Biomedical subjects

J L Olds

Publications and source records attributed to J L Olds.

16 recordsLinked to original sources

PubMed1995

Protein kinase C in the hippocampus is altered by spatial but not cued discriminations: a component task analysis.

The exact role of the mammalian hippocampus in memory formation remains essentially as an unanswered question for cognitive neuroscience. Experiments with humans and with animals indicate that some types of mnemonic associative processes involve hippocampal function while others do not. Support for the spatial processing hypothesis of hippocampal function has stemmed from the impaired performance of rats with hippocampal lesions in tasks that require spatial discriminations, but not cued discriminations. Previous procedures, however, have confounded the interpretation of spatial versus cued discrimination learning with the number and kinds of irrelevant stimuli present in the discrimination. An empirical set of data describing a role of protein kinase C (PKC) in different mnemonic processes is similarly being developed. Recent work has implicated the activation of this serine-threonine kinase in a variety of learning paradigms, as well as long-term potentiation (LTP), a model system for synaptic plasticity which may subserve some types of learning. The present study employs the principles of component task analysis to examine the role of membrane-associated PKC (mPKC) in hippocampal-dependent memory when all factors other than the type of learning were equivalent. The results indicate that hippocampal mPKC is altered by performance in hippocampally-dependent spatial discriminations, but not hippocampally-independent cued discriminations and provide a general experimental procedure to relate neural changes to specific behavioral changes.

Animals↗

PubMed1995

Alzheimer and beta-amyloid-treated fibroblasts demonstrate a decrease in a memory-associated GTP-binding protein, Cp20.

The two proteins most consistently identified in the brains of patients with Alzheimer disease (AD) have been beta-amyloid and tau, whose roles in the physiology or pathophysiology of brain cells are not fully understood. To identify other protein(s) involved in AD that have been implicated in physiological contexts, we undertook to analyze a specific memory-associated protein, Cp20, in fibroblasts from AD and control donors. Cp20, a GTP-binding protein that is a member of the ADP-ribosylation factor family, was significantly decreased in fibroblasts from AD patients. Normal control fibroblasts exposed to 10 nM beta-amyloid, the same concentration that induced AD-like K+ changes in control fibroblasts, showed a similar decrease in Cp20. Since it has been previously demonstrated that Cp20 is a potent regulator of K+ channels, these findings suggest that changes in this memory-associated protein may explain previously observed differences in AD K+ channels and suggest a pathophysiologic involvement linked to soluble beta-amyloid metabolism that could contribute to the characteristic memory loss of AD.

Alzheimer Disease↗

PubMed1995

Imaging protein kinase C activation in living sea urchin eggs after fertilization.

The fluorescent dye NBD-phorbol acetate was used to visualize the activation of protein kinase C (PKC) in living Lytechinus pictus eggs during fertilization. The dye interacts directly with PKC as determined using a competitive binding assay. Quantitative image analysis of sequential images from laser-scanning confocal microscopy showed a significant reorganization of the signal in the vicinity of the cortical granules and the plasma membrane that began immediately following fertilization and persisted up to 1 hr (P<0.0001). At the concentrations employed, the NBD-phorbol dye was not capable of inducing a significant translocation of the fluorescent signal to the membrane, nor did it appear to interfere with the cell cycle. It therefore seems likely that the present in vivo results reflect the previously reported in vitro activation of protein kinase C immediately subsequent to fertilization. Such an interpretation is parsimonious with the results of parallel subcellular fractionation experiments using an N-terminal polyclonal antibody to sea urchin PKC which showed a significant (P<0.037) translocation of the enzyme from the cytosolic fraction to the membrane fraction 40 min subsequent to fertilization. This study supports and extends previous in vitro data suggesting that PKC activation subsequent to fertilization occurs at or near the egg plasma membrane, perhaps in association with arachadonic acid-rich cortical granules.

Animals↗

PubMed1994

Lateralization of membrane-associated protein kinase C in rat piriform cortex: specific to operant training cues in the olfactory modality.

