Wendy A. Suzuki

Perirhinal and Parahippocampal Cortices of The Macaque Monkey: Projections to The Neocortex

We investigated the topographic and laminar organization of the efferent cortical projections of the perirhinal and parahippocampal cortices. Area 36 of the perirhinal cortex projects preferentially to areas TE and TEO, whereas area TF of the parahippocampal cortex projects preferentially to the posterior parietal cortex and area V4. Area TF projects to many regions of the frontal lobe, whereas area 36 projects mainly to the orbital surface. The insular and cingulate cortices receive projections from areas 36 and TF, whereas only area TF projects to the retrosplenial cortex. Projections to the superior temporal gyrus, including the dorsal bank of the superior temporal sulcus, arise predominantly from area TF. Area 36 projects only to rostral levels of the superior temporal gyrus. Area TF has, in general, reciprocal connections with the neocortex, whereas area 36 has more asymmetric connections. Area 36, for example, projects to more restricted regions of the frontal cortex and superior temporal sulcus than it receives inputs from. In contrast, it projects to larger portions of areas TE and TEO than it receives inputs from. The efferent projections of areas 36 and TF are primarily directed to the superficial layers of the neocortex, a laminar organization consistent with connections of the feedback type. Projections to unimodal visual areas terminate in large expanses of the cortex, but predominantly in layer I. Projections to other sensory and polymodal areas, in contrast, terminate in a columnar manner predominantly in layers II and III. In all areas receiving heavy projections, the projections extend throughout most cortical layers, largely avoiding layer IV. We discuss these findings in relation to current theories of memory consolidation. J. Comp. Neurol. 447:394–420, 2002.

The anatomy, physiology and functions of the perirhinal cortex

The perirhinal cortex is a polymodal association area that contributes importantly to normal recognition memory. A convergence of recent findings from lesion and electrophysiological studies has provided new evidence that this area participates in an even broader range of memory functions than previously thought, including associative memory and emotional memory, as well as consolidation functions. These results are consistent with neuroanatomical research showing that this area has strong and reciprocal connections with widespread cortical sensory areas and with other memory-related structures, including the hippocampal formation and amygdala.

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.

Organization of connections between the amygdaloid complex and the perirhinal and parahippocampal cortices in macaque monkeys.

Neuroanatomical studies in macaque monkeys have demonstrated that the perirhinal and parahippocampal (PRPH) cortices are strongly interconnected with the hippocampal formation. Recent behavioral evidence indicates that these cortical regions are importantly involved in normal recognition memory function. The PRPH cortices are also interconnected with the amygdaloid complex, although comparatively little is known about the precise topography of these connections. We investigated the topographic organization of reciprocal connections between the amygdala and the PRPH cortices by placing anterograde and retrograde tracers throughout these three regions. We found that there was an organized arrangement of connections between the amygdala and the PRPH cortices and that the deep (lateral, basal, and accessory basal) nuclei of the amygdaloid complex were the source of most connections between the amygdala and the PRPH cortices. The temporal polar regions of the perirhinal cortex had the strongest and most widespread interconnections with the amygdala. Connections from more caudal levels of the perirhinal cortex had a more discrete pattern of termination. Perirhinal inputs to the amygdala terminated primarily in the lateral nucleus, the magnocellular and parvicellular divisions of the basal nucleus, and the magnocellular division of the accessory basal nucleus. Return projections originated predominately in the lateral nucleus, the intermediate and parvicellular divisions of the basal nucleus, and the magnocellular division of the accessory basal nucleus. The interconnections between the amygdala and the parahippocampal cortex were substantially less robust than those with the perirhinal cortex and mainly involved the basal nucleus. Area TF was more strongly interconnected with the amygdala than was area TH. Input from the parahippocampal cortex terminated predominantly in the lateral half of the parvicellular division of the basal nucleus but also to a lesser extent in the magnocellular division of the basal nucleus and the lateral nucleus. Return projections originated predominantly in the magnocellular division of the basal nucleus and were directed almost exclusively to area TF.

The Neurophysiology of Memory

Abstract: How do the structures of the medial temporal lobe contribute to memory? To address this question, we examine the neurophysiological correlates of both recognition and associative memory in the medial temporal lobe of humans, monkeys, and rats. These cross‐species comparisons show that the patterns of mnemonic activity observed throughout the medial temporal lobe are largely conserved across species. Moreover, these findings show that neurons in each of the medial temporal lobe areas can perform both similar as well as distinctive mnemonic functions. In some cases, similar patterns of mnemonic activity are observed across all structures of the medial temporal lobe. In the majority of cases, however, the hippocampal formation and surrounding cortex signal mnemonic information in distinct, but complementary ways.

Entorhinal Cortex Lesions Disrupt the Relational Organization of Memory in Monkeys

Recent accounts suggest that the hippocampal system critically supports two central characteristics of episodic memory: the ability to establish and maintain representations for the salient relationships between experienced events (relational representation) and the capacity to flexibly manipulate memory (flexible memory expression). To test this proposal in monkeys, intact controls and subjects with bilateral aspiration lesions of the entorhinal cortex were trained postoperatively on two standard memory tasks, delayed nonmatchingto-sample (DNMS) and two-choice object discrimination (OD) learning, and three procedures intended to emphasize relational representation and flexible memory expression: a paired associate (PA) task, a transitive inference (TI) test of learning and memory for hierarchical stimulus relationships, and a spatial delayed recognition span (SDRS) procedure. The latter assessments each included critical “probe” tests that asked monkeys to evaluate the relationships among previously learned stimuli presented in novel combinations. Subjects with entorhinal cortex lesions scored as accurately as controls on all phases of DNMS and OD, procedures that can be solved on the basis of memory for individual stimuli. In contrast, experimental monkeys displayed deficits relative to controls on all phases of the PA, TI, and SDRS tasks that emphasized the flexible manipulation of memory for the relationships between familiar items. Together, the findings support the conclusion that the primate hippocampal system critically enables the relational organization of declarative memory.

Integrating What and When Across the Primate Medial Temporal Lobe

Structures of the medial temporal lobe provide distinct but complementary signals to encode temporal-order information. Episodic memory or memory for the detailed events in our lives is critically dependent on structures of the medial temporal lobe (MTL). A fundamental component of episodic memory is memory for the temporal order of items within an episode. To understand the contribution of individual MTL structures to temporal-order memory, we recorded single-unit activity and local field potential from three MTL areas (hippocampus and entorhinal and perirhinal cortex) and visual area TE as monkeys performed a temporal-order memory task. Hippocampus provided incremental timing signals from one item presentation to the next, whereas perirhinal cortex signaled the conjunction of items and their relative temporal order. Thus, perirhinal cortex appeared to integrate timing information from hippocampus with item information from visual sensory area TE.

Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults

The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50–69-year-old subjects who consumed either a high or low cocoa flavanol–containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.

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.”

Cortical inputs to the CA1 field of the monkey hippocampus originate from the perirhinal and parahippocampal cortex but not from area TE

We determined the cortical regions that project directly to the CA1 field of the monkey hippocampus by injecting the retrograde tracers Fast blue, Diamidino yellow or WGA-HRP into CA1 and examining the distribution of labeled cells. In the temporal lobe, large numbers of retrogradely labeled cells were observed in the perirhinal and parahippocampal cortices. Only an occasional labeled cell, however, was observed in the unimodal visual area TE. Additional projections to CA1 arose in the dorsal bank of the superior temporal sulcus, in the rostral and retrosplenial portions of the cingulate cortex, in the agranular insular cortex, and in the caudal orbitofrontal cortex.