[Brain substrates of the Pavlovian conditioning of discrete behavioral responses].
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Biomedical subjects
R F Thompson
Publications and source records attributed to R F Thompson.
Unilateral inferior olive NMDA lesion leads to unilateral deficit in acquisition and retention of eyelid classical conditioning.
New Zealand White rabbits (Oryctolagus cuniculus) were trained for acquisition (N = 21) or retention (N = 10) of classical eyelid conditioning with unilateral or bilateral N-methyl-DL-aspartate chemical lesions of the rostromedial dorsal accessory inferior olive (rmDAO; multiple injections totaling 76 to 342 nmol). In all instances, subjects were unable to learn or retain conditioning on the side contralateral to the lesion. Learning rates were comparable for lesions outside of the rmDAO and sham operates. These findings demonstrate a specific unilateral deficit whereas in previous research the answer to this question was ambiguous since electrolytic lesions effectively cause bilateral olivary lesions. This research agrees with the concept that the inferior olive projects essential information about the unconditioned stimulus to a cerebellar locus of learning and memory for classical conditioning.
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Acquisition of classically conditioned eyeblink response following bilateral lesions of flocculus and paraflocculus.
Stimulation of regions of the cerebellar flocculus can elicit eyeblinks, but the relationship of this floccular eyeblink zone to eyeblink classical conditioning is unknown. In this experiment, New Zealand white rabbits received bilateral lesions of the flocculus and paraflocculus and were subsequently classically conditioned with tone and corneal airpuff on the left and then the right eye. All animals reached training criterion on both eyes, with the exception of one animal whose lesion included the superior cerebellar peduncle and who was unable to learn on the ipsilateral eye. The lesioned group was not significantly different from unlesioned controls in rate of acquisition or conditioned or unconditioned response amplitude. These results indicate that the flocculus and paraflocculus are not by themselves the essential site of plasticity for classical conditioning of the rabbit eyeblink response.
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Emergence neophobia correlates with hippocampal and cortical glutamate receptor binding in rats.
Previous work from our laboratory indicated that emergence neophobia is highly correlated with perforant path long-term potentiation (LTP) in rats. In the present study, we examined the relationship between hippocampal and cortical alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors and emergence behavior in rats. Emergence neophobia was assessed in an exploratory task that provided a choice between a novel alley and a familiar nest box. Quantitative autoradiography using radiolabeled ligands specific for the AMPA subclass of glutamate receptors was performed on frozen brain sections. Both [3H]AMPA and [3H]CNQX (6-cyano-7-nitro-[3H]quinoxaline- 2,3-dione, an AMPA receptor antagonist) binding in the dentate gyrus (stratum moleculare), hippocampal area CA1 (stratum radiatum), and the parietal cortex overlying the hippocampus were significantly correlated with emergence behavior. The correlations indicated that neophobic rats, which had longer latencies to enter the novel alley, made fewer entries into the alley, and spent less time in the novel alley during a 10-min test than their neophilic counterparts, had higher levels of AMPA receptor binding. These results suggest that individual differences in specific hippocampal AMPA receptors reflect variability in a specific class of hippocampal-dependent behaviors.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Parallel augmentation of hippocampal long-term potentiation, theta rhythm, and contextual fear conditioning in water-deprived rats.
The influence of water deprivation on hippocampal long-term potentiation (LTP), theta rhythm, and contextual fear conditioning in rats was examined. In Experiment 1, hippocampal EEG activity and perforant path LTP were assessed in pentobarbital-anesthetized rats. Water deprivation did not affect baseline cell excitability or low-frequency synaptic transmission in the dentate gyrus, but it increased the magnitude of perforant path LTP and elevated the proportion of theta rhythm in the EEG. In Experiment 2, rats were classically conditioned to fear a novel context through the use of aversive footshocks. Water deprivation facilitated the rate of contextual fear conditioning but did not alter the asymptote of learning. Experiment 3 demonstrated that the facilitation of contextual fear conditioning was not due to a change in unconditional shock sensitivity. These results suggest that water deprivation exerts an influence on contextual fear conditioning by modulating hippocampal LTP and theta rhythm and that these processes serve to encode contextual information during learning.
