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Biomedical subjects

R E Hampson

Publications and source records attributed to R E Hampson.

At least 19 recordsLinked to original sources
PubMed1996

Hippocampal place fields: relationship between degree of field overlap and cross-correlations within ensembles of hippocampal neurons.

The capacity to record from multiple neurons in awake freely moving animals provides a means for characterizing organizational principles of place field encoding within ensembles of hippocampal neurons. In this study, cross-correlations between pairs of hippocampal place cells and degree of overlap between their respective place fields were analyzed during behavioral performance of delayed matching (DMS) or non-matching sample (DNMS) tasks, or while the same rats chased pellets in a different environment. The relationship between field overlap and cross-correlations of neural spike activity within ensembles was shown to be a positive, exponentially increasing, function. Place fields from the same neurons were markedly "remapped" between the Delay and Pellet-chasing tasks, with respect to physical location and size of fields. However individual pairs of place cells within each ensemble retained nearly the same degree of overlap and cross-correlation even though the spatial environment and the tasks differed markedly. This suggested that place cells were organized in functional "clusters" which exhibited the same inter-relations with respect to place field overlap and cross-correlations, irrespective of actual field of location. When cross-correlations between place cells were compared to placement of the array recording electrodes within the hippocampus, the strongest correlations were found along previously defined posterior-projecting fiber gradients between CA3 and CA1 subfields (Ishizuka et al. [1990], J Comp Neurol 295:580-623; Li et al. [1994] (J Comp Neurol 339:181-208). These findings suggest that the functional organization of place fields conforms to anatomical principles suspected to operate within hippocampal ensembles.

Animals↗
PubMed1996

Hippocampal ensemble activity during spatial delayed-nonmatch-to-sample performance in rats.

Multiple-cell recording from specially designed arrays of microwire electrodes allowed analysis of anatomically defined ensemble activity from 10 different locations within the hippocampus of rats (n = 7) performing a two-lever operant version of a spatial delayed-nonmatch-to-sample task (DNMS). Application of population analysis procedures to ensembles of single-neuron activity within the CA1 and CA3 fields revealed firing patterns related to task-relevant events within a DNMS trial. The patterns were extracted via a canonical discriminant analysis in the form of "roots" that represented sources of variance in firing within the ensemble, such as phase of the task (Sample or Nonmatch), spatial position of the lever press response (left or right), and correct versus error trials. Comparison of the ensemble firing on correct versus error trials revealed important insight into ensemble information encoding, such as "miscoding" of the response position and lack of distinct encoding of the response in the Sample phase, which became increasingly vulnerable to error as a function of the duration of delay interval. The extracted discriminant scores were reflective of multiple representations within ensembles and suggested that "conjunctions" of task-relevant features could be represented effectively by small numbers of hippocampal neurons. The findings support the long-held supposition that hippocampal neurons play a critical role in the encoding and retrieval of information in recognition memory tasks.

Animals↗
PubMed1995

Cannabinoids selectively decrease paired-pulse facilitation of perforant path synaptic potentials in the dentate gyrus in vitro.

Perforant path synaptic potentials recorded from the outer molecular layer of the dentate gyrus were tested for paired-pulse potentiation and stimulus sensitivity in the presence and absence of the potent cannabinoid receptor ligand, WIN 55,212-2. Extracellular perforant path synaptic potential amplitudes were increased by 51% in 2 mM Ca2+ medium and 60% in 3 mM Ca2+ medium at a conditioning-test (C-T) interval of 10 ms, decreasing to 10-15% facilitation at an 80 ms C-T interval. Exposure to the potent cannabinoid receptor ligand WIN 55,212-2 produced a marked and dose-dependent reduction in the amplitude of the facilitated perforant path synaptic potentials. Maximum paired-pulse facilitation was reduced to 35% and 25% in 2.0 and 5.0 microM WIN 55,212-2 respectively. The effect was selective for potentials facilitated at C-T intervals of 10-60 ms. Input/output (I/O) curves of perforant path field potentials were shifted to the right in a dose-dependent (2.0 and 5.0 microM) manner by WIN 55,212-2. Significant differences in peak amplitudes of perforant path potentials were obtained at all suprathreshold stimulus intensities. A comparison of WIN 55,212-2 (5 microM) with the GABAB receptor agonist baclofen (200 microM) showed that when both drugs were administered independently each produced similar decreases in perforant path paired-pulse potentiation. However when administered together at these concentrations baclofen and WIN failed to potentiate each other, suggesting nonadditivity due to effects on a common process.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1995

Role of cyclic AMP dependent protein kinase in cannabinoid receptor modulation of potassium "A-current" in cultured rat hippocampal neurons.

