Learning-induced Changes Research Articles

Hippocampal gene expression profiling in spatial discrimination learning

Learning and long-term memory are thought to involve temporally defined changes in gene expression that lead to the strengthening of synaptic connections in selected brain regions. We used cDNA microarrays to study hippocampal gene expression in animals trained in a spatial discrimination-learning paradigm. Our analysis identified 19 genes that showed statistically significant changes in expression when comparing Naı̈ve versus Trained animals. We confirmed the changes in expression for the genes encoding the nuclear protein prothymosin α and the δ-1 opioid receptor (DOR1) by Northern blotting or in situ hybridization. In additional studies, laser-capture microdissection (LCM) allowed us to obtain enriched neuronal populations from the dentate gyrus, CA1, and CA3 subregions of the hippocampus from Naı̈ve, Pseudotrained, and spatially Trained animals. Real-time PCR examined the spatial learning specificity of hippocampal modulation of the genes encoding protein kinase B (PKB, also known as Akt), protein kinase C δ (PKC δ), cell adhesion kinase β (CAK β, also known as Pyk2), and receptor protein tyrosine phosphatase ζ/β (RPTP ζ/β). These studies showed subregion specificity of spatial learning-induced changes in gene expression within the hippocampus, a feature that was particular to each gene studied. We suggest that statistically valid gene expression profiles generated with cDNA microarrays may provide important insights as to the cellular and molecular events subserving learning and memory processes in the brain.

Learning to juggle: on the assembly of functional subsystems into a task-specific dynamical organization.

We examined the development of task-specific couplings among functional subsystems (i.e., ball circulation, respiration, and body sway) when learning to juggle a three-ball cascade, with a focus on learning-induced changes in the coupling between ball movements and respiration and the coupling between ball movements and body sway. Six novices practiced to juggle three balls in cascade fashion for one hour per day for twenty days. On specific days (7 in total), ball movements, center-of-pressure (CoP) trajectories and respiration traces were measured simultaneously. Discrete, time-continuous and spectral analyses revealed that the spatio-temporal variability of the juggling patterns decreased with practice and that the degree to which the task constraints were satisfied increased gradually. No conclusive evidence was found for ball movement-respiration coupling. In contrast, clear-cut evidence was found for the presence of 1:3 and 2:3 frequency locking between the vertical component of the ball trajectories and both the anterior-posterior and the medio-lateral components of the CoP. Incidence and expression of these mode locks varied across individuals and altered in the course of learning. Gradual changes in locking strength, appearances and disappearances of mode locks, as well as abrupt transitions between coupled states were observed. These results indicate that dissimilar learning dynamics may arise in the functional embedding of subsystems into a task-specific organization and that motor equivalence is an inherent property of such emerging task-specific organizations.

An event-related potential study on visual perceptual learning under short-term and long-term training conditions.

The present study investigated learning-induced changes of event-related potentials in a visual discrimination task, focusing on making a comparison between short-term and long-term learning perceptual processes. Event-related potentials were recorded from two groups of human adults. One group (short-term training group) was given 1.5 h of training in a single day, and another group (long-term training group) was given the same training procedure (1.5 hour of training) on each of 3 consecutive days. The results demonstrated that for short-term training group, along with the reduction of reaction times, the amplitudes of N1 and N2 negativities over the central/parietal areas decreased during the training. For long-term training group, however, after long-term training, the N2 effect disappeared and the N1 effect occurred over the posterior areas. In addition, the amplitudes of N2 for long-term training group were less than those for short-term training group. Our results suggest that neural activity depends not only on perceptual mechanisms and on the parameters of the physical stimuli but also on the extent of the observer's previous learning.

Daily variation and appetitive conditioning-induced plasticity of auditory cortex receptive fields.

Long-term modification of cortical receptive field maps follows learning of sensory discriminations and conditioned associations. In the process of determining whether appetitive - as opposed to aversive - conditioning is effective in causing such plastic changes, it was discovered that multineuron receptive fields, when measured in rats under ketamine-sedation, vary substantially over the course of a week, even in the absence of classical conditioning and electrode movement. Specifically, a simple correlation analysis showed that iso-intensity frequency response curves of multiunit clusters and local field potentials recorded from auditory cortex are nonstationary over 7 days. Nevertheless, significant plastic changes in receptive fields, due to conditioned pairing of a pure tone and electrical stimulation of brain reward centres, are detectable above and beyond these spontaneous daily variations. This finding is based on a novel statistical plasticity criterion which compares receptive fields recorded for three days before and three days after conditioning. Based on a more traditional criterion (i.e. one day before and after conditioning), the prevalence of learning-induced changes caused by appetitive conditioning appears to be comparable to that described in previous studies involving aversive conditioning.

