Biomedical subjects

M F Bear

Publications and source records attributed to M F Bear.

At least 19 recordsLinked to original sources

PubMed1992

Effects of N-methyl-D-aspartate on quisqualate-stimulated phosphoinositide hydrolysis in slices of kitten striate cortex.

Stimulation of phosphoinositide (PI) hydrolysis by excitatory amino acids (EAAs) was studied in coronal slices of kitten visual cortex. Coincubation with N-methyl-D-aspartate (NMDA) markedly reduced the stimulation by quisqualate, however, this inhibition developed with a latency of > 10 min and occurred even when the NMDA exposure preceded, but did not overlap with, incubation in quisqualate. This time-course of NMDA inhibition of EAA-stimulated PI turnover places new constraints on its possible mechanism of inhibition.

Animals↗

PubMed1992

Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade.

We tested a theoretical prediction that patterns of excitatory input activity that consistently fail to activate target neurons sufficiently to induce synaptic potentiation will instead cause a specific synaptic depression. To realize this situation experimentally, the Schaffer collateral projection to area CA1 in rat hippocampal slices was stimulated electrically at frequencies ranging from 0.5 to 50 Hz. Nine hundred pulses at 1-3 Hz consistently yielded a depression of the CA1 population excitatory postsynaptic potential that persisted without signs of recovery for greater than 1 hr after cessation of the conditioning stimulation. This long-term depression was specific to the conditioned input, ruling out generalized changes in postsynaptic responsiveness or excitability. Three lines of evidence suggest that this effect is accounted for by a modification of synaptic effectiveness rather than damage to or fatigue of the stimulated inputs. First, the effect was dependent on the stimulation frequency; 900 pulses at 10 Hz caused no lasting change, and at 50 Hz a synaptic potentiation was usually observed. Second, the depressed synapses continued to support long-term potentiation in response to a high-frequency tetanus. Third, the effects of conditioning stimulation could be prevented by application of NMDA receptor antagonists. Thus, our data suggest that synaptic depression can be triggered by prolonged NMDA receptor activation that is below the threshold for inducing synaptic potentiation. We propose that this mechanism is important for the modifications of hippocampal response properties that underlie some forms of learning and memory.

2-Amino-5-phosphonovalerate↗

PubMed1992

Long-term potentiation in slices of kitten visual cortex and the effects of NMDA receptor blockade.

1. A slice preparation was used to study layer III field potentials (FPs) evoked by electrical stimulation of the white matter-layer VI border and their potentiation by patterned stimuli. 2. The dependence of the FP on recording position was investigated. The maximum field was recorded in layer III at a position radial to the site of stimulation. Because this negative FP reflects an excitatory synaptic current sink, this site was chosen for all subsequent experiments. 3. Under normal recording conditions, components of the layer III FP with latencies greater than 3 ms were completely abolished by kynurenate but unaffected by 2-amino-5-phosphonovalerate (AP5), indicating that this potential reflects the activation of non-NMDA excitatory amino acid receptors. 4. Addition of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline methiodide (BMI) broadened the field potential and revealed an AP5-sensitive component. By filling the recording pipette with BMI, it was possible to substantially reduce inhibition locally around the recording site while avoiding stimulus-driven and spontaneous epileptiform activity. 5. Tetanic stimulation elicited a long-term potentiation (LTP) of the FP in 14 of 17 experiments when the BMI-filled pipette method was used. 6. Addition of 100 microM D,L-AP5 significantly reduced the average probability and magnitude of LTP. Nonetheless, in 2 of 8 experiments, significant LTP was observed after a tetanus in the presence of AP5. Control experiments confirmed that this concentration of AP5 was sufficient to maximally block cortical NMDA receptors. 7. We conclude that LTP of layer III field potentials can be reliably elicited, provided that GABAA-receptor mediated inhibition is blocked locally at the site of recording and that NMDA receptors are recruited during the conditioning stimulation. However, activation of NMDA receptors is apparently not an obligatory step for the induction of use-dependent increases in synaptic strength in the kitten striate cortex.

2-Amino-5-phosphonovalerate↗

PubMed1991

Effects of age and visual experience on [3H] MK801 binding to NMDA receptors in the kitten visual cortex.

