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R F Thompson

Publications and source records attributed to R F Thompson.

At least 55 records · Page 3Linked to original sources
PubMed1997

The conditioned eyeblink response: a role for the GABA-B receptor?

In well-trained animals, infusion of the GABA-B agonist baclofen into the cerebellar interpositus nucleus and overlying cortex abolished the conditioned response (CR) with no effect on the unconditioned response (UR) with doses at or above 5.0 mM. Infusion of the GABA-B antagonist CGP 5584-5A alone had no effect on the CR or UR. However, administration of 5 mM baclofen soon after infusion of CGP 5584-5A (15 min) resulted in no reduction of percent CR and only partial reduction of CR amplitude. Naive animals given interpositus infusions of baclofen during training showed no learning, yet learned normally in postinfusion training. The distribution of (radiolabelled) baclofen was localized and remained within the cerebellum. The results presented here are consistent with a growing body of literature supporting the hypothesis that the memory trace for eyeblink conditioning is formed and stored in the cerebellum and may involve GABAergic mechanisms.

Animals↗
PubMed1997

Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning.

There is increasing evidence that, in addition to its major functional role in the regulation of fine motor control, the cerebellum is involved in other important functions, such as sensory-motor learning and memory. Classical conditioning of the eyeblink or nictitating membrane response (and other discrete behavioral responses) is a form of sensory-motor learning that depends crucially upon the cerebellum. Within the cerebellum, however, the relative importance of the cerebellar cortex and the deep cerebellar nuclei in eyeblink conditioning is unclear and disputed. Recent studies employing various mutant mice provide an effective approach to resolving this controversy. Eyeblink conditioning in spontaneous mutant mice deficit in Purkinje cells, the exclusive output neurons of the cerebellar cortex, indicate that both the cerebellar cortex and the interpositus nucleus are important. Furthermore, studies involving gene knockout mice suggest that long-term depression, a process of synaptic plasticity occurring in Purkinje cells, might be involved in eyeblink conditioning.

Animals↗
PubMed1997

Motor cortex lesions do not affect learning or performance of the eyeblink response in rabbits.

The possible modulatory role of motor cortex in classical conditioning of the eyeblink response was examined by ablating anterior neocortex in rabbits and training them with an auditory conditioned stimulus (CS) and an airpuff unconditioned stimulus (US) in either a delay (Experiment 1) or a trace (Experiment 2) conditioning paradigm. Topographic measures such as amplitude and onset latency were assessed during conditioning sessions for conditioned responses (CRs) and on separate test days for unconditioned responses (URs) by using a range of US intensities. No lesion effects were observed for learning or performance measures in acquisition or retention of either delay or trace conditioning. During trace conditioning, lesioned rabbits did, however, exhibit a trend toward impairment and demonstrated significantly longer CR latencies. Damage to motor and frontal cortex does not significantly affect eyeblink response performance or learning in either a delay or a trace conditioning paradigm.

Acoustic Stimulation↗
PubMed1996

Memory systems in the brain and localization of a memory.

It is now clear that there are a number of different forms or aspects of learning and memory that involve different brain systems. Broadly, memory phenomena have been categorized as explicit or implicit. Thus, explicit memories for experience involve the hippocampus-medial temporal lobe system and implicit basic associative learning and memory involves the cerebellum, amygdala, and other systems. Under normal conditions, however, many of these brain-memory systems are engaged to some degree in learning situations. But each of these brain systems is learning something different about the situation. The cerebellum is necessary for classical conditioning of discrete behavioral responses (eyeblink, limb flexion) under all conditions; however, in the "trace" procedure where a period of no stimuli intervenes between the conditioned stimulus and the unconditioned stimulus the hippocampus plays a critical role. Trace conditioning appears to provide a simple model of explicit memory where analysis of brain substrates is feasible. Analysis of the role of the cerebellum in basic delay conditioning (stimuli overlap) indicates that the memories are formed and stored in the cerebellum. The phenomenon of cerebellar long-term depression is considered as a putative mechanism of memory storage.

Animals↗
PubMed1996

Effect of phosphatidylserine on the binding properties of glutamate receptors in brain sections from adult and neonatal rats.

The effects of phosphatidylserine (PS) on the binding properties of the AMPA (alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) subtypes of glutamate receptors were analyzed by quantitative autoradiography of [3H]AMPA, [3H]6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and [3H]glutamate binding on rat brain tissue sections. Preincubation of brain sections with PS produced an increase in [3H]AMPA binding without modifying the binding properties of [3H]CNQX, an antagonist of AMPA receptors. This effect of PS appeared to be specific for the AMPA subtype of glutamate receptors as the same treatment did not modify [3H]glutamate binding to the NMDA receptors. Furthermore, the PS-induced increase in [3H]AMPA binding was different in various brain structures, being larger in the molecular layer of the cerebellum and almost absent in the striatum. Preincubation with calcium also augmented [3H]AMPA binding, and the lack of additivity of the effects of calcium and PS on [3H]AMPA binding strongly suggests that both treatments share a common mechanism(s) for producing increased agonist binding. Finally, the effect of PS on AMPA receptor properties was markedly reduced in rat brain sections prepared from neonatal rats at a developmental stage that is normally characterized by the absence of LTP expression in certain brain regions. The present data are consistent with the hypothesis that alteration in the lipid composition of synaptic membranes may be an important mechanism for regulating AMPA receptor properties, which could be involved in producing long-lasting changes in synaptic operation.