Partial blocking of NMDA receptors reduces plastic changes induced by short-lasting classical conditioning in the SI barrel cortex of adult mice.

The effect of blockade of N-methyl-D-aspartate (NMDA) receptors in the barrel cortex upon the learning-induced changes of the cortical body map was examined in adult mice. We have previously found that three sensory conditioning sessions, in which stimulation of a row of vibrissae was paired with a tail shock, produced an enlargement of the functional representation of a row of vibrissae stimulated during training. Implantation of the slow release polymer Elvax, containing 2-amino-5-phosphonovalerate (APV, 50 mM), in the vicinity of the barrel cortex was performed 1 day before conditioning to block NMDA receptors. The cortical representation of a trained row of vibrissae was visualized with 2-deoxyglucose (2DG) functional brain mapping 1 day after the completion of the conditioning procedure. The partial blockade of NMDA receptors within the barrel cortex reduced (by half) the expansion of the cortical representation of a trained row of vibrissae as compared to the enlargement of the cortical representation of a trained row found in untreated (60%) and Elvax-PBS implanted (47%) mice. The results provide evidence that the learning-induced processes of cortical map reorganization involve mechanisms that depend on NMDA receptor activation.

Theta-related cells in superior colliculus of the urethane-anaesthetized rat

Multiunit activity (MUA) was recorded chronically in the hippocampus (CA3) and the medial geniculate body (mMG) during habituation to a tone followed by conditioning (tone paired with footshock) or pseudoconditioning (tone/footshock unpaired) in rats previously trained in a lever-pressing for food task (VI 60). In the conditioned group pairing tones with footshocks rapidly induced an increase in the initial CS-evoked response in the mMG, followed by the emergence of a hippocampal response and a marked conditioned suppression of lever-pressing to the tone. In contrast, in the pseudoconditioned group, the stimulus induced only transient cellular changes in the hippocampus and in the mMG, while no behavioral suppression to the tone could be seen. Moreover, presentations of the CS 45 days later induced multiunit and behavioral responses in both structures, only in the conditioned group. These results are used for discussion of the role of learning-induced changes in the sensory structure (mMG) as compared with changes in an associative structure (hippocampus), during acquisition and retention of a conditioned response.

Learning-induced dynamic receptive field changes in primary auditory cortex of the unanaesthetized Mongolian gerbil.

Learning-induced changes of the spectro-temporal characteristics of primary auditory cortex (AI) units were studied by response plane analysis of recordings from the AI in unanaesthetized Mongolian gerbils. Using response planes obtained prior to and after auditory discrimination training bins of significant change were identified and their spectro-temporal distribution was studied. Bins of significant changes were generally found to be distributed over the entire spectro-temporal receptive field but occurred most frequently within the first 100 ms of response in the spectral neighbourhood (1.5 octaves) of the frequency of the reinforced conditioned stimulus. Training-induced response decreases occurred early after 10 ms for reinforced conditioned tones and tones in the frequency neighbourhood. Response increases occurred so early only for non-reinforced tones in the neighbourhood of the reinforced frequency and occurred later (after 40 ms) for the reinforced tones. The results are discussed in the light of dynamic disinhibition.

Learning-induced changes in rat piriform cortex activity mapped using multisite recording with voltage sensitive dye.

