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J F Disterhoft

Publications and source records attributed to J F Disterhoft.

18 recordsLinked to original sources
PubMed1992

Hippocampus-dependent learning facilitated by a monoclonal antibody or D-cycloserine.

Persistent neuronal plasticity, including that observed at some hippocampal synapses, requires N-methyl-D-aspartate (NMDA)-mediated transmission. NMDA receptor activation may be necessary for hippocampus-dependent learning as antagonists block acquisition in many such tasks. The behavioural effects of NMDA agonists are less well defined. We have shown that a monoclonal antibody (B6B21) displaced [3H]-glycine that was bound specifically to the NMDA receptor, and enhanced the opening of its integral cation channel in a glycine-like fashion, effects that were competitively antagonized by 7-chlorokynurenic acid. B6B21 also enhanced long-term potentiation in hippocampal slices. We report here that intraventricular infusions of B6B21 significantly enhances acquisition rates in hippocampus-dependent trace eye blink conditioning in rabbits, halving the number of trials required to reach a criterion of 80% conditioned responses. Peripheral injections of D-cycloserine, a partial agonist of the glycine site on the NMDA receptor which crosses the blood-brain barrier, also doubles rabbits' learning rates. Pseudoconditioning control experiments indicated a lack of nonspecific behavioural sensitization effects. Our data suggest that enhanced activation of the glycine coagonist site on the NMDA receptor/channel complex facilitates one form of associative learning and may be used in other learning tasks.

Animals↗
PubMed1992

Nimodipine increases excitability of rabbit CA1 pyramidal neurons in an age- and concentration-dependent manner.

1. Cellular properties were studied before and after bath application of the dihydropyridine L-type calcium channel antagonist nimodipine in aging and young rabbit hippocampal CA1 pyramidal cells in vitro. Various concentrations of nimodipine, ranging from 10 nM to 10 microM, were tested to investigate age- and concentration-dependent effects on cellular excitability. Drug studies were performed on a population of neurons at similar holding potentials to equate voltage-dependent effects. The properties studied under current-clamp conditions included steady-state current-voltage relations (I-V), the amplitude and integrated area of the postburst afterhyperpolarization (AHP), accommodation to a prolonged depolarizing current pulse (spike frequency adaptation), and single action-potential waveform characteristics following synaptic activation. 2. Numerous aging-related differences in cellular properties were noted. Aging hippocampal CA1 neurons exhibited significantly larger postburst AHPs (both the amplitude and the integrated area were enhanced). Aging CA1 neurons also exhibited more hyperpolarized resting membrane potentials with a concomitant decrease in input resistance. When cells were grouped to equate resting potentials, no differences in input resistance were noted, but the AHPs were still significantly larger in aging neurons. Aging CA1 neurons also fired fewer action potentials during a prolonged depolarizing current injection than young CA1 neurons. 3. Nimodipine decreased both the peak amplitude and the integrated area of the AHP in an age- and concentration-dependent manner. At concentrations as low as 100 nM, nimodipine significantly reduced the AHP in aging CA1 neurons. In young CA1 neurons, nimodipine decreased the AHP only at 10 microM. No effects on input resistance or action-potential characteristics were seen. 4. Nimodipine increased excitability in an age- and concentration-dependent manner by decreasing spike frequency accommodation (increasing the number of action potentials during prolonged depolarizing current injection). In aging CA1 neurons, this effect was significant at concentrations as low as 10 nM. In young CA1 neurons, nimodipine decreased accommodation only at higher concentrations (> or = 1.0 microM). 5. We conclude that aging CA1 neurons were less excitable than young neurons. In aging hippocampus, nimodipine restores excitability, as measured by size of the AHP and degree of accommodation, to levels closely resembling those of young adult CA1 neurons. These actions of nimodipine on aging CA1 hippocampal neurons may partly underlie the drug's notable ability to improve associative learning in aging rabbits and other mammals. Reversal of inhibitory postsynaptic potentials (IPSPs) by chloride ion and/or current injections into six motoneurons revealed the presence of inhibition during the period between phrenic bursts during fictive vomiting and also during the final phase of expulsion when phrenic discharge ceased by abdominal discharge continued. 3. Fictive coughing, evoked by repetitive electrical stimulation of superior laryngeal nerve afferents, was characterized by a large phrenic discharge followed immediately by a large abdominal nerve discharge. During fictive coughing, phrenic motoneurons retained their ramplike depolarizations throughout phrenic discharge; however, the amplitude of depolarization was greater than during inspiration. During the subsequent abdominal nerve discharge, the phrenic membrane potential usually underwent an initial rapid, transient hyperpolarization followed by a gradual repolarization associated with increased synaptic noise.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1990

Nimodipine enhances spontaneous activity of hippocampal pyramidal neurons in aging rabbits at a dose that facilitates associative learning.