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Behaviorism and neuroscience.
The influence of the methods and theories of behaviorism on theory and research in the neurosciences is examined, partly in light of Watson's (1913) original call-to-arms. Behaviorist approaches to animal behavior, particularly in the study of processes of learning and memory, have had a profound and continual influence in the area of neuroscience concerned with animal studies of brain substrates of behavior. Similarly, contemporary behaviorists have not been opposed to the study of neurobiological substrates of behavior. On the other hand, classical behaviorist views of thinking, that is, as reflex chains, have been largely discounted by developments in neuroscience. Classical behaviorism is viewed by many as being most at odds with the modern fields of cognitive psychology and cognitive neuroscience, particularly regarding "mind" and "consciousness." A modest attempt at reconciliation is offered.
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Organization of memory traces in the mammalian brain.
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A decision-analytic approach to postexposure rabies prophylaxis.
The risks and benefits of postexposure rabies prophylaxis were analyzed from clinical and economic perspectives. A decision-analytic model was constructed by using probability and outcome data from the literature and the state health department. Health outcomes were measured in quality-adjusted life years. In the base case (overweight adult male), treatment is optimal when the probability of animal rabidity is greater than 1 in 2000. Sensitivity analysis showed robustness in the treatment decision; however, the incremental cost-effectiveness ratio ($140,000/quality-adjusted life year) is sensitive to the rabidity probability. Treatment is optimal from the patient's perspective; however, it may not be cost-effective when the probability of rabidity is low.
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Teaching family and community dimensions of clinical family medicine in Venezuela.
BACKGROUND AND OBJECTIVES: In Venezuela, family medicine is taught and practiced almost exclusively in ambulatory care settings. This article describes the evolution of the educational strategies that emphasize family and community aspects of clinical practice within one residency program in the country of Venezuela. METHODS: Three distinct phases of development are depicted, beginning with a biomedical and individual-centered approach. Subsequent efforts to involve residents in the community provoked criticism. Resident-faculty dialogue led to modifications and to the success of the current program. Some of the specific educational strategies are: a structured weekly five-hour community afternoon, a 40-hour course titled "Family Dynamics and Counseling," use of the family-oriented home visit to introduce residents to the community aspects of health care, and completion of a community-based and health-related project. RESULTS: A sample of residents and graduates noted an improved doctor-patient relationship, improved ability to work with groups, and improved skills for incorporating preventive medicine with a community focus into their clinical practice. CONCLUSIONS: The community involvement is enthusiastically supported by the residents, as it is perceived as useful for clinical practice. The program prepares family physicians to become more responsive to the health needs and the reality of Venezuelan society.
Community Health Services↗
In search of engrams.
The body of literature presented in this paper indicate, as Marr and Albus hypothesized, that the cerebellum is involved in the regulation of classical conditioning. At present, the most parsimonious hypothesis is that the essential memory traces for classical conditioning of eyelid closure, limb flexion, and other discrete responses learned with an aversive US are formed in cerebellar cortex and interpositus nucleus. Both sites contain neuronal elements which encode both conditioned and unconditioned stimuli. Recordings from both cerebellar cortex and the deep nuclei model the topography of the conditioned response and precede the response in time. Lesions of the cortex massively impair conditioning and lesions of the interpositus nucleus completely and permanently abolish the conditioned response without affecting reflex performance.
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Postsynaptic factors in the expression of long-term potentiation (LTP): increased glutamate receptor binding following LTP induction in vivo.