We have investigated the postnatal development of N-methyl-D-aspartate (NMDA) receptors in kitten neocortex by measuring the density of [3H] MK801 binding sites. NMDA receptor density in area 17 markedly increases between postnatal day 7 and 35, and then remains at a high level into adulthood. Similar temporal changes were observed in area 6. A brief period of binocular deprivation did not alter the density of [3H] MK801 binding sites in either brain region. However, dark rearing kittens from birth resulted in a significant decrease after 35 and 120 days in both area 17 and area 6. These results demonstrate that the density of NMDA receptors does not effectively predict the capacity for visual cortical plasticity in kitten neocortex. In addition, these results show that dark rearing produces significant effects in areas of the kitten neocortex not normally associated with visual function.

Age Factors↗

PubMed1991

Stimulation of phosphoinositide turnover by excitatory amino acids. Pharmacology, development, and role in visual cortical plasticity.

Theoretical analysis suggests that in the visual cortex during early postnatal development, afferent activity can yield either an increase or a decrease in synaptic strength depending on the pattern of EAA receptor activation in cortical neurons. This motivated us to study the mechanism of EAA-stimulated phosphoinositide turnover in visual cortex. Available evidence suggests that PI hydrolysis is stimulated by EAAs primarily at a single receptor site (Q2 receptor), and that this site is distinct from both the traditional quisqualate (Q1) receptor and the NMDA receptor. NMDA does, however, inhibit EAA-stimulated PI turnover in visual cortex, confirming that the Q2 receptor is on visual cortical neurons (as opposed to glia). We find that Q2 receptors in the neocortex are expressed transiently during postnatal development. The developmental time-course of EAA-stimulated PI turnover correlates precisely with the critical period when synaptic modifications are most readily elicited in visual cortex by changes in sensory experience. The compound AP3 can inhibit EAA-stimulated PI turnover, probably by acting as a partial Q2 agonist, and under some circumstances AP3 evidently can interfere with experience-dependent synaptic modifications. Increases in synaptic strength in visual cortex, as elsewhere, have been linked specifically to activation of NMDA receptors. We propose that decreases in synaptic strength may be specifically related to activation of the Q2 receptor. Further tests of this hypothesis will require the development of selective and potent antagonists.

Amino Acids↗

PubMed1991

Synaptic plasticity in visual cortex: comparison of theory with experiment.

1. The aim of this work was to assess whether a form of synaptic modification based on the theory of Bienenstock, Cooper, and Munro (BCM) can, with a fixed set of parameters, reproduce both the kinetics and equilibrium states of experience-dependent modifications cortex. 2. According to the BCM theory, the connection strength of excitatory geniculocortical synapses varies as the product of a measure of input activity (d) and a function (phi) of the summed postsynaptic response. For all postsynaptic responses greater than spontaneous but less than a critical value called the "modification threshold" (theta), phi has a negative value. For all postsynaptic responses greater than theta, phi has a positive value. A novel feature of the BCM theory is that the value of theta is not fixed, but rather "slides" as a nonlinear function of the average postsynaptic response. 3. This theory permits precise specification of theoretical equivalents of experimental situations, allowing detailed, quantitative comparisons of theory with experiment. Such comparisons were carried out here in a series of computer simulations. 4. Simulations are performed by presenting input to a model cortical neuron, calculating the summed postsynaptic response, and then changing the synaptic weights according to the BCM theory. This process is repeated until the synaptic weights reach an equilibrium state. 5. Two types of geniculocortical input are simulated: "pattern" and "noise." Pattern input is assumed to correspond to the type of input that arises when a visual contour of a particular orientation is presented to the retina. This type of input is said to be "correlated" when the two sets of geniculocortical fibers relaying information from the two eyes convey the same patterns at the same time. Noise input is assumed to correspond to the type of input that arises in the absence of visual contours and, by definition, is uncorrelated. 6. By varying the types of input available to the two sets of geniculocortical synapses, we simulate the following types of visual experience: 1) normal binocular contour vision, 2) monocular deprivation, 3) reverse suture, 4) strabismus, 5) binocular deprivation, and 6) normal contour vision after a period of monocular deprivation. 7. The constraints placed on the set of parameters by each type of simulated visual environment, and the effects that such constraints have on the evolution of the synaptic weights, are investigated in detail.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

Cholinergic manipulation alters stimulus-evoked metabolic activity in cat somatosensory cortex.