Cannabinoid receptor agonists have been previously shown to enhance a potassium A-current (IA) in cultured rat hippocampal neurons. This effect has been further demonstrated to be dependent on G-protein linkage to adenylyl cyclase and levels of intracellular cyclic AMP (cAMP). The present study extends this analysis to the involvement of cAMP-dependent protein kinase (PKA) in this cascade. Specific activators and inhibitors of PKA were shown to have differential effects on the voltage dependence of IA. Specific activators of PKA produced a negative shift in voltage dependence of IA, whereas PKA inhibitors produced a positive shift in IA voltage dependence, the latter similar to that effected by the cannabinoid agonist WIN 55,212-2. Although the negative shift in IA induced by PKA stimulation could be reversed by PKA inhibitors, the positive shift produced by the PKA inhibitors alone was only 50-60% of the cannabinoid-produced shift in IA voltage dependence. This partial effect of PKA inhibition was confirmed by biochemical assays in the same cultured neurons that showed a similar 50-60% decrement in in vitro protein phosphorylation produced by PKA inhibitors. Results are discussed in terms of a diffusible second messenger linkage of the cannabinoid receptor to the A-current channel via the role of protein phosphorylation in modulation of IA.

Animals↗
PubMed1995

Cannabinoids modulate voltage sensitive potassium A-current in hippocampal neurons via a cAMP-dependent process.

Previous studies have shown that cannabinoid receptor analogs increase voltage-dependent potassium A-current (IA) in cultured hippocampal cells. Because cannabinoid receptors inhibit adenylate cyclase, the present study explored whether cAMP played a role in mediating this effect on IA. The specific issue of whether cannabinoid receptor modulation of voltage-dependent IA acts via a cAMP-dependent process was investigated. The cAMP analog, 8-bromo-cAMP, as well as the adenylate cyclase stimulant forskolin, produced concentration-dependent shifts in IA that were opposite those produced by cannabinoid receptor ligands. Moreover, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also produced a marked negative shift in the steady-state voltage dependence of IA and increased the effect of forskolin on IA. As shown in previous studies, the cannabinoid agonist WIN 55,212-2 increased IA via a decrease in steady-state voltage-dependent inactivation of IA. WIN 55,212-2 also reversed the effects of forskolin on IA. The electrophysiological studies were paralleled by direct assays of cAMP in these cells, where cannabinoids inhibited forskolin-stimulated cAMP by 50% in a pertussis toxin-sensitive manner. The results confirmed that pertussis toxin-sensitive cannabinoid receptor-mediated changes in IA were probably the result of inhibition of adenylate cyclase. The findings are discussed in terms of modulation of IA conductance properties via cannabinoid receptor-mediated inhibition of cAMP levels within the cell.

1-Methyl-3-isobutylxanthine↗
PubMed1993

Firing patterns of nucleus accumbens neurons during cocaine self-administration in rats.

The firing patterns of neurons in the nucleus accumbens (NA) were recorded in rats trained to self-administer cocaine via response contingent intravenous drug infusions. Recordings were obtained from permanently implanted multiple electrode arrays (8 microwires) inserted bilaterally into the NA and/or ventral striatum (NA-VS) in animals exhibiting stable responding (inter-infusion intervals, INT) during test sessions consisting of 16-30 drug delivery episodes. Electronically isolated and identified NA-VS neurons showed distinct patterns of phasic increases in firing relative to the occurrence of the reinforced lever press. Two particular firing patterns, however, were repeatedly encountered in different animals. In one type, a marked increase was observed in discharge following response contingent drug delivery. A second firing pattern showed two distinct temporally separated brief firing peaks (bursts), one immediately prior to the initiation of responding, and the other a brief discharge commencing within 200 ms after the initiation of drug delivery. The time between firing peaks was found to be modifiable by changing the response/reward (FR) ratio for drug delivery. A third finding was that the correlates of the self-administration response were not solely the result of drug infusion since, (1) phasic firing increases were not observed when the drug was delivered non-contingently during the same session and, (2) the emergence of patterns was frequently delayed within the session until after drug self-administration behavior stabilized at regular INTs. The findings are discussed in terms of the significance of NA-VS neuron firing correlates for the initiation and maintenance of cocaine self-administration.

