Integrating associative learning signals across the brain

Associative learning is defined as the ability to link arbitrary stimuli or actions together in memory. The neural correlates of this fundamental form of plasticity were first described in the hippocampus during delay eye blink conditioning and have since been examined using a variety of tasks in both rats and monkeys. In monkeys, the neural correlates of associative learning have been studied using conditional motor learning tasks where animals learn to associate particular visual stimuli with particular motor responses (i.e., touch left or touch right). Similar tasks have also been used to examine learning-related plasticity in motor-related areas throughout the frontal lobe and striatum. Here, we review the patterns of learning-related activity seen in these diverse brain areas during conditional motor learning. While each of these areas exhibits strong associative learning signals, the differential patterns and time courses of these signals provides insight into the unique contribution of each area to associative learning.     

A neuronal network model of associative memory and a brain theory

There are facts suggesting that the changes of excitability of neurons and conductance of synapses are responsible for learning and memory. In accordance with the idea, the author proposed a neuronal network model of associative memory, which can learn conditioned reflexes repeatedly together with its adaptive properties, without much interference with the previously existing memories. Further, a modified model can memorize dynamic images and establish motor patterns. An analysis of the structure of the model is presented, and some conclusions about this sort of model are drawn. A theory of memory and learning suggesting that the brain works by means of a mechanism similar to that of the model is proposed, as well as the explanations for some behavioral and clinical findings from the viewpoint of the model.     

Child neuropsychological assessment: A test of basic assumptions

Interpretations of child neuropsychological assessment findings are based on two largely untested assumptions regarding test validity. First, we assume that test results vary with the integrity of the CNS, or that they have neurological validity. Second, we assume that these results are associated with, or predict, problems in ecologically meaningful aspects of childhood functioning, such as academic learning or behavioral adjustment. Test results have psychological validity to the extent that this second assumption is met. To put these two assumptions to empirical test, the present study examined developmental outcomes in 113 school-age children who had been hospitalized earlier in life for Haemophilus influenzae type b meningitis. Only children without sensorineural hearing loss were considered. Analyses focused on associations of individual neuropsychological measures to acute-phase medical status, social-environmental variables, and behavioral and learning outcomes. Findings document both forms of test validity. Results also underscore the importance of assessing social factors, and highlight considerations involved in attempting to improve test utility.     

Associative learning in humans--conditioning of sensory-evoked brain activity

A classical conditioning paradigm was employed in two experiments performed on 35 human volunteers. In nine subjects, the presentation of Landolt rings (conditioned stimuli, CS + ) was paired with an electric stimulus (unconditioned stimuli, UCS) applied to the left median nerve. Neutral visual control stimuli were full circles (CS -) that were not paired with the UCS. The skin conductance response (SCR) was determined in a time interval of 5 s after onset of the visual stimuli, and it was measured in the acquisition and test phase. Associative learning was reflected by a SCR occurring selectively with CS +. The same experiment was repeated with another group of 26 adults while electroencephalogram (EEG) was recorded from 30 electrodes. For each subject, mean evoked potentials were computed. In 13 of the subjects, a conditioning paradigm was followed while the other subjects served as the control group (non-contingent stimulation). There were somatosensory and visual brain activity evoked by the stimuli. Conditioned components were identified by computing cross-correlation between evoked somatosensory components and the averaged EEG. In the visual evoked brain activity, three components with mean latencies of 105.4, 183.2, and 360.3 ms were analyzed. Somatosensory stimuli were followed by major components that occurred at mean latencies of 48.8, 132.5, 219.7, 294.8, and 374.2 ms latency after the shock. All components were analyzed in terms of latency, field strength, and topographic characteristics, and were compared between groups and experimental conditions. Both visual and somatosensory brain activity was significantly affected by classical conditioning. Our data illustrate how associative learning affects the topography of brain electrical activity elicited by presentation of conditioned visual stimuli.     

Selectively impaired associative learning in older people with cognitive decline

Older people with declining cognitive function typically display deficits in declarative memory processes, often most evident on tests of associative learning (AL). The hippocampal formation (HF) is thought to be critically involved in the encoding and retrieval of such associations, consistent with neuroimaging findings that the HF is damaged in early stages of neurodegenerative disease and in older people with AL impairments. In the clinic, older people with cognitive decline commonly report difficulties associating names with faces. However, we have observed that such people are particularly impaired on tests requiring the association of novel stimuli. In Experiment 1, a series of AL tasks were administered to older people with cognitive decline to determine whether they were impaired at simply making associations, or at making associations between novel stimuli. In Experiment 2, we measured HF function in these subjects by administering an AL task designed to differentiate between HF-damaged and HF-intact individuals. Our experimental protocols were guided by a computational model of HF function in AL described by Gluck and Myers (1997). Older people with cognitive decline displayed impaired performance on tasks designed to be highly dependent upon intact HF function, including a task in which novel patterns and spatial locations were to be associated. These results suggest that the AL impairments observed in older people with cognitive decline may be due to HF dysfunction.     