The role of acetylcholine (ACh) in cerebral cortical activity has recently been reevaluated. It now seems clear that this neurotransmitter increases the magnitude of cortical responses. Although substantial information has been gathered regarding the role of ACh in sensory information processing, little is known about the participation of ACh in the organization of maps in the cerebral cortex. To address this issue, we used 2 methods to manipulate the supply of ACh in the somatosensory cortex of cats: 1) unilateral neurotoxic lesions of the basal forebrain and 2) unilateral topical applications of the cholinergic antagonist, atropine. For each experimental condition, the animal received an injection of 2-deoxyglucose (2DG) while identical somatic stimuli were delivered to the right and left forepaws. In the somatosensory cortex, the 2DG uptake most often occurred in the form of patches that extended from layer II to IV. When the patches were reconstructed into 2-dimensional maps of activity throughout the somatosensory cortex, they formed strips that ran in the rostrocaudal direction. The reconstructed maps revealed that the 2DG patterns in ACh-depleted and the normal cortex were similar in their overall topographic distribution. Depletion or antagonism of ACh, however, caused the stimulus-evoked metabolic label to be reduced in dimension and density. Measurements of background activity levels were obtained by using 1) cytochrome oxidase histochemistry or 2) metabolic activity values in regions of somatosensory cortex that were not specifically stimulated. This analysis indicated that background values in the ACh-depleted hemispheres were not different from those in the normal hemispheres. The absence of ACh therefore appears to reduce the cortical response to stimulation, while background activity values do not change. These observations indicate that ACh plays a significant role in the processing of sensory information and the organization of somatosensory cortical maps.

Acetylcholine↗

PubMed1990

N-methyl-D-aspartate-evoked calcium uptake by kitten visual cortex maintained in vitro.

As a functional measure of NMDA receptor effectiveness in kitten striate cortex, the uptake of 45Ca by visual cortical slices was measured after 2 minute bath applications of N-methyl-D-aspartate (NMDA). Significant Ca uptake occurred in response to 12.5-100 microM NMDA in slices prepared from visual cortex of normal animals aged 28-48 days. Basal uptake (in the absence of NMDA) was increased and evoked uptake was decreased in visual cortical slices prepared from age-matched dark-reared animals. Four days of binocular deprivation in otherwise normally reared animals had no effect on basal uptake, but significantly lowered NMDA-evoked Ca uptake at agonist concentrations greater than 25 microM. These data suggest that even brief manipulations of sensory experience are sufficient to alter visual cortical calcium regulation.

Animals↗

PubMed1990

Binocular competition in the control of geniculate cell size depends upon visual cortical N-methyl-D-aspartate receptor activation.

The lateral geniculate nucleus relays visual information from the retina to cortex. One well-known anatomical consequence of monocular deprivation during early postnatal development is a shrinkage of neurons in the lamina of the lateral geniculate nucleus that receive input from the deprived eye. This is thought to reflect the competition of afferents subserving the two eyes, possibly at the level of the visual cortex. We find that blockade of N-methyl-D-aspartate receptors in kitten visual cortex disrupts this process of binocular competition. These data provide direct evidence that postsynaptic activation of cortical neurons is required for competitive changes in lateral geniculate cell size and suggest a role for N-methyl-D-aspartate receptors in anatomical as well as physiological plasticity in the mammalian visual system.

2-Amino-5-phosphonovalerate↗

PubMed1990

Basal forebrain projections to somatosensory cortex in the cat.

1. This investigation was designed to identify the source of cholinergic basal forebrain projections to somatosensory cortex in the cat. 2. Injections of horseradish peroxidase (HRP) into cortical areas 3a, 3b, and 1 after a 36 to 48-h survival period, labeled neurons in the basal forebrain. The distribution of retrogradely labeled neurons was compared with the distribution of cells labeled by choline acetyltransferase immunocytochemistry. Most retrogradely labeled neurons in the basal telencephalon were found on the border between the globus pallidus and adjacent structures. Sometimes labeled neurons were also found in both limbs of the diagonal band of Broca. 3. Excitotoxin lesions of these regions of the basal telencephalon led to a profound depletion of acetylcholinesterase-containing axons in primary somatosensory cortex. 4. These data lay necessary groundwork for tests of the hypothesis that the cholinergic projection modulates experience-dependent modifications in adult cat somatosensory cortex.

Acetylcholine↗

PubMed1990

Disruption of experience-dependent synaptic modifications in striate cortex by infusion of an NMDA receptor antagonist.