The functional activity of hippocampal neurons is strongly correlated with behavioral performance in a vertebrate model learning system, rabbit eyeblink conditioning. Using this system, we have previously shown that (a) complete removal of the hippocampus blocks acquisition of the conditioned response; (b) a calcium-dependent postsynaptic afterhyperpolarization is reduced in pyramidal cells recorded intracellularly in hippocampal slices taken from conditioned rabbits; and (c) nimodipine, a 1,4-dihydropyridine calcium-channel antagonist, facilitates acquisition of the conditioned response in aging rabbits. Although calcium-channel antagonists directly block neuronal calcium currents in vitro, they also alter cerebral blood flow in vivo. Thus, the effects of nimodipine on hippocampal neuronal activity in awake animals were examined, with controls for cerebrovascular changes. A total of 457 pyramidal cells and 160 theta cells were studied. During infusion of nimodipine, pyramidal cell firing activity was enhanced and theta interneuron activity was suppressed at all doses tested in aging animals. This effect was rapidly reversed when infusion of the drug ceased. The greatest enhancement of neuronal firing was seen at the most behaviorally effective dose of nimodipine. The enhancement of pyramidal cell firing was age-dependent, with greater increases in firing activity seen in aging than in young animals, but with a similar dose-dependent pattern of effects in the two age groups. Two other calcium-channel antagonists, nifedipine and flunarizine, did not significantly alter spontaneous firing rates of hippocampal neurons. A calcium-channel agonist, BAY-K-8644, produced less easily interpretable results. BAY-K-8644 enhanced interneuron activity at one dose, but enhanced pyramidal cell activity at a dose one log unit higher. The calcium-channel agonist's enhancement of pyramidal cell activity at the highest dose was sustained up to 1 h after drug infusion. Nimodipine's enhancement of the activity of hippocampal pyramidal cells is consistent with the hypothesis that these neurons, which play a necessary role in some forms of learning, may mediate the calcium-channel antagonist's behavioral effects.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1990

Learning-induced afterhyperpolarization reductions in hippocampus are specific for cell type and potassium conductance.

Hippocampal slices were prepared from rabbits trained in a trace eye-blink conditioning task and from naive and pseudoconditioned controls. Measurements of the post-burst afterhyperpolarization (AHP), action potential, and other cellular properties were obtained from intracellular recordings of CA1 pyramidal (N = 49) and dentate gyrus granule cells (N = 52). A conditioning-specific reduction in the amplitude of the AHP was found in CA1 cells but not in dentate granule cells. This reduction in the AHP was apparent at 50 ms after the end of a depolarizing current pulse, and was maintained for at least 650 ms. Other measured cell characteristics (input resistance, resting membrane potential, action potential shape, inward rectification, spike threshold) were not affected by training, in either CA1 pyramidal or dentate granule cells. Time-course measures indicate that both the medium, Ca2(+)-independent AHP and the slow, Ca2(+)-dependent AHP are reduced by conditioning. The slow AHP largely reflects the Ca2(+)-dependent K+ current, IAHP. Rising and falling slopes, peak amplitude, and width of individual action potentials were not changed by learning. This contrasts with observations from invertebrates in which action potential broadening was reported following learning. We conclude that the reduction in AHP that follows hippocampally-dependent associative learning occurs in specific hippocampal cell types and not others, and is mediated by changes in a Ca2(+)-independent AHP and a particular Ca2(+)-dependent K+ current, IAHP.

Action Potentials↗
PubMed1990

Hippocampectomy disrupts trace eye-blink conditioning in rabbits.

The role of the hippocampus (HPC) in trace eye-blink conditioning was evaluated using a 100-ms tone conditioned stimulus (CS), a 300- or 500-ms trace interval, and a 150-ms air puff unconditioned stimulus (UCS). Rabbits received complete hippocampectomy (dorsal & ventral), sham lesions, or neocortical lesions. Hippocampectomy produced differential effects in relation to the trace interval used. With a 300-ms trace interval, HPC-lesioned Ss showed profound resistance to extinction after acquisition. With a 500-ms trace interval, HPC-lesioned Ss did not learn the task (only 22% conditioned responses (CRs) after 25 sessions, whereas controls showed greater than 80% after 10 sessions), and on the few trials in which a CR occurred, most were "nonadaptive" short-latency CRs (i.e., they started during or just after the CS and always terminated prior to UCS onset). The authors conclude that the HPC encodes a temporal relationship between CS and UCS, and when the trace interval is long enough (e.g., 500 ms), that the HPC is necessary for associative learning of the conditioned eye-blink response.

Animals↗
PubMed1989

Nimodipine facilitates associative learning in aging rabbits.