Animals↗
PubMed1996

Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation.

Behavioral stress has detrimental effects on subsequent cognitive performance in many species, including humans. For example, humans exposed to stressful situations typically exhibit marked deficits in various learning and memory tasks. However, the underlying neural mechanisms by which stress exerts its effects on learning and memory are unknown. We now report that in adult male rats, stress (i.e., restraint plus tailshock) impairs long-term potentiation (LTP) but enhances long-term depression (LTD) in the CA1 area of the hippocampus, a structure implicated in learning and memory processes. These effects on LTP and LTD are prevented when the animals were given CGP39551 (the carboxyethylester of CGP 37849; DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, before experiencing stress. In contrast, the anxiolytic drug diazepam did not block the stress effects on hippocampal plasticity. Thus, the effects of stress on subsequent LTP and LTD appear to be mediated through the activation of the NMDA subtype of glutamate receptors. Such modifications in hippocampal plasticity may contribute to learning and memory impairments associated with stress.

2-Amino-5-phosphonovalerate↗
PubMed1996

Impaired classical eyeblink conditioning in cerebellar-lesioned and Purkinje cell degeneration (pcd) mutant mice.

Converging lines of evidence from rabbits, rats, and humans argue for the crucial involvement of the cerebellum in classical conditioning of the eyeblink/nictitating membrane response in mammals. For example, selective lesions (permanent or reversible) of the cerebellum block both acquisition and retention of eyeblink conditioning. Correspondingly, electrophysiological and brain-imaging studies indicate learning-related plasticity in the cerebellum. The involvement of the cerebellum in eyeblink conditioning is also supported by stimulation studies showing that direct stimulation of the two major afferents to the cerebellum (the mossy fibers emanating from the pontine nucleus and climbing fibers originating from the inferior olive) can substitute for the peripheral conditioned stimulus (CS) and unconditioned stimulus (US), respectively, to yield normal behavioral learning. In the present study, we examined the relative contribution of the cerebellar cortex versus deep nuclei (specifically the interpositus nucleus) in eyeblink learning by using mutant mice deficient of Purkinje cells, the exclusive output neurons of the cerebellar cortex. We report that Purkinje cell degeneration (pcd) mice exhibit a profound impairment in the acquisition of delay eyeblink conditioning in comparison with their wild-type littermates. Nevertheless, the pcd animals did acquire a subnormal level of conditioned eyeblink responses. In contrast, wild-type mice with lesions of the interpositus nucleus were completely unable to learn the conditioned eyeblink response. These results suggest that both cerebellar cortex and deep nuclei are important for normal eyeblink conditioning.

Animals↗
PubMed1996

Deficient cerebellar long-term depression, impaired eyeblink conditioning, and normal motor coordination in GFAP mutant mice.

Mice devoid of glial fibrillary acidic protein (GFAP), an intermediate filament protein specifically expressed in astrocytes, develop normally and do not show any detectable abnormalities in the anatomy of the brain. In the cerebellum, excitatory synaptic transmission from parallel fibers (PFs) or climbing fibers (CFs) to Purkinje cells is unaltered, and these synapses display normal short-term synaptic plasticity to paired stimuli in GFAP mutant mice. In contrast, long-term depression (LTD) at PF-Purkinje cell synapses is clearly deficient. Furthermore, GFAP mutant mice exhibited a significant impairment of eyeblink conditioning without any detectable deficits in motor coordination tasks. These results suggest that GFAP is required for communications between Bergmann glia and Purkinje cells during LTD induction and maintenance. The data support the notion that cerebellar LTD is a cellular mechanism closely associated with eyeblink conditioning, but is not essential for motor coordination tasks tested.

Animals↗
PubMed1996

Inactivation of brainstem motor nuclei blocks expression but not acquisition of the rabbit's classically conditioned eyeblink response.

Rabbits were eyeblink conditioned while their accessory abducens nucleus (ACC), facial nucleus (FN), and surrounding reticular formation (RF) were temporarily inactivated with microinjections of muscimol to determine whether these structures are critically involved in acquisition of the conditioned eyeblink response (CR). Rabbits performed no CRs or unconditioned responses (URs) during inactivation training. Training was continued without inactivation and rabbits performed the CR at asymptotic levels from the start of training without inactivation. They had fully learned the CR while their ACC, FN, and RF were inactivated, despite performing no CRs or URs at all during inactivation. These results rule out any critical role for neurons within the ACC, FN, or surrounding RF in acquisition of the classically conditioned eyeblink response.

