Event-related Potentials In Rats Research Articles

Adapted wavelet transform improves time-frequency representations: a study of auditory elicited P300-like event-related potentials in rats

Objective. Active auditory oddball paradigms are simple tone discrimination tasks used to study the P300 deflection of event-related potentials (ERPs). These ERPs may be quantified by time-frequency analysis. As auditory stimuli cause early high frequency and late low frequency ERP oscillations, the continuous wavelet transform (CWT) is often chosen for decomposition due to its multi-resolution properties. However, as the conventional CWT traditionally applies only one mother wavelet to represent the entire spectrum, the time-frequency resolution is not optimal across all scales. To account for this, we developed and validated a novel method specifically refined to analyse P300-like ERPs in rats. Approach. An adapted CWT (aCWT) was implemented to preserve high time-frequency resolution across all scales by commissioning of multiple wavelets operating at different scales. First, decomposition of simulated ERPs was illustrated using the classical CWT and the aCWT. Next, the two methods were applied to EEG recordings obtained from prefrontal cortex in rats performing a two-tone auditory discrimination task. Main results. While only early ERP frequency changes between responses to target and non-target tones were detected by the CWT, both early and late changes were successfully described with strong accuracy by the aCWT in rat ERPs. Increased frontal gamma power and phase synchrony was observed particularly within theta and gamma frequency bands during deviant tones. Significance. The study suggests superior performance of the aCWT over the CWT in terms of detailed quantification of time-frequency properties of ERPs. Our methodological investigation indicates that accurate and complete assessment of time-frequency components of short-time neural signals is feasible with the novel analysis approach which may be advantageous for characterisation of several types of evoked potentials in particularly rodents.

ID 389 – Studies of neuronal circuits underlying information processing through late P300 event-related potentials in rats

Cognitive event related potentials (ERPs) and oscillations synchrony (EROS) provide a powerful tool for studying brain’s synaptic function underlying information processing. The P300 component of ERPs indexing attention and working memory is altered in neurologic and psychiatric diseases, and is sensitive to pharmacological agents. Here, we investigated whether the P300-like potentials can be generated in rats performing an active auditory discriminant task, and to what extent this response is sensitive to modulation of the cholinergic neurotransmission. In the active oddball paradigm, behavior and auditory evoked potentials (AEPs) were simultaneously recorded in rats as they were presented with frequent non-target and rare target tones during baseline conditions and following the administration of donepezil and scopolamine. Rats that consistently discriminate target tones showed P300 peaks with early and late components. Donepezil enhanced P300 amplitude and evoked theta/gamma oscillations to target tones and attenuated scopolamine-induced deficits in behavioral and AEPs/EROS. We demonstrate that P300-like response can be elicited by rats engaged in stimulus discrimination processing and outline the relevance of the cholinergic system in this response. The AEP P300 paradigm is valuable for characterizing targets and/or drugs that may contribute to facilitation and/or suppression of synaptic responses underlying early and late P300 components.

The Alcohol Clamp: Applications, Challenges, and New Directions – An RSA 2004 Symposium Summary

This article summarizes the proceedings of a symposium organized and cochaired by Vijay Ramchandani and Sean O'Connor and presented at the 2004 Research Society on Alcoholism meeting in Vancouver, BC, Canada. The objectives of this symposium were: (1) to provide a rationale for the development and use of the alcohol clamp and the requirements for its use in alcohol challenge studies; (2) to highlight recent studies conducted using the alcohol clamp to identify sources of variation in the pharmacokinetics and pharmacodynamics of alcohol, as well as to address important research questions related to the relationship between the response to alcohol and the risk for alcoholism; and (3) to provide a perspective on progress, address limitations of the clamp, and identify new directions for alcohol challenge research. The symposium began with an introduction and overview of the alcohol clamp, by Vijay Ramchandani. This was followed by 4 presentations that highlighted recent studies conducted using the clamp including: (1) determination of the influence of alcohol dehydrogenase polymorphisms on alcohol elimination rates in a male Jewish population, by Yehuda Neumark; (2) examination of family history of alcoholism, recent drinking history, and levels and rates of administration as determinants of the response to alcohol and risk for alcoholism, by Sean O'Connor; (3) evaluation of the time course of ethanol intoxication on neuroendocrine function in humans, by Ulrich Zimmermann; and (4) a study of the effects of steady-state blood alcohol levels on auditory event-related potentials in rats, by Sandra Morzorati. Harriet de Wit summarized and discussed the research presented at the symposium and provided her perspective on future directions for research using the alcohol clamp.