Nimodipine is one of several dihydropyridines that block calcium channels. Originally administered to improve cerebral blood flow in elderly patients with chronic cerebrovascular disorders, nimodipine was noted to facilitate learning. These observations led to the present investigation of the effects of nimodipine on associative learning in aging rabbits. Nimodipine accelerated acquisition of conditioned eye-blink in both young and aging rabbits without altering the amplitude of responses to the conditioned or unconditioned stimuli or causing nonspecific responding. Thus, nimodipine may be a candidate for an effective treatment for age-related learning deficits.

Aging↗
PubMed1989

Hippocampal lesions impair memory of short-delay conditioned eye blink in rabbits.

Involvement of hippocampus in short-delay eye blink conditioning was reexamined during conditioned response (CR) consolidation. Rabbits received bilateral hippocampectomy, removal of overlying neocortex, or sham lesions and were trained with tone/puff pairings to early acquisition (consolidation) or well trained (overtraining); retention was tested. Two effects were observed: 1) Rabbits with hippocampal lesions showed less retention in the consolidation experiment than controls. Previous studies may not have found this because initial training was more complete. Overtrained hippocampal rabbits showed more retention, which agrees with this suggestion. 2) Hippocampectomized rabbits showed larger CR amplitudes in the overtraining experiment. The complementary roles of hippocampus in the consolidation process during early learning and in modulating the expression of the amplitude/time course of behavioral conditioned responses after associations are well learned are discussed.

Animals↗
PubMed1989

Classical conditioning reduces amplitude and duration of calcium-dependent afterhyperpolarization in rabbit hippocampal pyramidal cells.

1. The afterhyperpolarization (AHP) that follows action potentials was studied in CA1 hippocampal pyramidal cells from classically conditioned and control rabbits. Measurements of the AHP were obtained with intracellular recordings from CA1 cells within hippocampal slices. 2. The AHP of rabbit CA1 pyramidal cells was found to be accompanied by a conductance increase. The AHP was reduced by bath applications of the calcium channel blockers, cadmium and cobalt, by bath application of the cholinergic agonist, carbamylcholine chloride, and intracellular injection of the calcium chelator, ethylene glycol-bis(B-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). 3. The AHP was markedly reduced in cells from rabbits that were well-trained with the nictitating membrane conditioning procedure, as compared with cells from pseudoconditioned or naive control animals. The difference in AHP amplitudes between conditioned and control groups increased as the number of spikes elicited by the stimulation pulse increased from one to four. Both the duration (measured as the time constant of AHP decay) and amplitude of the AHP were reduced in cells from conditioned animals. 4. The reduced AHP in cells from conditioned animals remained reduced in a medium that contained 0.5 microM tetrodotoxin (TTX) and 5.0 mM tetraethylammonium chloride (TEA); the AHP following calcium spikes was measured under these conditions. Since this medium eliminated synaptic transmission elicited by Schaeffer collateral stimulation, the AHP reduction in pyramidal cells from conditioned animals was not due to a modification in synaptic properties. There were no significant differences in the mean voltage thresholds, amplitudes, or durations of calcium spikes between cells from animals in the three groups. Thus the AHP reduction appears to be due to a modification of a Ca2+ -dependent K+ conductance and was not due to a secondary effect of reductions in calcium conductances underlying the spike. 5. In medium containing TTX and TEA, the amount of injected current required to elicit a calcium spike (current threshold) was significantly greater in cells from conditioned animals than in cells from control animals. This increase in current threshold persisted in 4-aminopyridine (4-AP)-containing medium and so cannot be attributed entirely to conditioning-specific increases in the A-current. 6. The conditioning-specific AHP reduction resulted in increased excitability in cells from conditioned animals versus pseudoconditioned control animals. Cells from conditioned animals fired more spikes to trains of 100-ms depolarizing current pulses than did cells from controls.

4-Aminopyridine↗
PubMed1977

Differentiated short latency response increases after conditioning in inferior colliculus neurons of alert rat.

The responses of 35 inferior colliculus multiple units (MUs) to tone onset were measured in 10 freely moving rats before and after differential behavioral conditioning. MU response changes were found in the 16.8 msec after tone onset (includes 2 msec air travel time) after learning. Responses to CS+ onset increased in 12 of the 35 individual MUs, and in the group of MUs as a whole, after conditioning. The CS+--CS- difference increased in 17 of the 35 individual MUs, and in the group of MUs, after conditioning. The response differentiation was significant in the 3.6-6.4 msec interval after the tone reached the animal's ears, the time at which neuronal responses were first evident. Since the inferior colliculus increases were differentiated between CS+ and CS-, they could not be explained by sensitization caused by changed middle ear contractions or by alterations in orientation to the speakers.

Animals↗
PubMed1977

General-purpose timer from transistor logic to auxiliary equipment.