Action Potentials↗
PubMed1993

Hippocampal cell firing correlates of delayed-match-to-sample performance in the rat.

Hippocampal CA1 and CA3 neurons were recorded in rats performing a delayed-match-to-sample (DMTS) task. Complex spike cells showed significant firing peaks following sample and match responses and during delivery of water reward. Individual cells were classified into 4 subtypes according to the presence or absence of firing in each of these 3 phases. There were significant differences in delay interval firing among the 4 subtypes, but firing during the delay did not predict the correct response: 34% of the cells showed a linear change in firing during the delay. Further analyses revealed significant lever position firing biases in approximately 70% of the cells tested irrespective of subtype. The complexity of firing correlates of the neurons recorded in this DMTS task suggests that the hippocampus divides specific aspects of the performance demands of the task across different cell subtypes, which together provide sufficient information to resolve the matching-to-sample problem on any given trial.

Animals↗
PubMed1993

Cannabinoids modulate potassium current in cultured hippocampal neurons.

Characterization of the newly discovered G-protein-coupled cannabinoid receptor in brain requires determination of its functional significance. The effects are reported of several potent cannabinoid analogs (CP 55,244, CP 55,940, levonantradol and WIN 55,212-2) on cultured neurons from hippocampus, a brain region that exhibits high cannabinoid receptor density. The electrophysiological effects of cannabinoids were determined by whole-cell patch clamp recordings of voltage-dependent potassium currents. The voltage dependence of the rapidly inactivating potassium A current (IA), characteristic of hippocampal neurons, was significantly altered in a concentration-dependent manner by cannabinoid analogs. Decreased inactivation, which led to an increased activation of IA near resting levels in these cells, was observed after brief local extracellular applications of cannabinoids. These actions were blocked by pertussis toxin. Cellular dialysis of GTP-gamma-S mimicked the actions of cannabinoids on IA while blocking further effects due to added cannabinoids. The rank order of potency of the cannabinoid analogs was similar to that observed with respect to binding at cannabinoid receptors in brain membranes. The concentration-related effectiveness of cannabinoid analogs in modulating IA was similar to their potency in stimulating low Km GTPase in cell membranes isolated from the cannabinoid receptor-rich dentate gyrus. These data support the conclusion that cannabinoid effects on IA are mediated through G-protein-coupled receptors. This cannabinoid-induced shift in the voltage dependence of IA could serve to counteract fast, transient, depolarizing events such as action potentials and synaptic currents in hippocampal neurons.

Action Potentials↗
PubMed1993

Cannabinoid receptors: G-protein-mediated signal transduction mechanisms.

The recent discovery and cloning of cannabinoid receptors has provided a major breakthrough in the understanding of the biochemical mechanisms of action of delta 9-tetrahydrocannibinol (delta 9-THC). Cannabinoid receptors are coupled to G-proteins and inhibit adenylyl cyclase in a variety of systems. In the brain, cannabinoid-inhibited adenylyl cyclase and the receptors are particularly prevalent in the cerebellum, where they are localized to cerebellar granule cells (Fig. 1). In these cells, cannabinoid receptors are co-localized with other Gi/o-linked receptors such as gamma-aminobutyric acid (GABAB) receptors, where they share common effector systems (adenylyl cyclase catalytic units) but not common G-proteins. This sharing of effectors leads to the phenomenon of receptor convergence, in which agonists of different receptor types can produce the same biological response in certain cells. In cultured hippocampal neurons, cannabinoids also act through G-proteins to increase potassium conductance. In these cells, the predominant electrophysiological response at relatively low (microM) concentrations of cannabinoids is mediated through a voltage-sensitive potassium A current (IA) (Fig. 1). The action of cannabinoid receptors in this system is to shift the voltage sensitivity of IA channels to higher voltage ranges, thus increasing K+ conductance at lower membrane potentials and decreasing the probability of multiple action potentials. When combined with data from other groups showing a cannabinoid receptor-mediated decrease in calcium conductance, along with the unique localization of cannabinoid receptors in the brain, it is clear that these receptor-effector combinations are well situated to mediate many of the well-known neurobiological effects of delta 9-THC.