Antagonism of neuropeptide YY1 receptors does not inhibit ethanol's effects on cortical EEG and ERPs in Wistar rats.

Ethanol and neuropeptide Y (NPY) can have additive neurobehavioral effects. In the present study, the NPY Y1 receptor antagonist BIBP3226 was administered alone or in combination with a moderate dose of ethanol to determine whether it interacted with the neurobehavioral effects of ethanol. Male Wistar rats were implanted with cortical recording electrodes and a lateral ventricular cannula. The effects of 1 nmol BIBP3226, 0.75 g/kg ethanol and the combination (BIBP3226 + EtOH) on neurophysiological activity and locomotion were then assessed. Ethanol significantly increased 1-2 Hz parietal cortical power and this effect was partially antagonized by BIBP3226. Peak frequencies in the parietal cortical 6-8 Hz and 8-16 Hz bands were also altered by ethanol, but these effects were not reversed by BIBP3226. BIBP3226 or ethanol, when administered alone, did not alter motor activity or cortical event-related potentials (ERPs) but administration of BIBP3226 + EtOH reduced motor activity, reduced parietal cortical N1 ERP amplitude and increased frontal cortical N1 ERP latency. In the present study, the most prominent effect of antagonizing central NPY Y1 receptors was a facilitation of the effects of ethanol. In particular, the effects of combined administration of BIBP3226 and ethanol are indicative of enhanced sedation and possibly cognitive impairment.

Development of Acute Tolerance During Steady‐State Arterial Alcohol Concentrations: A Study of Auditory Event‐Related Potentials in Rats

The blood alcohol clamp is a method whereby alcohol is infused intravenously to maintain a predetermined arterial alcohol concentration (AAC) for an indefinite period of time. The objective of this study was to use the clamp to examine the effects of alcohol on event-related potentials (ERPs) in rats and to assess the development of tolerance during a single alcohol exposure. Adult male Wistar rats that had a chronic implant of EEG electrodes overlying the frontal cortex and were equipped with cannulae in the jugular vein, were clamped at 75 or 150 mg/dl via an intravenous infusion of 20% (v/v) alcohol. Auditory ERPs were recorded before the alcohol infusion (baseline) and at 5, 15, 120, 135, or 195 min after steady-state AAC was achieved. In a separate group of rats, test-retest reliability was examined by acquiring ERPs two to three times in the same rat at 60-min intervals. Dependent variables were calculated as changes from baseline for each time point for P1-N1 amplitude and P1 and N1 latencies. In the test-retest study, there were no differences in any of the dependent variables over time, indicating that the measures were stable and repeatable. Estimated AACs of 75 and 150 mg/dl significantly (p = 0.0001) decreased P1-N1 amplitude in a dose-related manner. During both clamps, the alcohol effect peaked at 120 min (p < 0.03) and decreased thereafter. Alcohol had no effect on P1 or N1 latencies. Pharmacologically relevant AACs significantly decreased the amplitude but not the latencies of the long-latency components of the rat auditory ERP. Acute tolerance developed because the amplitude of the ERP component recovered as AACs were held relatively constant.

Long latency event-related potentials in rats: response of amygdala, nucleus accumbens, dorsal hippocampus and frontal cortex to changes in reward characteristics of conditioned stimuli

Circuits involving major afferents to the ventral striatum from the frontal cortex, amygdala and hippocampus have been implicated in the selective processing of conditioned stimuli predictive of `important events' or reward-related processes. We utilized an animal model of event-related potentials (ERPs) to explore the relationship between these brain areas during the performance of a conditioning/extinction task. Significant reductions in the N1 component in cortex and P2 component in amygdala of the rat ERP were found as a consequence of removal of the food reward previously associated with the stimuli. Lesions of the nucleus basalis magnocellularis were without effect on the pattern of ERP morphology changes associated with the removal of the reward. Since the N1 component of the ERP has been linked to attentional processes, these studies suggest that elimination of reward characteristics of conditioning stimuli can lead to a specific reductions in `attention' and or `sensory reaction' in frontal cortex and amygdala but not to general habituation to these stimuli or in other areas of the CNS.