Rats were trained on an olfactory and a control modality (auditory or visual) discrimination task and brain membrane-associated protein kinase C (mPKC) was subsequently assessed using quantitative autoradiography of radiolabelled phorbol ester binding. In rats which received olfactory-cued training, mPKC showed a highly significant lateralization in the piriform cortex but not in the hippocampus. Both olfactory-trained rats and control modality rats showed a significant increase in mPKC in the hippocampus when compared to naive rats. Thus, while behavioral training procedures appeared to result in a hippocampal increase in the activated state of this enzyme as has been reported elsewhere, only olfactory learning produced an piriform cortex lateralization in the activated state of the enzyme. While the functional significance of such a change in the distribution of protein kinase C is still unclear, it does suggest that the monitoring of this enzyme's activational state may prove to be a useful tool in the study of memory formation in a wide variety of behavioral contexts.

Animals↗

PubMed1993

Gated informational transfer within the mammalian hippocampus: a new hypothesis.

Presented here is a position paper that advocates a novel and testable hypothesis concerning the role and function of the mammalian hippocampal formation especially with regards to neonatal neural development. The present paper is based upon recent electrophysiological and biochemical studies of the developing rabbit hippocampus and proposes that by gating the transfer of sensory information through the trisynaptic circuit, the hippocampus allows, in a permissive sense, the buildup of cognitive maps, either in the hippocampus itself, or in other brain loci such as the neocortex. The model makes certain predictions that can be experimentally tested and therefore may prove useful for organizing future data in research into hippocampal function.

Aging↗

PubMed1993

Quantitative distribution of protein kinase C alpha, beta, gamma, and epsilon mRNAs in the hippocampus of control and nictitating membrane conditioned rabbits.

We used oligonucleotide in situ hybridization and film autoradiography to quantitate the distributions of protein kinase C (PKC) alpha, beta, gamma, and epsilon mRNAs in subregions of rabbit hippocampus. Levels of each of the hippocampal PKC isozyme mRNAs and patterns of their regional distributions were remarkably invariant between individuals. Within stratum pyramidale, the highest levels of PKC alpha mRNA were in the CA2 region, while PKC beta mRNA was maximally expressed in CA1, and PKC epsilon mRNA in CA3; PKC gamma mRNA was abundantly expressed throughout Ammon's horn. Previous experiments employing quantitative autoradiography for [3H]PDBU (Olds et al., Science, 245 (1989) 866-869) revealed an increase in membrane-bound PKC in the CA1 region of rabbit hippocampus up to 3 days following classical conditioning of the nictitating membrane response. We report here that there were no differences in levels of PKC alpha, beta, gamma, or epsilon mRNA between conditioned and control rabbits in any hippocampal region one day after training. These data are consistent with the hypothesis that PKC is post-translationally activated and translocated to the membrane during memory storage.

Acoustic Stimulation↗

PubMed1993

Cell specificity of molecular changes during memory storage.

The aeolid nudibranch, Hermissenda crassicornis, exhibits Pavlovian conditioning to paired light and rotational stimuli and it has been suggested that protein kinase C(PKC) may play a critical role in the cellular mechanism for this conditioned behavioral response in the B-cell photoreceptor. The present study was designed to further examine learning-specific PKC involvement in identified cellular areas, particularly those in the visual-vestibular network, of the Hermissenda nervous system after Pavlovian conditioning. As used in previous vertebrate studies, the highly specific PKC radioligand, [3H]phorbol-12,13-dibutyrate ([3H]-PDBU), was used to determine the binding characteristics of the molluscan protein receptor considered to be PKC. The binding was specific, saturable, and could be displaced by a soluble diacylglycerol analogue. The binding activity was distributed evenly between the cytosol and the membrane. All of these analyses suggest that [3H]PDBU binds primarily to PKC in Hermissenda as it does in many other systems. Computerized grain image analysis was then used to determine the cellular localization of PKC as a function of Pavlovian conditioning. The medial and intermediate B photoreceptor and the optic ganglion showed significantly increased [3H]PDBU binding in conditioned animals. The present results provide the first report of an associative learning change of a key signal transduction component in identified neurons.

Animals↗

PubMed1993

Lithium decreases membrane-associated protein kinase C in hippocampus: selectivity for the alpha isozyme.