Animals↗
PubMed1993

Effects of delta-9-tetrahydrocannabinol on delayed match to sample performance in rats: alterations in short-term memory associated with changes in task specific firing of hippocampal cells.

The effects of delta-9-tetrahydrocannabinol (delta-9-THC) were studied during performance of a delayed match to sample (DMTS) task in rats. Correlated hippocampal cellular activity was also assessed in terms of the effects of cannabinoids on well characterized task specific changes in firing rate which occurred during various phases of a DMTS trial. Results show a surprising correlation between the delay and dose (0.75-2.0 mg/kg)-dependent behavioral deficit produced by delta-9-THC in this task and similar effects produced by damage to the hippocampus and related structures. However, unlike the effects of hippocampal lesions or neurotoxic damage, the effects of delta-9-THC were completely reversible within 24 hr of injection. Neither control injection of the vehicle nor equivalent concentrations of the nonpsychoactive cannabinoid, cannabidiol, produced alterations in DMTS performance levels. Simultaneous recordings from identified hippocampal complex spike cells at the highest dose of drug indicated that the DMTS deficit was associated with a specific decrease in hippocampal cell discharge during the Sample (but not the Match) phase of the task. In nine identified neurons (including four observed during both control and drug conditions) recorded from six different animals in which the effects of delta-9-THC were manifested, no indication of Sample phase firing was observed. Although there were slight but significant reductions in Match and Reinforcement phase related firing during THC sessions, highly significant increases in firing in these phases were still present, indicating that elimination of Sample phase firing did not reflect a nonspecific effect of delta-9-THC on hippocampal cell activity. These findings strongly suggest that performance of the DMTS task was selectively impaired by the lack of Sample phase discharge of hippocampal neurons during the DMTS trial, and that this effect could serve as the basis for the well characterized short-term memory and other cognitive deficits reported in humans after smoking marijuana.

Action Potentials↗
PubMed1992

Information processing in the dentate gyrus.

The dentate gyrus is viewed as playing a major role in the generation of epileptiform activity. The ramifications of disrupted neuronal activity in the dentate gyrus are discussed with emphasis on the role of the dentate gyrus in processing sensory information. Several features of conditioned auditory-evoked potentials reflective of activity in the perforant path are described with respect to the activity of dentate granule cells. Comparisons of the sequential changes which occur in the perforant path synaptic activity and dentate granule cell discharge reveal an inverse relationship between synaptic input from the perforant path and degree of cell firing on any given trial. This inverse relationship is addressed in terms of extra-hippocampal projections to the cortex as well as recurrent connections to the enthorhinal area and the cells of origin of the perforant path. It is concluded that the perforant path regulates the response of the dentate granule cells to sensory input from the neocortex by decreasing synaptic drive when granule cell activity is high and increasing that synaptic drive when granule cell activity is low. This extra-hippocampal control of perforant path activity serves to 'clamp' the dentate granule cell response rate within a tightly controlled range to guarantee that granule cells will have some response capacity to 'unexpected' sensory experiences.

Afferent Pathways↗
PubMed1989

Effects of delta-9-tetrahydrocannabinol on sensory evoked hippocampal activity in the rat: principal components analysis and sequential dependency.

The effects of delta-9-tetrahydrocannabinol (delta-9-THC) were assessed on identified hippocampal sensory evoked potentials obtained from rats during performance of a two-tone discrimination task. Techniques which analyzed the trial-to-trial sequential and serial dependence underlying the variance in evoked potential amplitude were utilized. Waveforms of averaged tone-evoked potentials (AEPs) recorded from the outer molecular layer of the dentate gyrus (OM) were subjected to principal components analysis which revealed eight principal components accounting for 90.3% of the total variance in the set of OM AEP waveforms. Five of the eight components were altered significantly in comparison to vehicle injection sessions after administration of either a 1.0- or 2.0-mg/kg dose of delta-9-THC. These alterations accounted for the amplitude and latency changes in the OM AEP described in a previous report. In addition, delta-9-THC also disrupted the trial-to-trial sequential dependency of the OM AEPs. An important result showed that delta-9-THC selectively influenced the serial dependence of the OM AEP. These results implicate delta-9-THC as a potent disruptor of temporally specific information as it is processed by the hippocampus and suggest that such disruption may be the basis of delta-9-THC effects on memory processes in humans.

