99(6):3009-26

Abstract

Evidence has accumulated suggesting that the median raphe (MR) mediates hippocampal theta desynchronization. However, few studies have evaluated theta-related neural circuitry during MR manipulation. In urethane-anesthetized rats, we investigated the effects of MR stimulation on hippocampal field and cell activity using high-frequency (100 Hz), theta burst (TBS), and slow-frequency electrical stimulation (0.5 Hz). We demonstrated that high-frequency stimulation of the MR did not elicit deactivated patterns in the forebrain, but rather elicited low-voltage activity in the neocortex and small-amplitude irregular activity (SIA) in the hippocampus. Both hippocampal phasic theta-on and -off cells were inhibited by high-frequency MR stimulation, although MR stimulation failed to affect cells that had neither state or phase relationships with theta field activity. TBS of the MR-induced theta field activity phase locked to the stimulation. Slow-frequency stimulation elicited a state-dependent reset of theta phase through a short-latency inhibition (5 ms) in phasic theta-on cells. Subpopulations of phasic theta-on cells responded in either oscillatory or nonoscillatory patterns to MR pulses, depending on their intraburst interval. off cells exhibited a state-dependent modulation of cell firing occurring preferentially during nontheta. The magnitude of MR-induced reset varied as a function of the phase of the theta oscillation when the pulse was administered. Therefore high-frequency stimulation of the MR appears to disrupt hippocampal theta through a state-dependent, short-latency inhibition of rhythmic cell populations in the hippocampus functioning to switch theta oscillations to an activated SIA field state.

PMID: 18046004

Schall KP, Kerber J, Dickson CT

J. Neurophysiol. 2008 Feb;99(2):888-99

Abstract

Coordinated patterns of state-dependent synchronized oscillatory activity have been suggested to play differential roles in both the encoding and consolidation phases of hippocampal-dependent memories. Previous studies have concentrated on the mutually exclusive patterns of theta and sharp-wave/ripple activity because these were thought to be the only collective oscillatory patterns expressed in the hippocampus. Recently we (and others) have described a novel rhythmic activity expressed during anesthesia and deep sleep, the hippocampal slow oscillation (SO). In an attempt to describe the differential effects of theta and the SO on processing in the hippocampal circuit, we performed evoked potential analysis of two major pathways (the commissural and perforant) in urethan-anesthetized rats across spontaneously expressed theta and SO states. We show that synaptic excitability was significantly enhanced in all pathways during the SO as compared with theta with the exception of the medial perforant path to the dentate gyrus, which showed greater excitability during theta. Furthermore, within each ongoing rhythm, there was a phase-dependent modulation of synaptic excitability. This occurred across all sites and similarly favored the falling phase (positive to negative) of both theta and the SO. Differential effects on the input, processing, and output circuitries of the hippocampus across mutually exclusive coordinated oscillatory patterns expressed during different states may be relevant for the staging of memory processes in the medial temporal lobe.

PMID: 18604300

Ma L, Alonso A, Dickson CT

Neural Plast. 2008;2008:814815

Abstract

The entorhinal cortex (EC) is a nodal and independent mnemonic element of the medial temporal lobe memory circuit as it forms a bidirectional interface between the neocortex and hippocampus. Within the EC, intra- and inter-lamellar associational connections occur via horizontal and columnar projections, respectively. We undertook a comparative study of these two inputs as they converge upon EC layer II cells using whole-cell patch techniques in an adult rat EC horizontal slice preparation in which the deepest layers (V-VI) had been dissected out. Electrical stimulation of layers I and III during GABA blockade allowed us to study excitatory synaptic properties and plasticity in the horizontal and columnar fibre systems, respectively. Both pathways exhibited AMPA- and NMDA-receptor mediated transmission and both exhibited long-term potentiation (LTP) after high-frequency (tetanic) stimulation. LTP in the horizontal, but not in the columnar pathway, was blocked by NMDA receptor antagonism. Intriguingly, LTP in both appeared to be mediated by post synaptic increases in Ca2+ that may be coupled to differing second messenger pathways. Thus, the superficial excitatory horizontal and columnar associative pathways to layer II have divergent mechanisms for LTP which may endow the EC with even more complex and dynamic processing characteristics than previously thought.

PMID: 18414674

Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT

PLoS ONE 2008;3(4):e2004

Abstract

BACKGROUND: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state.

METHODOLOGY/PRINCIPAL FINDINGS: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state alternations in sleep transiently disrupted state alternations under urethane.

CONCLUSIONS/SIGNIFICANCE: Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state alternations.

PMID: 17366610

Wolansky T, Pagliardini S, Greer JJ, Dickson CT

J. Comp. Neurol. 2007 May;502(3):427-41

Abstract

It has been reported that application of substance P (SP) to the medial portion of the entorhinal cortex (EC) induces a powerful antiepileptic effect (Maubach et al. [1998] Neuroscience 83:1047-1062). This effect is presumably mediated via inhibitory interneurons expressing the neurokinin-1 receptor (NK(1)R), but the existence of NK(1)R-expressing inhibitory interneurons in the EC has not yet been reported. The present immunohistochemical study was performed in the rat to examine the existence and distribution of NK(1)R-expressing neurons in the EC as well as any co-expression of other neurotransmitters/neuromodulators known to be associated with inhibitory interneurons: gamma-aminobutyric acid (GABA), parvalbumin (PARV), calretinin (CT), calbindin (CB), somatostatin (SST), and neuropeptide Y (NPY). Our results indicated that NK(1)R-positive neurons were distributed rather sparsely (especially in the medial EC), primarily in layers II, V, and VI. The results of our double-immunohistochemical staining indicated that the vast majority of NK(1)R-expressing neurons also expressed GABA, SST, and NPY. In addition, CT was co-expressed in a weakly stained subgroup of NK(1)R-expressing neurons, and CB was co-expressed very rarely in the lateral EC, but not in the medial EC. In contrast, SP-immunopositive axons with fine varicosities were distributed diffusely throughout all layers of the EC, appearing to radiate from the angular bundle. SP may be released in a paracrine manner to activate a group of NK(1)R-expressing entorhinal neurons that co-express GABA, SST, and NPY, exerting a profound inhibitory influence on synchronized network activity in the EC.