To assess the possibility that NMDA receptors play a special role in visual cortical plasticity, the selective antagonist 2-amino-5-phosphonovaleric acid (APV) was continuously infused into the striate cortex of kittens as the visual environment was manipulated during the critical period. The cortex was studied using single-unit recording from sites between 3 and 6 mm from the infusion cannulae. One week of D,L-APV infusion coincident with monocular deprivation or "reverse suture" produced a concentration-dependent increase in the percentage of neurons that (1) lacked normal orientation selectivity and (2) were responsive to stimulation of the deprived eye. These effects outlasted the presence of the drug in the tissue. APV treatment also prevented the acquisition of selectivity and visual responsiveness that normally results from monocular visual experience after dark-rearing. Lasting effects of chronic APV infusion were not observed in adult striate cortex. The effects of APV on kitten striate cortex depended on the presence of the D stereoisomer as infusion of L-APV was without effect. Estimates of extracellular concentration using 3H-APV indicated that significant effects could be obtained with concentrations as low as 20 microM D,L-APV. Recordings from units during infusion indicated that visual responses were reduced by APV. Nonetheless, a normal percentage of visually responsive neurons was found at sites greater than or equal to 3 mm from the infusion cannula. There was no evidence that chronic APV infusion affected the sampling frequency of recorded neurons or disrupted cytoarchitecture at the sites further than 3 mm from the infusion cannula. Taken together, the data indicate that the effects of APV on kitten striate cortex are likely due specifically to the blockade of NMDA receptors. These data are considered in relation to several hypotheses concerning the role of NMDA receptors in the experience-dependent development of striate cortex.

2-Amino-5-phosphonovalerate↗

PubMed1989

A biochemical correlate of the critical period for synaptic modification in the visual cortex.

Stimulation of phosphoinositide hydrolysis by excitatory amino acids was studied in synaptoneurosomes of kitten striate cortex at several postnatal ages. Ibotenate and glutamate stimulated phosphoinositide turnover during the second and third postnatal months; N-methyl-D-aspartate and DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) were without effect. The developmental profile of ibotenate-stimulated phosphoinositide turnover parallels the postnatal changes in cortical susceptibility to visual deprivation. The transient increase in ibotenate-stimulated phosphoinositide turnover does not occur in visual cortex of kittens reared in complete darkness.

Aging↗

PubMed1989

Blockade of NMDA-receptors prevents ocularity changes in kitten visual cortex after reversed monocular deprivation.

We investigated in the striate cortex of kittens whether the recovery from the effects of monocular deprivation that occurs after reverse occlusion requires activation of N-methyl-D-aspartate (NMDA) receptors. The right eye of 3-4-week-old kittens was closed by lid suture for one week. Subsequently this eye was reopened and the left eyelid sutured closed for another week. During this second week, the NMDA-receptor antagonist, 2-amino-5-phosphonovaleric acid (APV), was infused from an osmotic minipump into the left visual cortex (50 nmol/h), while the right visual cortex was infused only with vehicle solution (saline) as control. At the end of the second week, the ocular dominance of striate cortical neurons was assessed with single unit recording. In the control hemispheres, the large majority of neurons was dominated by the newly opened eye, while in the APV-treated hemispheres most neurons were still dominated by the newly deprived eye. In addition, neurons in the APV-treated hemispheres were less responsive and showed a reduction of orientation tuning. These data confirm that chronic blockade of cortical NMDA-receptors disrupts the disconnection of deprived pathways after monocular deprivation and reduces both responsiveness and orientation selectivity of cortical neurons. In addition they indicate that blockade of NMDA-receptors prevents also vision-dependent recovery of deprived pathways after reverse occlusion.

2-Amino-5-phosphonovalerate↗

PubMed1989

Postnatal changes in glutamate stimulated phosphoinositide turnover in rat neocortical synaptoneurosomes.