Animals↗
PubMed1989

Hippocampal place cells: stereotypy and plasticity.

Hippocampal complex spike cells were recorded during exploration for water delivered to cups located in various regions of an elevated platform. Place fields were recorded with a video monitoring system that recorded movements as the animal explored each of the 5 cup locations where water was delivered on the platform. Plasticity of place cell firing as a function of selective water delivery to specific cup locations on the platform was also examined. Several characteristics of place cell firing were studied that indicated a high degree of control by factors such as relative direction of movement and trajectory through the field. Time-shift analyses indicated cell firing was most representative of the place field at the time of spike occurrence. It was demonstrated that place fields possess borders in which firing was increased or decreased upon entering or leaving a particular region of the platform. The most important finding from this investigation was the pronounced degree of plasticity exhibited by place cells. Selective delivery of water to a single location on the platform was sufficient in most of the cases tested to shift the location of the field to the location where water was available. These findings suggest hippocampal place cell firing, although highly influenced by spatial and directional features of the environment, can readily change under conditions in which significant stimuli are added or removed from those locations.

Animals↗
PubMed1988

Control of sensory activation of granule cells in the fascia dentata by extrinsic afferents: septal and entorhinal inputs.

Three groups of rats were trained to perform a differential discrimination task in a 2-tone operant conditioning paradigm. One group received electrolytic lesions of the medial septal nuclei, another received electrolytic or knife cut lesions of the entorhinal cortex. These groups were compared with a normal control group. Recordings of granule cells in the fascia dentata were obtained in all animals during criterion performance of the behavioral task. Both lesions produced disruption of behavioral discrimination in the form of increased error and intertrial responding. Granule cell discharges to the tone stimuli were disrupted by each type of lesion. Septal lesions reduced the differential discharge tendency to CS+ and CS- and changed granule cell firing on all trials to statistically resemble firing on CS- trials in normal animals. Extensive lesions in the entorhinal cortex or knife cuts that severed the perforant path caused near elimination of the tone-evoked discharges to both the CS+ and CS-tones. Septal and entorhinal lesions caused marked changes in the sequential dependence of the granule cell discharge compared with intact animals. Results are discussed in terms of the control of the granule cell discharge by the remaining afferent pathways in each type of lesion condition.

Acoustic Stimulation↗
PubMed1987

Sequential dependencies regulate sensory evoked responses of single units in the rat hippocampus.

Unit activity from 3 major types of hippocampal cells were recorded from the CA1, CA3 and dentate granule cell layers of the hippocampus in awake freely moving rats. Units were classified as complex spike (ComSp), theta and dentate granule cells (G-cell) based on their spontaneous and stimulus-evoked firing characteristics. Single trial records for each cell type were collected during criterion performance of a two-tone discrimination task. Results showed that: tone-evoked discharges of theta- and G-cells, but not ComSp cells, were influenced by the reward status of the tone presented; the firing tendency of all cell types was significantly influenced by the preceding trial sequence; different types of preceding trial sequences including single and double alternation and runs of positive or negative trials significantly affected the firing tendency of all 3 cell types; the pattern of theta- and G-cell discharges differed with respect to latency to peak discharge and the duration of the discharge following long runs of similar trials. These effects were similar to previously described sequential influence on synaptically identified sensory evoked potentials in the dentate gyrus.

Acoustic Stimulation↗
PubMed1987

Processing of sensory information in the hippocampus.

The functional significance of the mammalian hippocampal formation is considered within the context of specific neural circuits responsible for the processing of sensory information. The anatomic and physiologic features of the major input pathways from the hypothalamus, septum, and entorhinal cortex are reviewed with regard to sensory activation of hippocampal cell fields. A model is presented which interrelates the functional plasticity of hippocampal synaptic processes to reciprocal connections between input and output pathways. The manner in which sensory responsiveness is modulated in the rat dentate gyrus as a function of both cognitive and behavioral factors is described. The hippocampus is discussed with respect to its role as a short-term item-specific store of behaviorally relevant sensory information.

Animals↗