Hippocampal function during associative learning in patients with posttraumatic stress disorder

In the last decade several studies have shown memory deficits in patients with posttraumatic stress disorder (PTSD) which have been associated with a reduced hippocampus volume. However, until now we do not know how or whether these structural abnormalities turn into functional abnormalities. Thus, the primary purpose of the present study was the investigation of the hippocampal function using functional magnet resonance imaging (fMRI).We compared PTSD patients and healthy control participants using an associative learning paradigm consisting of two encoding and one retrieval condition. During fMRI scanning participants had to learn face-profession pairs. Afterwards only faces were presented as cue stimuli for associating the category of the prior learned target profession and the participants had to decide whether this face belonged to a scientific or an artistic profession. Additionally, cognitive functioning, i.e. memory and attention, was examined using neuropsychological standard tests.During encoding PTSD patients showed stronger hippocampal and weaker prefrontal activation compared to healthy control participants. During retrieval the two groups did not differ neither in hippocampus activation nor in accuracy of retrieval. PTSD patients however showed a reduced activation in the left parahippocampal gyrus and other memory-related brain regions. We did not find any significant memory differences between PTSD patients and healthy control participants.The results suggest that PTSD has an effect on memory-related brain function despite intact memory functioning. In particular the hippocampal/parahippocampal regions and the prefrontal cortex show functional alterations during associative learning and memory.     

Remodeling of hippocampal synapses after hippocampus-dependent associative learning

The aim of this study was to determine whether hippocampus-dependent associative learning involves changes in the number and/or structure of hippocampal synapses. A behavioral paradigm of trace eyeblink conditioning was used. Young adult rabbits were given daily 80 trial sessions to a criterion of 80% conditioned responses in a session. During each trial, the conditioned (tone) and unconditioned (corneal airpuff) stimuli were presented with a stimulus-free or trace interval of 500 msec. Control rabbits were pseudoconditioned by equal numbers of random presentations of the same stimuli. Brain tissue was taken for morphological analyses 24 hours after the last session. Synapses were examined in the stratum radiatum of hippocampal subfield CA1. Unbiased stereological methods were used to obtain estimates of the total number of synapses in this layer as well as the area of the postsynaptic density. The data showed that the total numbers of all synaptic contacts and various morphological subtypes of synapses did not change in conditioned animals. The area of the postsynaptic density, however, was significantly increased after conditioning in axospinous nonperforated synapses. This structural alteration may reflect an addition of signal transduction proteins (such as receptors and ion channels) and the transformation of postsynaptically silent synapses into functional ones. The findings of the present study indicate that cellular mechanisms of hippocampus-dependent associative learning include the remodeling of existing hippocampal synapses. Further studies examining various time points along the learning curve are necessary to clarify the issue of whether these mechanisms also involve the formation of additional synaptic contacts.     

Storage and recall capabilities of fuzzy morphological associative memories with adjunction-based learning

We recently employed concepts of mathematical morphology to introduce fuzzy morphological associative memories (FMAMs), a broad class of fuzzy associative memories (FAMs). We observed that many well-known FAM models can be classified as belonging to the class of FMAMs. Moreover, we developed a general learning strategy for FMAMs using the concept of adjunction of mathematical morphology.In this paper, we describe the properties of FMAMs with adjunction-based learning. In particular, we characterize the recall phase of these models. Furthermore, we prove several theorems concerning the storage capacity, noise tolerance, fixed points, and convergence of auto-associative FMAMs. These theorems are corroborated by experimental results concerning the reconstruction of noisy images. Finally, we successfully employ FMAMs with adjunction-based learning in order to implement fuzzy rule-based systems in an application to a time-series prediction problem in industry.     