Effect of vagal autotransplantation and bifemelane hydrochloride on cholinergic markers and event-related potentials in rats with lesions of the nucleus basalis magnocellularis.

In rats lesioned by injecting the ibotenic acid (8 micrograms/site) into the unilateral nucleus basalis magnocellularis (NBM), the effect of treatment with bifemelane hydrochloride (BIF) or autotransplantation of the vagal nodosal ganglion was studied electrophysiologically by serial measurement of the event-related potential (ERP, P300) for 4 weeks. In addition, the effects on cholinergic markers were assessed by determining the specific binding of [3H]QNB (quinuclidinyl benzilate) to the muscarinic acetylcholine receptor (mAChR) as well as the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). The P300 latency was delayed and its amplitude remained low for 4 weeks in NBM-lesioned rats. In contrast, a return to normal occurred after 2-3 weeks in rats given daily intraperitoneal injections of BIF (15 mg/kg) and in autotransplanted rats. In lesioned rats, the cortical ChAT and AChE activities on the affected side did not recover, but the postsynaptic receptor response was transiently activated soon after lesioning. BIF increased specific mAChR binding (an early increase of affinity and a subsequent increase of receptor density) as well as presynaptic ChAT activity. Transplantation achieved the early activation of mAChR binding (increased receptor density) and continuously increased ChAT activity. Thus, the postsynaptic compensatory receptor mechanism of denervation supersensitivity acted as an early response to the depression of presynaptic cholinergic activity, but it could not improve the P300 response until the subsequent increase of cortical ChAT activity. Improvement of P300 combined with cortical cholinergic recovery after nodosal ganglion grafting or administration of BIF suggests that the neocortical ACh level may play an important role in regulating ERP.

Effects of metamfetamine on auditory P3 component of event-related potentials in rats

Three rats were trained with an oddball paradigm, in which 5 kHz frequent and 10 kHz target rare tones were presented with a probability of 0.8 and 0.2. Pressing the lever within 2 s following the onset of the target tones was rewarded with a drop of food paste. Long latency event-related potentials (ERPs) corresponding to those in humans could be recorded in rats. After the administration of metamfetamine (0.2 mg/kg), the amplitude of surface and intracortical N1 increased, indicating an augmentation of the primary cortical response. Surface P3 showed a decrease of amplitude, accompanied by an increase of intracortical negativity. These alterations of ERPs may be caused by the dysregulation of central noradrenergic system.

Long-latency event-related potentials in rats: Effects of task and stimulus parameters

Animal models of event-related potentials have recently been developed in rats in order to gain further understanding of the psychobiological variables which underlie these waveforms. In the present study, unanesthetized male Wistar rats, chronically implanted with electrodes, were utilized in order to: (i) compare event-related potentials recorded following the presentation of passively presented auditory stimuli from different neocortical, hippocampal and perihippocampal sites; (ii) test the effects of changes in stimulus probability and loudness on event-related potentials recorded from those sites; and (iii) record event-related potentials from rats who were actively performing in a tone discrimination task. The results of these studies showed that in all electrode sites (frontal cortex, parietal cortex, entorhinal cortex, hippocampus) a series of large amplitude potentials in the 10–200 ms latency range could be recorded in response to passively presented stimuli. Late positive potentials in the 300–400 ms range were only identified in recordings from the posterior cortex, entorhinal area, and dorsal hippocampus. Some of these late positive components were also found to be sensitive to changes in stimulus probability. A similar series of waves were detected in a paradigm where rats were required to actively discriminate between two tones; however, the morphologies of the waveforms were found to be more distinct. These studies suggest that rats may be good subjects for the exploration of the neural origins of event-related potentials. These studies demonstrate that rats performing in an auditory discrimination task can generate electrophysiological potentials which are time locked to the onset of a “cognitively relevant” stimulus (event-related potentials). These potentials can be recorded in limbic (hippocampus and amygdala) and cortical (parietal cortex) brain sites. The event-related potentials recorded in rats respond to changes in stimulus parameters in a similar fashion to those previously described in monkeys and human subjects. The identification of a rat model of event-related potentials provides an opportunity to further explore the neural origins of event-related potentials, to estimate the role of genetics in determining individual variation in waveforms, as well as to provide electrophysiological assays of the effects of various drugs on neurosensory and cognitive processing.