Abducens Nerve↗
PubMed1996

Hippocampal lesions impair contextual fear conditioning in two strains of mice.

Two different strains of mice, C57BL/6J and BALB/c, with hippocampal, cortical, or sham lesions, underwent contextual fear conditioning. In both strains, contextual fear, as measured by the freezing response, was significantly impaired in hippocampus-lesioned animals compared with sham control animals. Fear conditioning was not affected in the cortical-lesioned group. Moreover, there was a strain difference in fear conditioning: The C57BL/6J mice exhibited freezing more frequently than the BALB/c mice. Consistent with previous hippocampal lesion studies in rats, these results indicate that contextual fear conditioning in mice also requires the intact hippocampus. This study provides a basis for evaluating hippocampal synaptic mechanisms in relation to contextual fear conditioning in widely available gene knockout or transgenic mice.

Animals↗
PubMed1996

Classical conditioning with electrical stimulation of cerebellum as both conditioned and unconditioned stimulus.

Stimulating electrodes were implanted in rabbit cerebellum, providing an electrical conditioned stimulus (CS) activating cortical parallel fibers and thence Purkinje and other cells, and an electrical unconditioned stimulus (US) activating underlying white matter and eliciting unconditioned responses. Paired CS-US presentations led to the development of conditioned responses, which showed extinction following CS-alone trials and reacquisition with significant savings on reinstatement of paired trials. Increased local excitability as a result of paired training (but not following unpaired stimulus presentations) was observed in cerebellar cortex, as manifested in substantial decreases in CS threshold for response elicitation in all subjects. This preparation offers a model for the study of plastic neuronal interactions within cerebellar networks critically involved in associative learning.

Animals↗
PubMed1996

Hippocampal responses to corticosterone and stress, one of which is the 35,000 M(r) protein, glycerol phosphate dehydrogenase.

Previously, the synthesis of a hippocampal 35,000 M(r) protein increased in response to glucocorticoid treatment and a variety of stressors. We now show by immunoprecipitation that this cytosolic protein is glycerol 3-phosphate dehydrogenase (E.C.1.1.1.8; GPDH). In addition, four polypeptides encoded by glucocorticoid-induced mRNAs co-migrated with hippocampal protein synthetic products on two-dimensional polyacrylamide gels, including 35,000 M(r) protein of approximately pl 6.3, that had previously been identified as GPDH by hybrid-selection with a GPDH cDNA clone. The 35,000 M(r) in vitro translation product was also immunoprecipitated with the GPDH antibody. Using radiolabeled hippocampal slices and two-dimensional gel analysis, a 35,000 M(r) polypeptide of approximately pl 6.4 increased five-fold after 30 min of intermittent tail-shock. This protein was found predominantly in the 20,000 x g pellet and did not immunoprecipitate with the GPDH antibody. However, a 35,000 M(r) polypeptide was also found in the cytosol as a minor component after stress, which did immunoprecipitate with the GPDH antibody. Therefore, there are at least two shock-induced 35,000 M(r) proteins, one of which is GPDH. These results establish that increases in GPDH mRNA prevalence and protein synthesis occur in response to both glucocorticoids and stress in the adult rat hippocampus. Based on the increased enzyme activity seen in the nervous system in response to glucocorticoids, dietary restriction, and nerve injury, the induction of GPDH may have functional consequences in cellular adaptation to stress.

Animals↗
PubMed1995

Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKC gamma mutant mice.

It is generally believed that a smooth execution of a compound movement, or motor coordination, requires learning of component movements as well as experience-based refinement of the motor program as a whole. PKC gamma mutant mice display impaired motor coordination but intact eyeblink conditioning, a form of component movement learning. Cerebellar long-term depression, a putative cellular mechanism for component motor learning, is also unimpaired. Thus, PKC gamma mutant mice are defective in refinement of the motor program. In the accompanying paper, we demonstrate that innervation of multiple climbing fibers onto Purkinje cells persists in adulthood in these mutant mice. We propose that this defective elimination of surplus climbing fibers underlies motor discoordination.

Animals↗
PubMed1995

Inactivation of the superior cerebellar peduncle blocks expression but not acquisition of the rabbit's classically conditioned eye-blink response.