Differential brain activity during emotional versus nonemotional reversal learning

The ability to change an established stimulus-behavior association based on feedback is critical for adaptive social behaviors. This ability has been examined in reversal learning tasks, where participants first learn a stimulus-response association (e.g., select a particular object to get a reward) and then need to alter their response when reinforcement contingencies change. Although substantial evidence demonstrates that the OFC is a critical region for reversal learning, previous studies have not distinguished reversal learning for emotional associations from neutral associations. The current study examined whether OFC plays similar roles in emotional versus neutral reversal learning. The OFC showed greater activity during reversals of stimulus-outcome associations for negative outcomes than for neutral outcomes. Similar OFC activity was also observed during reversals involving positive outcomes. Furthermore, OFC activity is more inversely correlated with amygdala activity during negative reversals than during neutral reversals. Overall, our results indicate that the OFC is more activated by emotional than neutral reversal learning and that OFC's interactions with the amygdala are greater for negative than neutral reversal learning.     

Effects of learning on cytochrome oxidase activity in cuttlefish brain

Using cytochrome oxidase (CO) histochemistry, the effects of instrumental conditioning in cuttlefish central nervous system were examined. The posterior superior frontal lobe showed an increase of CO labelling just after training, whereas the anterior superior frontal lobe exhibited a decrease of CO staining 24 h post-training. These findings provide the first metabolic evidence for the involvement of the superior frontal lobe in learning and memory processes in cuttlefish. It is concluded that CO histochemistry can be used to provide a functional mapping of learning-induced plasticity in cuttlefish brain.     

Acute inactivation of the inferior olive blocks associative learning

Can acute inactivation of the inferior olive block associative learning? We anaesthetized the inferior olive with lidocaine while rabbits simultaneously: (i) performed conditioned nictitating membrane responses to a flashing light to which they had already been trained; and (ii) underwent their first experience with classical conditioning of the same response to a tone. Inactivation of the inferior olive immediately and reversibly abolished the performance of conditioned responses and prevented learning during rabbits' initial conditioning with a tone-conditioned stimulus. When olivary function was restored, rabbits showed no signs of having learned under olivary anaesthesia. The experiment demonstrates that an acute disruption in olivary function can block learning, in addition to severely degrading motor control. The results are interpreted to indicate the importance of the inferior olive in optimizing learning, perhaps through a general role in regulating temporal processing.     

Altered development of hippocampus-dependent associative learning following early-life adversity

Little is known about how childhood adversity influences the development of learning and memory and underlying neural circuits. We examined whether violence exposure in childhood influenced hippocampus-dependent associative learning and whether differences: a) were broad or specific to threat cues, and b) exhibited developmental variation. Children (n = 59; 8–19 years, 24 violence-exposed) completed an associative learning task with angry, happy, and neutral faces paired with objects during fMRI scanning. Outside the scanner, participants completed an associative memory test for face-object pairings. Violence-exposed children exhibited broad associative memory difficulties that became more pronounced with age, along with reduced recruitment of the hippocampus and atypical recruitment of fronto-parietal regions during encoding. Violence-exposed children also showed selective disruption of associative memory for threat cues regardless of age, along with reduced recruitment of the intraparietal sulcus (IPS) during encoding in the presence of threat. Broad associative learning difficulties may be a functional consequence of the toxic effects of early-life stress on hippocampal and fronto-parietal cortical development. Difficulties in the presence of threat cues may result from enhanced threat processing that disrupts encoding and short-term storage of associative information in the IPS. These associative learning difficulties may contribute to poor life outcomes following childhood violence exposure.     

Neural correlates of associative learning and memory in veterans with posttraumatic stress disorder

Impaired attention and memory are symptoms frequently associated with posttraumatic stress disorder (PTSD). Although patients with PTSD frequently report memory difficulties and empirical research provides support for a memory deficit in PTSD, as of yet, no fMRI study has adequately investigated the neural correlates of learning and memory of neutral (i.e. not trauma related) material in patients with PTSD compared to controls. Twelve male veterans with PTSD, and twelve male veterans without PTSD, were recruited, and matched for age, region and year of deployment. Encoding and retrieval of 12 word-pair associates was assessed during fMRI in both experimental groups. Compared to controls veterans with PTSD revealed underactivation of the frontal cortex, and overactivation of the temporal cortex during the encoding phase. Retrieval of the paired associates resulted in underactivation of right frontal cortex, bilateral middle temporal gyri, and the left posterior hippocampus/parahippocampal gyrus in patients with PTSD. Deficits in memory performance in PTSD appear to be related to altered activity in fronto-temporal areas during both the encoding and retrieval phase of memory processing.     