We investigated the effects of lithium on alterations in the amount and distribution of protein kinase C (PKC) in discrete areas of rat brain by using [3H]phorbol 12,13-dibutyrate quantitative autoradiography as well as western blotting. Chronic administration of lithium resulted in a significant decrease in membrane-associated PKC in several hippocampal structures, most notably the subiculum and the CA1 region. In contrast, only modest changes in [3H]phorbol 12,13-dibutyrate binding were observed in the various other cortical and subcortical structures examined. Immunoblotting using monoclonal anti-PKC antibodies revealed an isozyme-specific 30% decrease in hippocampal membrane-associated PKC alpha, in the absence of any changes in the labeling of either the beta (I/II) or gamma isozymes. These changes were observed only after chronic (4 week) treatment with lithium, and not after acute (5 days) treatment, suggesting potential clinical relevance. Given the critical role of PKC in regulating neuronal signal transduction, lithium's effects on PKC in the limbic system represent an attractive molecular mechanism for its efficacy in treating both poles of manic-depressive illness. In addition, the decreased hippocampal membrane-associated PKC observed in the present study offers a possible explanation for lithium-induced memory impairment.

Animals↗

PubMed1993

Protein kinase C: a nexus in the biochemical events that underlie associative learning.

We have proposed that protein kinase C, an enzyme critical to cell regulation of growth, secretion and differentiation, is a part of a sequence of molecular events that underlie learning and memory. Electrophysiological, biochemical and neuro-imaging methods have been employed to show that the enzyme changes its distribution as a result of memory storage within the neural networks that are necessary for the acquisition and performance of various learning tasks in several species. We propose here, a model of protein kinase C as a molecular signal for the association of synaptic input that is parsimonious with the recent data, mainly from our laboratory, concerning its function in memory formation.

Animals↗

PubMed1991

Protein kinase C redistribution within CA3 stratum oriens during acquisition of nictitating membrane conditioning in the rabbit.

This manuscript describes experiments designed to investigate protein kinase C redistribution occurring during acquisition of the rabbit nictitating membrane (NM) conditioned response (CR). The first experiment defined the acquisition phase of the NM response for our laboratory. A group of rabbits (n = 6) was given 2 days of paired NM training; a second group (n = 6) was given 2 days of unpaired NM training. The data document a variable level of responding on day 1 for rabbits given paired training (mean +/- SEM, 21 +/- 11% CRs) but show that on day 2 most rabbits reached the behavioral asymptote (five of six rabbits responding with greater than 85% CRs). Rabbits responding at the behavioral asymptote were defined as having acquired the NM conditioned response. These data were interpreted to indicate that 1 day of training initiated processes necessary for behavioral acquisition (i.e., responding at the behavioral asymptote). A quantitative film autoradiographic study of [3H]phorbol 12,13-dibutyrate binding was then used to determine the distribution of hippocampal protein kinase C in rabbits sacrificed after receiving either 1 day of paired stimuli (n = 10), 1 day of unpaired stimuli (n = 6), or no stimuli (n = 6). Autoradiograms were analyzed by measuring binding in strictly defined regions of interest and from transept profiles. A significant increase in binding of the phorbol ester was found in the CA3 stratum oriens in the paired group relative to unpaired and naive controls. No other significant differences were found.

Analysis of Variance↗

PubMed1991

A role for protein kinase C in associative learning.

Recent work suggests that protein kinase C (PKC), an enzyme that has a critical role in the regulation of cell growth and differentiation, also participates in the sequence of molecular events that underlie learning and memory. By means of electrophysiological, biochemical, and neuro-imaging methods it has been demonstrated that, in the brain, the distribution of PKC changes as a result of memory storage. The changes in distribution occur within the same ensembles of nerve cells that are necessary for the acquisition and performance of various learning tasks in several species. Here we review the data pertaining to a model that has been proposed to account for the participation of PKC as a molecular signal for cotemporal synaptic input during associative learning.

Alzheimer Disease↗

PubMed1990

Contraction of neuronal branching volume: an anatomic correlate of Pavlovian conditioning.

Associative memory of the mollusc Hermissenda crassicornis, previously correlated with changes of specific K+ currents, protein phosphorylation, and increased synthesis of mRNA and specific proteins, is here shown to be accompanied by macroscopic alteration in the structure of a single identified neuron, the medial type B photoreceptor cell. Four to five days after training, terminal arborizations of B cells iontophoretically injected with Ni2+ ions and then treated with rubeanic acid were measured with charge-coupled device (CCD)-digitized pseudocolor images of optical sections under "blind" conditions. Boundary volumes enclosing medial-type B-cell arborizations from classically conditioned animals were unequivocally reduced compared with volumes for naive animals or those trained with unpaired stimuli. Branch volume magnitude was correlated with input resistance of the medial type B-cell soma. Such associative learning-induced structural changes may share function with "synapse elimination" described in developmental contexts.

