Sylvia Wirth

Dynamic Analysis of Learning in Behavioral Experiments

Understanding how an animals ability to learn relates to neural activity or is altered by lesions, different attentional states, pharmacological interventions, or genetic manipulations are central questions in neuroscience. Although learning is a dynamic process, current analyses do not use dynamic estimation methods, require many trials across many animals to establish the occurrence of learning, and provide no consensus as how best to identify when learning has occurred. We develop a state-space model paradigm to characterize learning as the probability of a correct response as a function of trial number (learning curve). We compute the learning curve and its confidence intervals using a state-space smoothing algorithm and define the learning trial as the first trial on which there is reasonable certainty (>0.95) that a subject performs better than chance for the balance of the experiment. For a range of simulated learning experiments, the smoothing algorithm estimated learning curves with smaller mean integrated squared error and identified the learning trials with greater reliability than commonly used methods. The smoothing algorithm tracked easily the rapid learning of a monkey during a single session of an association learning experiment and identified learning 2 to 4 d earlier than accepted criteria for a rat in a 47 d procedural learning experiment. Our state-space paradigm estimates learning curves for single animals, gives a precise definition of learning, and suggests a coherent statistical framework for the design and analysis of learning experiments that could reduce the number of animals and trials per animal that these studies require.

Functional Magnetic Resonance Imaging Activity during the Gradual Acquisition and Expression of Paired-Associate Memory

Recent neurophysiological findings from the monkey hippocampus showed dramatic changes in the firing rate of individual hippocampal cells as a function of learning new associations. To extend these findings to humans, we used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine the patterns of brain activity during learning of an analogous associative task. We observed bilateral, monotonic increases in activity during learning not only in the hippocampus but also in the parahippocampal and right perirhinal cortices. In addition, activity related to simple novelty signals was observed throughout the medial temporal lobe (MTL) memory system and in several frontal regions. A contrasting pattern was observed in a frontoparietal network in which a high level of activity was sustained until the association was well learned, at which point the activity decreased to baseline. Thus, we found that associative learning in humans is accompanied by striking increases in BOLD fMRI activity throughout the MTL as well as in the cingulate cortex and frontal lobe, consistent with neurophysiological findings in the monkey hippocampus. The finding that both the hippocampus and surrounding MTL cortex exhibited similar associative learning and novelty signals argues strongly against the view that there is a clear division of labor in the MTL in which the hippocampus is essential for forming associations and the cortex is involved in novelty detection. A second experiment addressed a striking aspect of the data from the first experiment by demonstrating a substantial effect of baseline task difficulty on MTL activity capable of rendering mnemonic activity as either “positive” or “negative.”

Analysis of Between-Trial and Within-Trial Neural Spiking Dynamics

Recording single-neuron activity from a specific brain region across multiple trials in response to the same stimulus or execution of the same behavioral task is a common neurophysiology protocol. The raster plots of the spike trains often show strong between-trial and within-trial dynamics, yet the standard analysis of these data with the peristimulus time histogram (PSTH) and ANOVA do not consider between-trial dynamics. By itself, the PSTH does not provide a framework for statistical inference. We present a state-space generalized linear model (SS-GLM) to formulate a point process representation of between-trial and within-trial neural spiking dynamics. Our model has the PSTH as a special case. We provide a framework for model estimation, model selection, goodness-of-fit analysis, and inference. In an analysis of hippocampal neural activity recorded from a monkey performing a location-scene association task, we demonstrate how the SS-GLM may be used to answer frequently posed neurophysiological questions including, What is the nature of the between-trial and within-trial task-specific modulation of the neural spiking activity? How can we characterize learning-related neural dynamics? What are the timescales and characteristics of the neurons biophysical properties? Our results demonstrate that the SS-GLM is a more informative tool than the PSTH and ANOVA for analysis of multiple trial neural responses and that it provides a quantitative characterization of the between-trial and within-trial neural dynamics readily visible in raster plots, as well as the less apparent fast (1-10 ms), intermediate (11-20 ms), and longer (>20 ms) timescale features of the neurons biophysical properties.

Spontaneous voice–face identity matching by rhesus monkeys for familiar conspecifics and humans

Recognition of a particular individual occurs when we reactivate links between current perceptual inputs and the previously formed representation of that person. This recognition can be achieved by identifying, separately or simultaneously, distinct elements such as the face, silhouette, or voice as belonging to one individual. In humans, those different cues are linked into one complex conceptual representation of individual identity. Here we tested whether rhesus macaques (Macaca mulatta) also have a cognitive representation of identity by evaluating whether they exhibit cross-modal individual recognition. Further, we assessed individual recognition of familiar conspecifics and familiar humans. In a free preferential looking time paradigm, we found that, for both species, monkeys spontaneously matched the faces of known individuals to their voices. This finding demonstrates that rhesus macaques possess a cross-modal cognitive representation of individuals that extends from conspecifics to humans, revealing the adaptive potential of identity recognition for individuals of socioecological relevance.

Facilitation of olfactory recognition by lateral entorhinal cortex lesion in rats.