The effects of acute cocaine administration on auditory event-related potentials in rats

Cocaine administration has been shown to affect several sites in the limbic forebrain. The nucleus accumbens has been implicated as an important site for the reinforcing aspects of this drug whereas, the amygdala and hippocampus may be more involved in drug conditioning and/or drug induced changes in the perception of stimuli. In the present study, auditory event-related potentials (ERPs) were utilized to explore the effects of cocaine on sensory processing in several limbic sites. Eleven adult male Wistar rats were stereotaxically implanted with electrodes aimed at the dentate gyrus, dorsal hippocampus (CA1–CA2), amygdala, and nucleus accumbens. The rats received intraperitoneal injections of either saline, 2.5, 5.0, 10.0 or 20 mg/kg of cocaine. The ERPs were recorded in response to an auditory ‘oddball’ paradigm consisting of frequently and infrequently presented tones. Cocaine was found to produce a dose dependent decrease in the variance of the amplitude of several ERP components in the amygdala and the hippocampal formation but not in the accumbens. Cocaine also produced a decrease in the latency of the N1 component in the amygdala. No significant changes were observed in the amplitude of the ERP components following any of the cocaine doses studied, suggesting that cocaine may not increase the salience of auditory stimuli in these structures. The observed reduction in the variance of the ERPs may suggest an increased focussing of the animals' attention to the auditory stimuli. These studies also suggest that the sensory/cognitive aspects involved in cocaine's actions, as quantified by ERPs, may primarily involve the hippocampal formation and the amygdala, but not the nucleus accumbens.

Long latency event related potentials in rats: The effects of changes in stimulus parameters and neurochemical lesions

Animal models of event related potentials (ERPs) have recently been developed in order to gain further understanding of the psychobiological variables which may underlie these brain potentials. In the present study, unanaesthetized rats were utilized in order to evaluate the effects on rat ERP morphology of changes in the auditory stimulus parameters used to elicit these potentials such as tone probability and intensity. In addition, the consequences of reductions in norepinephrine (NE) produced by six-hydroxydopamine (6-OHDA) lesions to the area of the dorsal noradrenergic bundle in ERP wave forms were evaluated. Forty, experimentally naive, male rats chronically implanted with electrodes were used in this study. The results of these studies showed that in all electrode sites (frontal cortex, ventral thalamus, dorsal hippocampus, locus coeruleus) a series of large amplitude potentials in the 10-200 msec latency range could be recorded, some of which were sensitive to changes in the auditory stimulus parameters such as probability and tone intensity. Late positive potentials in the 300-400 msec range could be identified in recordings from the dorsal hippocampus and were found to be sensitive to probability independent of tone intensity. Dorsal noradrenergic bundle lesions were also found to produce significant changes in these rat ERP components. Lesioned animals were found to have increases in amplitude to the early negative potentials (in the 50-100 msec range) in response to frequent tones in cortical leads and decreases in the amplitude of the late positive potentials (in the 300-400 msec range) recorded in hippocampal leads in response to infrequent tones. These findings are consistent with a role for NE in the forebrain in the processing of novel or "selective" stimuli.

Long latency event-related potentials in rats: Effects of dopaminergic and serotonergic depletions

The effects of serotonergic and dopaminergic depletions on event-related potentials (ERPs) generated by an auditory “oddball” paradigm were evaluated. Eighteen rats received either sham or six-hydroxydopamine (6-OHDA) lesions to the ventral tegmental area (VTA), and were subsequently implanted with electrodes in the frontal cortex, dorsal hippocampus (DHPC), and amygdala (AMYG). In these animals, a series of large amplitude potentials in the 10–200 ms latency range could be recorded from all the brain areas tested. In addition, late positivities (in the 300–400 ms range) were identified in DHPC and AMYG. 6-OHDA lesions to the VTA were found to produce a 30–46% reduction in dopamine, but did not significantly alter any of the ERP components. A second series of rats were implanted with electrodes in cortex and DHPC. These rats then received vehicle injections and subsequently injections of parachlorophenylalanine (PCPA). PCPA produced a 50% depletion of serotonin concomitant with significant reductions in the negative components in the 50–100 ms range recorded in hippocampus and cortex. These studies support a role for serotonin but not dopamine in the processing of passively presented auditory stimuli and further suggest that the rat may be a good model for the exploration of long latency ERPs.