Cynthia A. Erickson

Neural Mechanisms of Visual Working Memory in Prefrontal Cortex of the Macaque

Prefrontal (PF) cells were studied in monkeys performing a delayed matching to sample task, which requires working memory. The stimuli were complex visual patterns and to solve the task, the monkeys had to discriminate among the stimuli, maintain a memory of the sample stimulus during the delay periods, and evaluate whether a test stimulus matched the sample presented earlier in the trial. PF cells have properties consistent with a role in all three of these operations. Approximately 25% of the cells responded selectively to different visual stimuli. Half of the cells showed heightened activity during the delay after the sample and, for many of these cells, the magnitude of delay activity was selective for different samples. Finally, more than half of the cells responded differently to the test stimuli depending on whether they matched the sample. Because inferior temporal (IT) cortex also is important for working memory, we compared PF cells with IT cells studied in the same task. Compared with IT cortex, PF responses were less often stimulus-selective but conveyed more information about whether a given test stimulus was a match to the sample. Furthermore, sample-selective delay activity in PF cortex was maintained throughout the trial even when other test stimuli intervened during the delay, whereas delay activity in IT cortex was disrupted by intervening stimuli. The results suggest that PF cortex plays a primary role in working memory tasks and may be a source of feedback inputs to IT cortex, biasing activity in favor of behaviorally relevant stimuli.

The neurobiology of memory changes in normal aging

Cognitive alterations occur over the lifespan of every species studied and have been quantified carefully in humans, other primates and rodents. Correspondingly, changes in hippocampal function have been associated with a number of observed memory impairments across species. It appears that humans, alone, show Alzheimers disease-like cognitive and neural pathology spontaneously. Thus, a comparison of normal age-related changes in cognition in other animals can help disambiguate the boundary between normal and pathological states of aging in humans. Another important contribution made from studying aging in non-human species is the ability to examine, in more detail, the basic neural mechanisms that may be responsible for brain aging in these species. So far, most of the functional neurobiological studies have been conducted in the aged rat. We propose that the link between rodent and human work can be made much stronger by combining neurophysiological and behavioral investigation of normal aging in the non-human primate.

How do rhesus monkeys ( Macaca mulatta) scan faces in a visual paired comparison task

When novel and familiar faces are viewed simultaneously, humans and monkeys show a preference for looking at the novel face. The facial features attended to in familiar and novel faces, were determined by analyzing the visual exploration patterns, or scanpaths, of four monkeys performing a visual paired comparison task. In this task, the viewer was first familiarized with an image and then it was presented simultaneously with a novel and the familiar image. A looking preference for the novel image indicated that the viewer recognized the familiar image and hence differentiates between the familiar and the novel images. Scanpaths and relative looking preference were compared for four types of images: (1) familiar and novel objects, (2) familiar and novel monkey faces with neutral expressions, (3) familiar and novel inverted monkey faces, and (4) faces from the same monkey with different facial expressions. Looking time was significantly longer for the novel face, whether it was neutral, expressing an emotion, or inverted. Monkeys did not show a preference, or an aversion, for looking at aggressive or affiliative facial expressions. The analysis of scanpaths indicated that the eyes were the most explored facial feature in all faces. When faces expressed emotions such as a fear grimace, then monkeys scanned features of the face, which contributed to the uniqueness of the expression. Inverted facial images were scanned similarly to upright images. Precise measurement of eye movements during the visual paired comparison task, allowed a novel and more quantitative assessment of the perceptual processes involved the spontaneous visual exploration of faces and facial expressions. These studies indicate that non-human primates carry out the visual analysis of complex images such as faces in a characteristic and quantifiable manner.

Clustering of perirhinal neurons with similar properties following visual experience in adult monkeys

The functional organization of early visual areas seems to be largely determined during development. However, the organization of areas important for learning and memory, such as perirhinal cortex, may be modifiable in adults. To test this hypothesis, we recorded from pairs of neurons in perirhinal cortex of macaques while they viewed multiple complex stimuli. For novel stimuli, neuronal response preferences for pairs of nearby neurons and far-apart neurons were uncorrelated. However, after one day of experience with the stimuli, response preferences of nearby neurons became more similar. We conclude that specific visual experience induces development of clusters of perirhinal neurons with similar stimulus preferences.

Memory impairment in aged primates is associated with region-specific network dysfunction.