The localization of sites of memory formation within the mammalian brain has proven to be a formidable task even for simple forms of learning and memory. Recent studies have demonstrated that reversibly inactivating a localized region of cerebellum, including the dorsal anterior interpositus nucleus, completely prevents acquisition of the conditioned eye-blink response with no effect upon subsequent learning without inactivation. This result indicates that the memory trace for this type of learning is located either (i) within this inactivated region of cerebellum or (ii) within some structure(s) efferent from the cerebellum to which output from the interpositus nucleus ultimately projects. To distinguish between these possibilities, two groups of rabbits were conditioned (by using two conditioning stimuli) while the output fibers of the interpositus (the superior cerebellar peduncle) were reversibly blocked with microinjections of the sodium channel blocker tetrodotoxin. Rabbits performed no conditioned responses during this inactivation training. However, training after inactivation revealed that the rabbits (trained with either conditioned stimulus) had fully learned the response during the previous inactivation training. Cerebellar output, therefore, does not appear to be essential for acquisition of the learned response. This result, coupled with the fact that inactivation of the appropriate region of cerebellum completely prevents learning, provides compelling evidence supporting the hypothesis that the essential memory trace for the classically conditioned eye-blink response is localized within the cerebellum.

Animals↗
PubMed1995

Enhanced glutamatergic neurotransmission facilitates classical conditioning in the freely moving rat.

Centrally active drugs that enhance alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-gated currents by increasing the amplitude and duration of fast, excitatory synaptic responses in the hippocampus have recently been described. The effects of the compound 1-(1,3-benzodioxol-5-ylcarbonyl) perperidine (BDP) on associative and non-associative aspects of the classically conditioned eyeblink response in the freely moving rat were examined. Rats injected with BDP blinked significantly more to an acoustic stimulus of 85 dB than did vehicle controls, indicating that the drug enhances alpha responding to discrete auditory cues. Using a less intense stimulus of 80 dB, rats injected with BDP did not exhibit alpha responding or pseudo-conditioning, yet learned the conditioned response at a facilitated rate. These results suggest that increasing excitatory neurotransmission enhances the processing of sensory information and may contribute to subsequent contingency detection.

Acoustic Stimulation↗
PubMed1995

Developmental changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor properties and expression in the rat hippocampal formation.

The developmental changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor properties in rat hippocampus were evaluated with quantitative autoradiography of ligand binding and in situ hybridization performed in adjacent sections with antisense oligonucleotides for AMPA receptor subunits (GluR1-3, flip and flop splice variants). Specific 3H-AMPA binding in different hippocampal subfields increased between postnatal day 7 and 15 and was higher in CA3 during the postnatal period when compared to adult levels. This effect was mostly due to high levels of high affinity binding sites in cell body layers during the developmental period. By contrast, autoradiograms of 3H-AMPA binding predominantly to the low affinity binding sites indicated an absence of these sites in cell body layers and the overall levels of binding exhibited little overshoot compared to adult levels during the developmental period. The changes in binding of the antagonist of the AMPA receptor, 6-nitro-7-cyanoquinoxaline-2,3-dione were markedly different from those for the high affinity AMPA binding sites but quite similar to those for the low affinity sites. The binding was extremely low at postnatal day 7 and increased rapidly between postnatal day 7 and 15 and slowly between postnatal day 15 and adult. Low levels of binding were observed in the cell body layer at every postnatal age. The changes in expression of messenger RNAs for the different subunits of the AMPA receptors were well correlated with the modifications in high affinity AMPA binding sites measured in the cell body layers also exhibiting an increased expression of the receptors at the transcriptional level during the developmental period as compared to adult levels. The relative expression of the GluR2 subunits decreased during the postnatal period and the time course for this reduction paralleled that for the increased vulnerability of hippocampal pyramidal neurons to a variety of insults. The results indicate that both the messenger RNAs for the subunits and the AMPA receptors exhibit increased levels of expression during the postnatal period compared to adult levels. They also suggest that nascent receptors might bind AMPA with high affinity before their insertion in membranes into functional receptors that have low affinity for agonists and high affinity for antagonists. The changes in subunit composition of the receptors during the postnatal period may have important implications for mechanisms of plasticity as well as of neuropathology.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses.

New Zealand male rabbits (Oryctolagus cuniculus) were trained on a trace eyeblink conditioning paradigm using a 250-ms tone conditioned stimulus, a 100-ms airpuff unconditioned stimulus, and a 500-ms trace interval. Rabbits received bilateral hippocampal aspirations either 1 day or 1 month after learning. Controls consisted of time-matched sham-operated and neocortical aspirated rabbits. When retested on the trace paradigm, rabbits with hippocampal aspirations 1 day after learning were significantly and substantially impaired in the retention of trace conditioned responses. In contrast, rabbits that received hippocampal aspirations 1 month after training retained trace conditioned responses at a level comparable to that of the controls. Moreover, hippocampectomy had no effect on the retention of delay eyeblink conditioning. Thus, the hippocampus appears to be necessary for the retention of recently acquired, but not remotely acquired, trace conditioned responses.

Animals↗