Glutamate was found to stimulate the accumulation of [3H]inositol phosphate in synaptoneurosomes prepared from rat neocortex during a narrowly defined period of postnatal development. No glutamate stimulation was observed on the day of birth, even though high levels of phosphoinositide (PIns) turnover were observed with the muscarinic agonist carbachol. Glutamate-stimulated PIns turnover reached a maximum at one week of age, and decreased to adult levels by five weeks of age. Of the glutamate analogs tested, only ibotenate produced significant stimulation. N-Methyl-D-aspartate (NMDA) showed negligible stimulation and kainate showed only minor stimulation at the highest concentration tested (1 mM). Glutamate stimulation was not blocked by either the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) or the broad spectrum glutamate antagonist kynurenic acid. These results suggest that a specific subclass of excitatory amino acid receptor linked to PIns metabolism, or a phospholipase associated with the receptor, is transiently expressed in the neocortex during early postnatal development.

Aging↗

PubMed1989

Visual experience regulates gene expression in the developing striate cortex.

We have examined the regulation of expression of the genes for the neuronal growth-associated protein GAP43, the type II calcium/calmodulin-dependent protein kinase, and glutamic acid decarboxylase in the kitten visual cortex during normal postnatal development and after a period of visual deprivation. We find that the mRNA transcripts of these genes display very different patterns of normal development but are all increased in the visual cortex of animals reared in the dark. Upon exposure to light, the transcript of the GAP43 gene drops to near-normal levels within 12 hr.

Aging↗

PubMed1987

Blockade of "NMDA" receptors disrupts experience-dependent plasticity of kitten striate cortex.

Intracortical infusion of the "N-methyl-D-aspartate" (NMDA) receptor blocker D,L-2-amino-5-phosphonovaleric acid (APV) renders kitten striate cortex resistant to the effects of monocular deprivation. In addition, 1 week of continuous APV treatment (50 nanomoles per hour) produces a striking loss of orientation selectivity in area 17. These data support the hypothesis that crucial variables for the expression of activity-dependent synaptic modifications are a critical level of postsynaptic activation and calcium entry through ion channels linked to NMDA receptors.

2-Amino-5-phosphonovalerate↗

PubMed1985

Glutamic acid decarboxylase activity decreases in mouse neocortex after lesions of the basal forebrain.

Glutamic acid decarboxylase (GAD) activity was measured in the cerebral cortex of animals after acute and chronic lesions to basal forebrain cholinergic nuclei. Such lesions were shown to result in an extensive depletion of cholinergic markers in parietal cerebral cortex. A statistically significant 30% decrease in GAD activity was first detected at 6 weeks postlesion and was still measurable 8 months after the lesion. These results suggest that cholinergic inputs to cortex indirectly or directly influence GABAergic transmission in cortex.

Animals↗

PubMed1985

Glutamic acid decarboxylase in the striate cortex of normal and monocularly deprived kittens.

Degeneration of the thalamic fibers in the visual cortex of turtles leads to an increase in the numerical density of cortical synapses with flattened vesicles and symmetrical membrane differentiations (Smith, L. M., and F. F. Ebner (1980) Soc. Neurosci. Abstr. 6: 328). This change correlates with an increase in the cortical activity of glutamic acid decarboxylase (GAD), the synthetic enzyme for gamma-aminobutyric acid (GABA). These data are consistent with the hypothesis that removal of thalamic input activity is the stimulus for cortical GABAergic neurons to form new synapses. Pharmacological evidence suggests that even simple environmental deprivation may induce a similar increase in the numerical density of GABAergic synapses in kitten striate cortex (Duffy, F. H., S. R., Snodgrass, J. L. Burchfiel, and J. L. Conway (1976) Nature 260: 256-257). We have examined this possibility in monocularly deprived kittens using methods to localize and measure GAD. GAD in kitten striate cortex was localized using immunocytochemistry. GAD-positive cells were found in all layers and were uniformly distributed in layers II to VI. Immunoreactivity associated with axon terminals (puncta), in contrast, was laminated with a distinct band in layer IV. Monocular deprivation (MD), by either unilateral enucleation or lid closure, had no detectable effect on the distribution of GAD in striate cortex. The band of layer IV puncta remained uniform even under conditions that produced alterations in layer IV cytochrome oxidase activity. We measured GAD activity in homogenates of striate cortex to address the possibility that MD causes an absolute change in the density of GABAergic synapses. Again, however, GAD activity in the binocular and monocular segments of striate cortex was found to be unaffected by early enucleation. These data suggest two conclusions: first, that the numerical density of GABAergic synapses in visual cortex is not regulated directly by thalamic activity, and second, that changes in GABAergic synapse density do not account for the ocular dominance shift observed in kitten striate cortex after MD.

Animals↗