The piriform cortex (PCx) has a potential role in storage and recall of olfactory information. This study is a first extensive investigation of the spatiotemporal distribution of activity in the PCx induced by learned sensory inputs following conditioning. In a conditioned group, rats chronically implanted with four electrodes in the olfactory bulb were trained to associate the electrical stimulation of a given bulbar electrode with a positive reinforcement, while stimulation of a different electrode predicted a negative reinforcement. In a familiarized group, rats received the same protocol of daily electrical stimulation with no associated reinforcement. At the end of the conditioning or familiarization episode, activity evoked in the PCx was optically mapped using a 144 photodiode array. In the anaesthetized rats, PCx maps were recorded in response to stimulation of each of the four bulbar electrodes using either high (0.5-1 mA) or low (0.1 mA) test current intensities. Low intensity stimulation revealed that conditioning selectively enhanced the probability of occurrence of a signal composed of a single late (56-73 ms) component which occurred almost simultaneously on a large PCx area. In the conditioned group, high intensity stimulation through either of the four electrodes revealed a potentiation of the early (17-30 ms) disynaptic component of the PCx response in the most posterior part of the PCx as well as a homogeneous increase of the late (39-52 ms) component spread over the PCx areas. These data suggest that learning induces synaptic changes at different nodes of the PCx circuitry.

NEUROMUSCULAR ADAPTATIONS IN EXERCISE SCIENCE 749

This symposium will review the growing evidence that demonstrates the potential for adaptation and plasticity in the human neuromuscular system. The segmental control system presents an excellent model for the study of adaptations resulting from either motor learning or exercise training. Reggie Edgerton will discuss a model which demonstrates the possibilities of learning-induced changes in spinal centers. Adaptations in segmental reflex processing, including changes in H-reflexes and crossed spinal reflexes will be discussed by David Koceja. Muscle fatigue also comparises a useful model for the study of short-term neuromuscular adaptation. Fatigue can be caused by a number of different mechanisms that result in a reduced ability to perform a motor task. The dominant mechanism appears to be task-dependent and the task dependency hypothesis of muscle fatigue will be presented by Roger Enoka. Finally, increasing evidence suggests that the manner in which the nervous system controls motor unit activation can be altered as a result of aging and exercise. Gary Kamen will discuss adaptations to motor unit discharge behavior, including possible changes in motor unit firing rate and motor unit synchronization.

Tumor Necrosis Factor‐α (TNF‐α), Interferon‐γ, and Interleukin‐6 but Not TNF‐β Induce Differentiation of Neuroblastoma Cells: The Role of Nitric Oxide

Previous observations have implicated GABA as a neurotransmitter released by the vestibular sensory neurons ("hair cells") of the snail Hermissenda onto visual sensory neurons, the type B cells, whose cell bodies are the sites of biophysical and biochemical changes during and following Pavlovian conditioning. Still other observations demonstrated that light-GABA pairings that simulate stimuli presented during Pavlovian conditioning cause prolonged elevation of intracellular Ca2+ and transformation of GABA-induced synaptic inhibition into excitation. Intracellular Ca2+ signals in response to GABA perfused onto the postsynaptic type B terminal branches are shown here to be prolonged on days after conditioning, but not after control paradigms. These and past results demonstrate two separate sites, i.e., the cell body and the terminal branches, for learning-induced changes after Pavlovian conditioning.

Hippocampus, theta, and spatial memory

The past 18 months have witnessed interesting developments in several areas of hippocampal research. First, the mechanisms of hippocampal theta are becoming clear, as is its role in spatial coding; each theta cycle appears to act as a clock mechanism against which the firing of the place cells can be timed. Second, there has been a continued strengthening in the support for the spatial theory of hippocampal function from single unit and lesion experiments; particularly important is the finding that the deficit in (non-spatial) delayed non-match to sample memory experiments in the monkey following medial temporal lobe damage stems from the part of the cortex which surrounds the hippocampus, and not from the hippocampus itself. Third, in contrast, it is proving more difficult than originally thought to show a causal relationship between long-term potentiation at the synaptic level and place learning-induced changes in hippocampal synapses.

Learning-induced changes of auditory receptive fields

Classical conditioning specifically modifies receptive fields in primary and secondary auditory cortical areas to favor the frequency of a tone signal over other frequencies, including tuning shifts toward, or to, this frequency. This plasticity of receptive fields is associative and highly specific, can develop very rapidly, can be expressed under anesthesia and can be maintained indefinitely. Muscarinic receptors in the cortex may be involved. Non-lemniscal thalamic nuclei also develop receptive field plasticity that may contribute to cortical plasticity.

Association between brain temperature and dentate field potentials in exploring and swimming rats.