Several lines of evidence indicate that LTP in the hippocampus is associated with a change in the properties of postsynaptic glutamate receptors. In the present study, we used quantitative autoradiography to examine the binding properties of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl-D-aspartate subclasses of glutamate receptors in frozen brain sections obtained from rats in which perforant-path LTP was induced in vivo. Induction of LTP resulted in a selective increase in [3H]AMPA binding in those hippocampal subfields receiving perforant-path axons. Increases in [3H]AMPA binding in dentate gyrus (stratum moleculare) were highly correlated with the magnitude of LTP recorded in this structure. Scatchard analyses of [3H]AMPA and 6-cyano-7-nitro-[3H]quinoxaline-2,3-dione (an AMPA receptor antagonist) binding in the dentate gyrus indicated that LTP induction resulted in an increase in the number of AMPA receptor binding sites. No changes in the binding of 3H-labeled N-[1-(thienyl)cyclohexyl]piperidine (an N-methyl-D-aspartate receptor antagonist) were observed in any hippocampal subfield. These results suggest that a modification in postsynaptic AMPA receptors plays a role in the expression of synaptic enhancement following LTP induction in the hippocampus.
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Projections from the auditory cortex to the pontine nuclei in the rabbit.
The pontine projection from the auditory cortex was studied in 24 New Zealand albino rabbits using the method of anterograde transport of HRP-WGA. Microinjections of HRP-WGA (0.03-0.1 microliter) were made in the auditory cortex, which was located by electrophysiological criteria. The auditory cortex was shown to project ipsilaterally to ventral and lateral regions in the caudal pontine nuclei, and to the dorsolateral pontine nuclei in more rostral sections. Labeled terminals were also occasionally seen in the caudal medial pontine nuclei. These results suggest that the auditory cortex can modulate cerebellar input from caudal regions of the pontine nuclei, which project to cerebellar regions shown to be important for classical conditioning.
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Localization of a memory trace in the mammalian brain.
The localization of sites of memory formation within the brain has proven to be a formidable task even for simple forms of learning and memory. In order to localize a particular site of memory formation within the brain, the rabbit eyeblink response was classically conditioned while regions of the cerebellum or red nucleus were temporarily inactivated by microinfusions of the gamma-aminobutyric acid agonist muscimol. Cerebellar inactivation completely blocked learning but had no effect on subsequent learning after inactivation, whereas red nucleus inactivation did not prevent learning but did block the expression of conditioned responses. The site of memory formation for this learned response thus appears to be localized within the cerebellum.
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Cerebellar cortical lesions and reacquisition in classical conditioning of the nictitating membrane response in rabbits.
Portions of cerebellar cortex, particularly Larsell's hemisphere VI, have been identified as involved but not essential for the acquisition and retention of classical conditioning of the nictitating membrane (NM) response in rabbit. The present experiment was undertaken to examine the effect of lesions of cerebellar cortical regions projecting to anterior dorsolateral interpositus nucleus. Lesions of relatively equal size, including hemisphere VI and additionally more medial, anterior, or lateral cerebellar cortex were made after rabbits were classically conditioned. The effect of these cerebellar cortical lesions on retention to tone versus light conditioned stimulus (CS) and the timing of the conditioned response was evaluated. In spite of relatively large cerebellar cortical lesions, reacquisition of the conditioned NM response occurred quite rapidly. Whether the lesion was more medial and anterior or more lateral did not affect retention. Retention was significantly poorer with light CS than with tone CS. Timing of CRs was not affected by these lesions of cerebellar cortex, but the lesions spared most of the anterior lobe. The parasagittal zone C3 covering the longitudinal band of tissue from anterior lobe to the paramedian lobule and projecting to dorsolateral anterior interpositus requires additional exploration for its role in classical NM conditioning.
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Vasopressin induction of long-lasting potentiation of synaptic transmission in the dentate gyrus.