Age-related deficits in episodic memory result, in part, from declines in the integrity of medial temporal lobe structures, such as the hippocampus, but are not thought to be due to widespread loss of principal neurons. Studies in rodents suggest, however, that inhibitory interneurons may be particularly vulnerable in advanced age. Optimal encoding and retrieval of information depend on a balance of excitatory and inhibitory transmission. It is not known whether a disruption of this balance is observed in aging non-human primates, and whether such changes affect network function and behavior. To examine this question, we combine large-scale electrophysiological recordings with cell-type-specific imaging in the medial temporal lobe of cognitively assessed, aged rhesus macaques. We found that neuron excitability in the hippocampal region CA3 is negatively correlated with the density of somatostatin-expressing inhibitory interneurons in the vicinity of the recording electrodes in the stratum oriens. By contrast, no hyperexcitability or interneuron loss was observed in the perirhinal cortex of these aged, memory-impaired monkeys. These data provide a link, for the first time, between selective increases in principal cell excitability and declines in a molecularly defined population of interneurons that regulate network inhibition.

Differential effects of experience on tuning properties of macaque MTL neurons in a passive viewing task

The structures of the medial temporal lobe (MTL) have been shown to be causally involved in episodic and recognition memory. However, recent work in a number of species has demonstrated that impairments in recognition memory seen following lesions of the perirhinal cortex (PRh) can be accounted for by deficits in perceptual discrimination. These findings suggest that object representation, rather than explicit recognition memory signals, may be crucial to the mnemonic process. Given the large amount of visual information encountered by primates, there must be a reconsideration of the mechanisms by which the brain efficiently stores visually presented information. Previous neurophysiological recordings from MTL structures in primates have largely focused on tasks that implicitly define object familiarity (i.e., novel vs. familiar) or contain significant mnemonic demands (e.g., conditional associations between two stimuli), limiting their utility in understanding the mechanisms underlying visual object recognition and information storage. To clarify how different regions in the MTL may contribute to visual recognition, we recorded from three rhesus macaques performing a passive viewing task. The task design systematically varies the relative familiarity of different stimuli enabling an examination of how neural activity changes as a function of experience. The data collected during this passive viewing task revealed that neurons in the MTL are generally not sensitive to the relative familiarity of a stimulus. In addition, when the specificity (i.e., which images a neuron was selective for) of individual neurons was analyzed, there was a significant dissociation between different medial temporal regions, with only neurons in TF, but not CA3 or the PRh, altering their activity as stimuli became familiar. The implications of these findings are discussed in the context of how MTL structures process information during a passive viewing paradigm.

Comparison of long-term enhancement and short-term exploratory modulation of perforant path synaptic transmission

Long-term enhancement (LTE/LTP) is an artificially induced form of synaptic change that may underlie memory storage in the hippocampus; however, there is as yet no evidence that this process occurs naturally as a result of normal neural activity. In the dentate gyrus, synaptic change does occur in conjunction with an animals recent history of exploratory behavior. This change, which persists for a short time (ca. 30 min) following cessation of exploration, has been called short-term exploratory modulation (STEM). This experiment examined the relationship between LTE and STEM by comparing the magnitude of STEM before and after induction of LTE in rats with chronically implanted stimulating electrodes in the perforant path and recording electrodes in the fascia dentata. The absolute magnitude of STEM was the same before and after LTE saturation, suggesting that the processes are independent of each other. Furthermore, quantitative and qualitative analyses of the types of changes seen in the evoked-potential waveforms reveal different types of alteration. LTE includes an increase in EPSP slope, whereas STEM reflects an increase in EPSP onset. These data suggest that it is unlikely that STEM and LTE reflect the same synaptic process, and are at least partly consistent with recent reports suggesting that STEM may be mediated by activity-dependent changes in brain temperature.

Aging in rhesus macaques is associated with changes in novelty preference and altered saccade dynamics.

Studies demonstrating recognition deficits with aging often use tasks in which subjects have an incentive to correctly encode or retrieve the experimental stimuli. In contrast to these tasks, which may engage strategic encoding and retrieval processes, the visual paired comparison (VPC) task measures spontaneous eye movements made toward a novel as compared with familiar stimulus. In the present study, seven rhesus macaques aged 6 to 30 years exhibited a dramatic age-dependent decline in preference for a novel image compared with one presented seconds earlier. The age effect could not be accounted for by memory deficits alone, because it was present even when familiarization preceded test by 1 second. It also could not be explained by an encoding deficit, because the effect persisted with increased familiarity of the sample stimulus. Reduced novelty preference did correlate with eye movement variables, including reaction time distributions and saccade frequency. At long delay intervals (24 or 48 hours) aging was paradoxically associated with increased novelty preference. Several explanations for the age effect are considered, including the possible role of dopamine.