This paper describes a low-cost circuit for the control and timing of auxiliary experimental equipment by a variety of signals from 5 V, integrated-circuit logic. The circuit is designed for variable timing and switching up to 240 AC V at 3 A, with two independent timing parameters, delay and duration, in response to positive-going or to negative-going logic signal transitions.

Electronics, Medical↗
PubMed1976

Trial sequence of changed unit activity in auditory system of alert rat during conditioned response acquisition and extinction.

1. The activity of units in the auditory system of alert, freely moving rats was studies during the acquisition and extinction of a tone-signaled, appetitive classically conditioned response. Responses of neurons in inferior colliculus (N = 28), medial geniculate (N = 32), posterior nucleus of thalamus (N = 28), pretectal region (N = 19), and cortex (N = 100) were studies in 74 rats across 10-trial blocks. 2. During behavioral acquisition, neurons in posterior nucleus of thalamus were the first to show response increments to CS+ onset. They were followed by neurons in cortex, pretectal region, medial geniculate, inferior colliculus and by movement behavior. 3. Prestimulus background rates during acquisition showed significant decrements in cortical neurons. These background decrements began to be evidenced in the trial series before the response increases in posterior nucleus. These data strengthened the suggestion of a previous study that posterior nucleus responses could be dependent on tonic modulation from cortex. 4. Extinction appeared to be largely a reverse of acquisition. Cortex and behavior showed response decrements first in the trial series. They were followed by medial geniculate, pretectal region, posterior nucleus, and inferior colliculus neurons. 5. The hypothesis was advanced that the auditory lemniscal adjunct afferent system may play a primary role in the early phases of auditory conditioned-response acquisition.

Acoustic Stimulation↗
PubMedDate not supplied

Dietary nimodipine improves associative learning in aging rabbits.

The effects of oral nimodipine on the acquisition of the conditioned eye-blink response in aging rabbits were examined. Three groups of rabbits were compared: young and aging controls fed NIH-09 rabbit chow and aging rabbits fed rabbit chow containing 860 ppm nimodipine. Aging control rabbits are dramatically impaired in the acquisition of this task compared to young controls. Aging rabbits receiving nimodipine reached a behavioral criterion of 4 conditioned responses in any block of 5 trials significantly faster than aging controls. Young controls reached this criterion faster than the aging controls. There were no significant group effects on either the amplitude or the latency of the conditioned response. This study extends earlier reports that IV nimodipine enhances the associative learning abilities of aging rabbits and examined the route of administration most likely to be used clinically in aging humans.

Aging↗
PubMedDate not supplied

Neuron activity in rat hippocampus and motor cortex during discrimination reversal.

Chronic unit activity and gross movement were recorded from rats during two discrimination reversals in a classical appetitive conditioning situation. The anticipatory movement decreased in response to the former CS+ tone and increased to the previous CS- tone after each reversal. Hippocampus and motor cortex were differently related to these two kinds of behavioral change. Response rates of hippocampal neurons were more closely related to the increased movement response to the former CS- which now signaled food. Motor cortex neuron responses were more closely correlated with the decrease in movement responses to the former CS+ which became neutral after the reversal. It appeared that hippocampal neurons could have been involved in one cognitive aspect of the situation, motor cortex neurons in another. The data were related to current functional concepts of these brain regions.

Animals↗
PubMedDate not supplied

Nimodipine ameliorates aging-related changes in open-field behaviors of the rabbit.

The open-field behavior of old rabbits (32-50 months) was compared to that of young-controls (3 months). Old rabbits engaged in less grooming and rearing behaviors and were more active than young controls. The old rabbits demonstrated a pattern of ambulation which did not indicate a preference for any particular area of the open-field. In contrast, young rabbits exhibited a very stereotypic pattern of exploration in the open-field, engaging in relatively low levels of ambulation confined to the area near the sides of the open-field. Old rabbits fed a diet which included 860 ppm nimodipine showed behaviors in the open-field which closely approximated those of the young-controls. Nimodipine-treated rabbits made fewer crossings and more rears and grooms than the old controls. These results indicate that very specific aging-related changes occur in the open-field behaviors of rabbits, and that nimodipine effectively reverses these aging-associated changes. These data are consistent with previous studies that have shown improvements in open-field behaviors by old rats receiving nimodipine.

Aging↗
PubMedDate not supplied

Associative learning and long-term potentiation: cellular mechanisms compared.

The potential relationship of LTP (Long Term Potentiation) to behavioral learning is an important issue. An important question in whether the cellular mechanisms of LTP and naturally occurring learning, share the same "memory" formation process or whether these two phenomena are subserved by two different types of storage processes. We would suggest that at least in the case of the hippocampal region, LTP could well share common mechanisms of formation with well studied examples of both cognitive and non-cognitive, or habit memory. We have considered several lines of evidence which demonstrate striking similarities between the phenomena of learning, especially associative learning and LTP.

Animals↗