Vasopressin receptors are present in both the developing and mature dentate gyrus of the rat brain and are of the V1 vasopressor type. Because vasopressin has been shown to influence memory function when injected into the dentate gyrus, the influence of this peptide on an electrophysiological model of learning and memory using the field excitatory postsynaptic potential (EPSP) of the dentate gyrus was investigated. Results of these studies showed that nanomolar concentrations of [Arg8]-vasopressin induced a prolonged increase in the amplitude and slope of the evoked population response in the presence of 1.5 mM calcium. Moreover, the expression of the vasopressin-induced potentiation of the EPSP persisted following removal of vasopressin from the perfusion medium. The vasopressin-induced sustained increase has been termed long-term vasopressin potentiation (LTVP). The closely related neuropeptide oxytocin had no effect upon the EPSP of the dentate gyrus. Preincubation of hippocampal slices in a selective V1 antagonist blocked the expression of LTVP. The ability of the V1 antagonist to block LTVP demonstrates that the potentiation induced by vasopressin is receptor-specific. In the presence of 2.5 mM calcium, the effect of vasopressin was opposite to that observed in 1.5 mM calcium. Under the conditions of 2.5 calcium, vasopressin induced a prolonged depression in the amplitude and slope of the EPSP. Expression of both potentiation and depression appeared within 5 minutes of application and persisted for the length of the observation, 60 minutes. These experiments demonstrate that vasopressin can induce long-lasting changes in the excitability of dentate gyrus neurons that are both calcium-dependent and receptor-specific.
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Cycloheximide prevents kainate-induced neuronal death and c-fos expression in adult rat brain.
The present study was directed at evaluating the possible involvement of protein synthesis in excitotoxin-induced neuronal damage and prolonged expression of the proto-oncogene, c-fos. Kainic acid-induced seizure activity elicited varying degrees of neuronal damage and cell loss in selectively vulnerable regions of the adult rat limbic system. Pretreatment with cycloheximide, a protein synthesis inhibitor, did not alter behavioral seizure characteristics, but markedly attenuated damage to susceptible neuronal populations. A prolonged increase in c-fos mRNA was observed by in situ hybridization up to 16 h after the onset of seizures in regions exhibiting neuronal death. Pretreatment with cycloheximide did not affect the transient induction of c-fos observed in numerous structures, but significantly reduced the prolonged expression of c-fos mRNA in kainate-vulnerable regions. Despite producing massive seizure activity, systemic kainic acid administration during the early postnatal period did not induce any neuronal death, and did not result in prolonged c-fos expression in any brain structures. The developmental onset of selective neuronal vulnerability coincided with that of prolonged c-fos expression in susceptible neuronal populations. In adult rats, seizure activity induced by pentylenetetrazole did not produce neuronal damage nor did it produce prolonged c-fos expression. These results not only demonstrate that kainate-induced neurotoxicity and the prolonged expression of c-fos are both prevented by cycloheximide, but also strengthen idea that prolonged c-fos expression is a marker of neuronal death.
Aging↗
Interpositus lesion abolition of the eyeblink conditioned response is not due to effects on performance.
Classical conditioning of the rabbit eyeblink response was used to study the effects of cerebellar lesions on performance in animals trained with low-intensity unconditioned stimuli (US). Animals were trained with 1 of 2 low-intensity corneal-airpuff USs paired with a tone-conditioned stimulus. This study confirms earlier findings demonstrating the differential effects of lesions of deep cerebellar nuclei on the conditioned (CR) and unconditioned responses (UR). Lesions of the anterior interpositus nucleus of the cerebellum in animals that were successfully conditioned abolished CRs without affecting UR performance.
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Lidocaine infusion in a critical region of cerebellum completely prevents learning of the conditioned eyeblink response.
New Zealand white rabbits were implanted with cannulas in the dorsal or ventral aspect of the anterior interpositus nucleus. Three days (and 6 days for some dorsal-infusion animals) of standard tone-airpuff training was given with continuous infusion (constant rate of 0.2 microL/min) of lidocaine or saline. All animals were then given 3 days of training with no infusion. All lidocaine-infused animals exhibited no conditioned responses in the 3 or 6 days of infusion training. Dorsal-infusion animals learned in the subsequent 3 days of no infusion training as if naive, that is, they exhibited no savings. Animals with ventral cannula locations learned during infusion training, as shown in postinfusion training. These results strongly support the hypothesis that the essential memory trace for eyeblink conditioning is formed and stored in the cerebellum.
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