Animals↗

PubMed1990

Discrimination learning alters the distribution of protein kinase C in the hippocampus of rats.

Protein kinase C (PKC), an enzyme that plays an essential role in eukaryotic cell regulation (Nishizuka, 1988; Huang et al., 1989), is critical to memory storage processes both in the marine snail Hermissenda crassicornis and in the rabbit (Alkon et al., 1988; Bank et al., 1988; Olds et al., 1989). Specifically, activation of PKC mimics neurobiological correlates of classical conditioning in both Hermissenda and the rabbit, and the distribution of the enzyme within the rabbit hippocampus changes after Pavlovian conditioning. Here, we report that the amount of PKC, as assayed by specific binding of 3H-phorbol-12,13-dibutyrate (3H-PDBU), decreased significantly within the hippocampal CA3 cell region in rats trained to solve a water maze task either by cognitive mapping or by visual discrimination strategies, but not in control rats. Furthermore, hippocampal lesions interfered with acquisition of both of these tasks. We interpret these findings to support the conclusion that distributional changes of PKC within the mammalian hippocampus play a crucial role in memory storage processes.

Animals↗

PubMed1989

Imaging of memory-specific changes in the distribution of protein kinase C in the hippocampus.

Activation of protein kinase C (PKC) can mimic the biophysical effects of associative learning on neurons. Furthermore, classical conditioning of the rabbit nictitating membrane (a form of associative learning) produces translocation of PKC activity from the cytosolic to the membrane compartments of the CA1 region of the hippocampus. Evidence is provided here for a significant change in the amount and distribution of PKC within the CA1 cell field of the rabbit hippocampus that is specific to learning. This change is seen at 1 day after learning as focal increments of [3H]phorbol-12,13-dibutyrate binding to PKC in computer-generated images produced from coronal autoradiographs of rabbit brain. In addition, 3 days after learning, the autoradiographs suggest a redistribution of PKC within CA1 from the cell soma to the dendrites.

Animals↗

PubMed1985

A sequential double-label autoradiographic method that quantifies altered rates of regional glucose metabolism.

An autoradiographic sequential double-label variant of the deoxyglucose method for measurement of local glucose utilization has been developed. This technique takes advantage of the short half-life of the positron emitter, 18F (t 1/2 = 110 min) relative to that of 14C. Sequential injection of [18F]fluorodeoxyglucose (FDG) and 14C-labeled FDG allows the production of two separable autoradiograms, each of which represents the same 20-micron brain slice, but under potentially different cerebral metabolic states. We have used this technique to demonstrate that ibotenic acid-lesioned rat striatum is selectively refractory to the depressing effects of barbiturate anesthesia upon brain glucose utilization. The described method has applicability to the analysis of small changes in regional cerebral metabolism in localized brain regions and represents a solution to the problem of intersubject variability inherent in conventional approaches to the deoxyglucose method.

Animals↗

PubMed1985

Dendritic transport. I. Colchicine stimulates the transport of lysosomal enzymes from cell bodies to dendrites.

Injection of colchicine into the lateral cerebral ventricle of the rat was found to induce a paradoxical translocation of two lysosomal enzymes, dipeptidyl peptidase II (Dpp II) and acid phosphatase, from the soma of neurons to the dendrites. Following a single injection of colchicine, neuronal somata, which normally contain the bulk of these lysosomal enzymatic activities, become depleted of these enzymes, whereas dendrites become abnormally enriched. All neurons which contained these enzymes, except those of the mesencephalic nucleus of the trigeminal nerve, displayed this phenomenon. Lysosomal enzyme translocation into dendrites was observed in the mitral cell layer within 1 hr after a colchicine injection and could be induced in most neuronal populations by injections of colchicine as low as 25 micrograms. Five days after a 100-micrograms colchicine injection, a normal pattern of enzyme distribution was observed, indicating that the effect of colchicine was reversible. Enzyme translocation was not accompanied by gross changes in cell morphology, nor did it result in the specific loss of neuronal cell bodies which contained these enzymes. The results indicate that colchicine, under conditions known to inhibit axoplasmic transport, stimulates the transport of lysosomal enzymes from the cell body to the dendrites.

Acid Phosphatase↗