Attempts to correlate behavioral learning with cellular changes, such as increased synaptic efficacy, have often relied on increased extracellular potentials as an index of enhanced synaptic strength. A recent example is the enlarged excitatory field potentials in the dentate gyrus of rats that are learning spatial relations by exploration. The altered hippocampal field potentials do not reflect learning-specific cellular changes but result from a concomitant rise in brain temperature that is caused by the associated muscular effort. Enhanced dentate field excitatory potentials followed both passive and active heating and were linearly related to the brain temperature. These temperature-related effects may mask any learning-induced changes in field potential.

Learning of a hippocampal-dependent conditioning task changes the binding properties of AMPA receptors in rabbit hippocampus

The N-methyl-D-asparate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtypes of glutamate receptors have been shown to play critical roles in various forms of synaptic plasticity (i.e., learning and memory, long-term potentiation). We previously demonstrated that the binding of [3H]AMPA to the AMPA subtype of glutamate receptors was selectively increased in hippocampus following classical conditioning of the rabbit nictitating membrane response in a delay paradigm. We report here that the same effect was observed in a variant of this learning paradigm that requires the participation of the hippocampus, i.e., trace conditioning of the rabbit nictitating membrane. The binding of [3H]TCP (N-[1-(2-thienyl)cyclo-hexyl]-3,4-piperidine) to the NMDA receptor remained unchanged in all the experimental groups tested. Paired presentations of conditioned and unconditioned stimuli resulted in an increased binding of [3H]AMPA, an agonist of the AMPA receptors, in several hippocampal subfields while the binding of an antagonist, [3H]CNQX (6-nitro-7-cyanoquinoxaline-2,3-dione), was decreased. The results suggest that the learning-induced changes in binding of the ligands to the AMPA receptor reflect changes in affinity of the receptor rather than in the number of sites. These results support the hypothesis that changes in hippocampal glutamate receptors are a corollary of synaptic plasticity in certain forms of learning.

Learning-induced changes in D 2 receptors of rat brain are sexually dimorphic

Pharmacological agents known to stimulate monoamine systems improve memory, and destruction of the dopaminergic systems or dopamine depletion lead to impairments in various learning-related tasks. These reported effects of the central dopaminergic system imply the involvement of D 2 receptors. The aim of the present study was to investigate changes in [ 3H]spiroperidol binding in seven areas of rat brain following informal and active avoidance learning. Littermate male and female rats were reared until 3 months of age in standard colony conditions and treated as active controls or in enriched environmental conditions and exposed to pole-jump active avoidance trials. Female rats acquired avoidance behavior more rapidly than males. Among the brain regions, only the hippocampus showed significant variations in D 2 receptor binding between the groups; sex differences and learning-sex interaction were observed in the corpus striatum. There was an inverse correlation between learning performance and hippocampal D 2 receptor binding. Our results show that learning affects hippocampal D 2 receptors in a sexually dimorphic pattern.

Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala

Data derived from in vitro preparations indicate that NMDA receptors play a critical role in synaptic plasticity in the CNS. More recently, in vivo pharmacological manipulations have suggested that an NMDA-dependent process may be involved in specific forms of behavioral plasticity. All of the work thus far has focused on the possible role of NMDA receptors in the acquisition of responses. However, there are many examples in the behavioral literature of learning-induced changes that involve the reduction or elimination of a previously acquired response. Experimental extinction is a primary example of the elimination of a learned response. Experimental extinction is well described in the behavioral literature, but has not received the same attention in the neurobiological literature. As a result, the neural mechanisms that underlie this important form of learning are not at all understood. In the present experiments, the fear-potentiated startle paradigm was employed to begin to investigate neural mechanisms of extinction. The results show that infusion of the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (AP5) into the amygdala, a limbic structure known to be important for fear conditioning, dose-dependently blocked extinction of conditioned fear. Control experiments showed that the blockade of extinction was neither the result of the permanent disruption of amygdaloid function nor the result of decreased sensitivity of the animals to the conditioned stimulus. Infusion of AP5 into the interpositus nucleus of the cerebellum, a control site, did not block extinction. Finally, intra-amygdala infusion of a selected dose of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione did not block extinction of conditioned fear. These results, together with a previous report from our laboratory (Miserendino et al., 1990), demonstrate the importance of the amygdala in the elaboration of conditioned fear and suggest that an NMDA-dependent process might underlie the extinction of conditioned fear.

Dementia in Newfoundland: identification of a geographical isolate?