Myelin basic protein-specific protein methylase I activity in shiverer mutant mouse brain

Myelin basic protein (MBP)-specific protein-arginine N-methyltransferase (protein methylase I) activity in homozygous shiverer (shi/shi) mutant mouse brain is significantly higher than in the normal littermate brain at the onset of myelination. While the enzyme activity (expressed as pmol of S-adenosyl-L-[methyl-14C]methionine used/min/mg enzyme protein) increases coincidently during the period of myelination in the normal brain (15-18 days of age), it decreases significantly in the mutant brain during this period of time. These results are in contrast to those found with another dysmyelinating mutant, jimpy (jp/Y) mice, in which the enzyme activity in the mutant brains is similar to that in the normal animals but remains unchanged during the myelination process. There is no difference in the weight and protein concentration of the normal and shiverer mutant brains with corresponding ages, and the histone-specific protein methylase I activity is also unaffected in the shiverer brain.     

Visual-visual associative learning and reward-association learning in monkeys: the role of the amygdala

Three Cynomolgus monkeys (Macaca fascicularis) took part in an experiment on visual learning set in an automatic apparatus. Each new visual discrimination problem was solved using a visual secondary reinforcer consisting of a white line. If the monkey chose the correct stimulus (by touching it), the white line appeared over the correct stimulus. Primary food reward was delivered only after a new problem was solved to a criterion, and the problem was then replaced by a new one. Thus, within-problem learning did not rely on primary reinforcement but on the visual secondary reinforcer. The animals were trained preoperatively in visual learning set with this procedure and were assessed postoperatively for their ability to learn new visual discriminations with the same procedure. Bilateral amygdalectomy did not significantly impair the animals' learning ability in this task. Learning remained unimpaired when transection of the uncinate fascicle and of the fornix was added to amygdalectomy. The effect of bilateral amygdalectomy in this task was much less severe than in a similar task we previously studied, with auditory secondary reinforcers. The results show that the involvement of the amygdala in processes of secondary reinforcement depends on the sensory properties of the secondary reinforcer. From these and other recent results, we conclude that the sensory attributes of a reinforcer are easily associated with a discriminative stimulus when they are in the same modality and same spatial location as the discriminative stimulus and that this sensory-sensory association is independent of the amygdala.     

Developmental sensitivity of associative learning to cholesterol synthesis inhibitors.

Patients with Smith-Lemli-Opitz syndrome, a genetic disorder associated with severe mental retardation, are unable to convert 7-dehydrocholesterol to cholesterol. Treatment of rats with agents that block cholesterol synthesis produces a sterol profile reminiscent of Smith-Lemli-Opitz patients i.e., low levels of cholesterol accompanied by the appearance of its immediate precursor 7-dehydrocholesterol. In previous work, chronic inhibition of cholesterol synthesis in just-weaned rats impaired acquisition of the classically conditioned eyeblink response. The present study had two primary goals--(1) to determine whether the learning impairment depended on the age in which treatment was initiated; and (2) to determine whether the deficit was associative or due to performance factors. Consistent with earlier work, acquisition of the eyeblink conditioned response was impaired when the 30-day treatment was initiated on postnatal day (PND) 21. Reactivity to acoustic stimuli and to eyelid stimulation were normal, suggesting that the learning impairment was associative in nature. The learning impairment was transitory; acquisition was normal when evaluated 30 days after the cessation of treatment. When treatment was initiated 30 days after weaning (PND 51), acquisition of the eyeblink response was normal. However, brain sterols of young adult rats were less affected than those of just-weaned rats. Thus, there is a developmental sensitivity to cholesterol synthesis blocking agents both in terms of their effects on brain sterols and new motor learning.     

Effects of an acute seizure on associative learning and memory

Past studies have demonstrated that inducing several seizures or continuous seizures in neonatal or adult rats results in impairments in learning and memory. The impact of a single acute seizure on learning and memory has not been investigated in mice. In this study, we exposed adult 129SvEvTac mice to the inhalant flurothyl until a behavioral seizure was induced. Our study consisted of 4 experiments where we examined the effect of one seizure before or after delay fear conditioning. We also included a separate cohort of animals that was tested in the open field after a seizure to rule out changes in locomotor activity influencing the results of memory tests. Mice that had experienced a single seizure 1 h, but not 6 h, prior to training showed a significant impairment in associative conditioning to the conditioned stimulus when compared with controls 24 h later. There were no differences in freezing one day later for animals that experienced a single seizure 1 h after associative learning. We also found that an acute seizure reduced activity levels in an open-field test 2 h but not 24 h later. These findings suggest that an acute seizure occurring immediately before learning can have an effect on the recall of events occurring shortly after that seizure. In contrast, an acute seizure occurring shortly after learning appears to have little or no effect on long-term memory. These findings have implications for understanding the acute effects of seizures on the acquisition of new knowledge.