An original olfactory recognition task was developed in order to examine the effect of lateral entorhinal cortex (LEC) lesion on olfactory mnesic processes. The task was based on the spontaneous exploratory behavior of rats toward odor sources. It consisted of a learning phase during which an odor was presented twice and in a recognition test, during which the same odor plus a new one was presented. The time rats spent sniffing the odor sources was measured. Olfactory recognition was identified by a short investigatory duration for the familiar odor as compared to a normal investigatory duration for the new odor during the test. The first three experiments aimed to validate the procedure. Experiment 1 was designed to show the decay of investigatory behavior caused by repeated exposure of the rats to one odor. Experiment 2 showed that normal rats display recognition when a short (5 or 40 min) pre-test delay was used, but not when a long pre-test delay (120 min) was used. Experiment 3 showed that FG7142, a well-known promnesic drug, enhanced the performance of the rats in this test as it allowed recognition at longer pre-test delays. The last experiment aimed at testing the effects of aspirative lesion of the LEC. Therefore, LEC-lesioned and sham-lesioned rats were submitted to variable pre-test delays. The experiment showed that an entorhinal lesion did not produce an impairment, but on the contrary facilitated olfactory recognition, as lesioned rats displayed recognition for delays at which sham-operated rats did not. These results show that LEC lesion apparently prolongs the duration of the olfactory mnesic trace. This effect might result from a modification of the functioning of structures innervated by the LEC. In this regard, it is noteworthy that LEC lesion produced a sprouting of septo-hippocampal fibers in the dentate gyrus of the hippocampus as assessed by acetylcholinesterase staining. Although the functional significance of this regrowth is not fully understood, the possible role of this sprouting should be considered.

Representation of well-learned information in the monkey hippocampus.

In the neocortex, extensive training results in enhanced neuronal selectivity for learned stimuli relative to novel stimuli. This enhanced selectivity has been taken as evidence for learning-related plasticity. Much less is known, in contrast, about the representation of well-learned information in the hippocampus. In this study, we examined the responses of individual hippocampal neurons to well-learned and novel stimuli presented in the context of an associative learning task. There was no difference in the response magnitude or visual response latency of hippocampal neurons to the well-learned and novel stimuli. In contrast, hippocampal neurons responded significantly more selectively to the well-learned stimuli relative to the novel stimuli. These findings show that hippocampal cells, like neocortical cells, show greater selectivity to well-learned stimuli compared to novel stimuli.

Functional interaction between entorhinal cortex and basolateral amygdala during trace conditioning of odor aversion in the rat.

In rats, conditioned odor aversion (COA) occurs only if the time interval separating the odor from the subsequent intoxication is very short suggesting that the memory trace of the odor is subject to rapid decay. Recent results from our laboratory have found that lesion of the entorhinal cortex (EC), and activation of the basolateral nucleus of the amygdala (BLA) rendered COA tolerant to long interstimulus interval. The present study examined whether the odor memory trace depends on the interaction between the EC and the BLA. Rats lesioned in the EC received infusions of muscimol (a GABA(A) receptor agonist) into the BLA immediately after the odor presentation during acquisition of COA. Injection of muscimol into BLA prevented tolerance of COA to long interstimulus interval induced by EC lesions. This suggests that EC modulates the short-term memory trace of the odor by controlling the GABAergic activity of the BLA during acquisition of COA.

Comparison of Associative Learning-Related Signals in the Macaque Perirhinal Cortex and Hippocampus

Strong evidence suggests that the macaque monkey perirhinal cortex is involved in both the initial formation as well as the long-term storage of associative memory. To examine the neurophysiological basis of associative memory formation in this area, we recorded neural activity in this region as monkeys learned new conditional-motor associations. We report that a population of perirhinal neurons signal newly learned associations by changing their firing rate correlated with the animals behavioral learning curve. Individual perirhinal neurons signal learning of one or more associations concurrently and these neural changes could occur before, at the same time, or after behavioral learning was expressed. We also compared the associative learning signals in the perirhinal cortex to our previous findings in the hippocampus. We report global similarities in both the learning-related and task-related activity seen across these areas as well as clear differences in the within and across trial timing and relative proportion of different subtypes of learning-related signals. Taken together, these findings emphasize the important role of the perirhinal cortex in new associative learning and suggest that the perirhinal cortex together with the hippocampus contribute importantly to conditional-motor associative memory formation.

Facilitative Effects of EGb 761 on Olfactory Recognition in Young and Aged Rats

The aim of the present study was to evaluate the effects of chronic and acute treatment by the Gingko biloba extract, EGb 761 (IPSEN, France) on olfactory short-term memory in rats, using a spontaneous recognition procedure. The effects of a daily EGb 761 treatment (30 or 60 mg/kg) over a period of 30 days (Experiment 1) were evaluated in young male rats. Those of a single injection of EGb 761 were assessed either in young male rats at 60 or 120 mg/kg (Experiment 2) or in aged female rats at 60 mg/kg (Experiment 3). Results showed that, at the highest dose (60 mg/kg), chronic EGb 761 treatment enhanced the recognition performances, allowing recognition at delays at which control animals did not show any recognition. Acute treatment enhanced recognition at both doses tested. The results of the third experiment showed that EGb 761 had an overall enhancement effect on the performances of aged rats. In summary, our results provide evidence for a short-term memory enhancement effect of EGb 761 in both young and aged rats.

State-space algorithms for estimating spike rate functions

The accurate characterization of spike firing rates including the determination of when changes in activity occur is a fundamental issue in the analysis of neurophysiological data. Here we describe a state-space model for estimating the spike rate function that provides a maximum likelihood estimate of the spike rate, model goodness-of-fit assessments, as well as confidence intervals for the spike rate function and any other associated quantities of interest. Using simulated spike data, we first compare the performance of the state-space approach with that of Bayesian adaptive regression splines (BARS) and a simple cubic spline smoothing algorithm. We show that the state-space model is computationally efficient and comparable with other spline approaches. Our results suggest both a theoretically sound and practical approach for estimating spike rate functions that is applicable to a wide range of neurophysiological data.