The aims were (1) to identify from death certificates regions with an increased incidence of dementia mortality; and (2) to determine whether a previously observed excess of patients with Alzheimer disease originating from a small area could be confirmed in a survey of death certificates. The study identified all individuals dying with dementia, recorded on death certificates as an immediate, antecedent, underlying, or contributing cause of death. Rather than the usual residence, the birthplace of these individuals was used to determine regional differences in dementia mortality. A comparison was made of two areas to test the significance of a geographical isolate of persons. To test for a possible genetic component of the excess, an analysis was made of the frequencies of family names. To test for a possible environmental component an analysis was made of standard measurements of drinking water quality. The survey data were derived from all 1985 and 1986 deaths in the province of Newfoundland. Based on the current census population, the prevalence of dementia at death for 1985 and 1986 was 34 and 37/100,000. For both years there was a significant excess of persons originating from a small area (95% CI, 1.1-20.7%, and 2.5-20.4%). This excess could not be explained by differences in age, sex, ethnic origin, or by variation in mobility patterns. The study area has a high concentration of aluminium in the drinking water. An analysis of the family names gave inconclusive evidence of a clustering among the dementia cases. If all contributing causes of death are recorded and the birthplace of individuals is noted, mortality statistics can reveal regional differences in dementia rates. This shows the need to examine areas smaller than census districts to identify subpopulation variation in the prevalence of dementia. Environmental influences can vary substantially in areas relatively close together, as evidenced in measurements of drinking water chemistry. Genetic influences are more likely to be revealed from the birthplace of individuals, which may indicate a common ancestry.

Discriminative long-term retention of rapidly induced multiunit changes in the hippocampus, medial geniculate and auditory cortex

Multiunit activity was chronically recorded in the hippocampus (CA3 field), the magnocellular medial geniculate (MGm) and the auditory cortex (AC) of rats during acquisition (12 daily sessions, 10 trials per session) and long-term retention of differential classical conditioning (tones paired with footshocks). Marked increases of multiunit discharges to CS + presentations were first detected in the MGm (5–10 trials) followed (10–20 trials) by the emergence of discriminative responses in the hippocampus and in the AC. During long-term retention tests, 45 days after the end of conditioning, CS + selective responses were observed in the 3 structures. We propose that learning-induced changes in the conditioned stimulus (CS) sensory pathway can have the same temporal stability as the sensory plasticity observed during development or post injury in adult animals.

Learning-induced change in neural activity during acquisition and consolidation of a passive avoidance response in the rat

Time-dependent alterations in neural activity have been established during the acquisition and consolidation of a stepdown passive avoidance paradigm. Change in neural activity was established by administering a glucose analogue, [3H]2-deoxyglucose, 50min prior to sacrifice and estimating perchloric acid soluble counts in nine hand dissected brain regions. Change in [3H]2-deoxyglucose uptake was closely paralleled in both trained and yoked animals for up to 40min following task acquisition however the striatum was the only area to exhibit a task-specific increase in [3H]2-deoxyglucose uptake at 20-30min after training. Longterm changes in neural activity were also apparent as the amygdala and brainstem showed increased [3H]2-deoxyglucose uptake at the 24 h time point. No further paradigm-specific changes were apparent at 48 h. These findings are concluded to suggest that the striatum is involved in the early events of acquiring a passive avoidance response and the amygdala and brainstem during the later events.

Multiunit changes in hippocampus and medial geniculate body in free-behaving rats during acquisition and retention of a conditioned response to a tone

Multiunit activity (MUA) was recorded chronically in the hippocampus (CA3) and the medial geniculate body (mMG) during habituation to a tone followed by conditioning (tone paired with footshock) or pseudoconditioning (tone/footshock unpaired) in rats previously trained in a lever-pressing for food task (VI 60). In the conditioned group pairing tones with footshocks rapidly induced an increase in the initial CS-evoked response in the mMG, followed by the emergence of a hippocampal response and a marked conditioned suppression of lever-pressing to the tone. In contrast, in the pseudoconditioned group, the stimulus induced only transient cellular changes in the hippocampus and in the mMG, while no behavioral suppression to the tone could be seen. Moreover, presentations of the CS 45 days later induced multiunit and behavioral responses in both structures, only in the conditioned group. These results are used for discussion of the role of learning-induced changes in the sensory structure (mMG) as compared with changes in an associative structure (hippocampus), during acquisition and retention of a conditioned response.