Here we describe a model of medial temporal lobe organization in which parallel “what” and “where” processing streams converge within the hippocampus to represent events in the spatio-temporal context in which they occurred; this circuitry also mediates the retrieval of context from event cues and vice versa, which are prototypes of episodic recall. Evidence from studies in animals are reviewed in support of this model, including experiments that distinguish characteristics of episodic recollection from familiarity, neuropsychological and recording studies that have identified a key role for the hippocampus in recollection and in associating events with the context in which they occurred, and distinct roles for parahippocampal region areas in separate “what” and “where” information processing that contributes to recollective and episodic memory.

There is now converging evidence from studies in animals and humans that the medial temporal lobes (MTLs) harbor anatomically distinct processing pathways for object and scene information. Recent functional magnetic resonance imaging studies in humans suggest that this domain-specific organization may be associated with a functional preference of the anterior-lateral part of the entorhinal cortex (alErC) for objects and the posterior-medial entorhinal cortex (pmErC) for scenes. As MTL subregions are differentially affected by aging and neurodegenerative diseases, the question was raised whether aging may affect the 2 pathways differentially. To address this possibility, we developed a paradigm that allows the investigation of object memory and scene memory in a mnemonic discrimination task. A group of young (n = 43) and healthy older subjects (n = 44) underwent functional magnetic resonance imaging recordings during this novel task, while they were asked to discriminate exact repetitions of object and scene stimuli from novel stimuli that were similar but modified versions of the original stimuli ("lures"). We used structural magnetic resonance images to manually segment anatomical components of the MTL including alErC and pmErC and used these segmented regions to analyze domain specificity of functional activity. Across the entire sample, object processing was associated with activation of the perirhinal cortex (PrC) and alErC, whereas for scene processing, activation was more predominant in the parahippocampal cortex and pmErC. Functional activity related to mnemonic discrimination of object and scene lures from exact repetitions was found to overlap between processing pathways and suggests that while the PrC-alErC pathway was more involved in object discrimination, both pathways were involved in the discrimination of similar scenes. Older adults were behaviorally less accurate than young adults in discriminating similar lures from exact repetitions, but this reduction was equivalent in both domains. However, this was accompanied by significantly reduced domain-specific activity in PrC in older adults compared to what was observed in the young. Furthermore, this reduced domain-specific activity was associated to worse performance in object mnemonic discrimination in older adults. Taken together, we show the fine-grained functional organization of the MTL into domain-specific pathways for objects and scenes and their mnemonic discrimination and further provide evidence that aging might affect these pathways in a differential fashion. Future experiments will elucidate whether the 2 pathways are differentially affected in early stages of Alzheimer's disease in relation to amyloid or tau pathology.

A major controversy in memory research concerns whether recognition is subdivided into distinct cognitive mechanisms of recollection and familiarity that are supported by different neural substrates. Here we developed a new associative recognition protocol for rats that enabled us to show that recollection is reduced, whereas familiarity is increased following hippocampal damage. These results provide strong evidence that these processes are qualitatively different and that the hippocampus supports recollection and not familiarity.Some of the most compelling data on recognition memory and hippocampal function involve the use of signal detection analyses. In these analyses, subjects are initially presented with a stimulus list and are then required to identify test stimuli as the same (old) items or different (new) stimuli across a range of confidence levels or response biases. In normal human subjects, the receiver operating characteristic (ROC) function for lists of single items is typically asymmetrical (featuring an above-zero y intercept), interpreted by some to reflect a threshold for recollection, and has a curvilinear shape, reflecting the strength of familiarity (the dual process model 1 ). A major alternative view is that recognition is supported by qualitatively similar memory signals, wherein for each the degree of curvilinearity reflects the sum of the strengths of memory components and the asymmetry reflects greater variability in strength for old than for new items (the unequal variance model 2 ). According to this latter view, familiarity and recollection differ only in sensitivity, such that familiarity reflects the detection of weaker memories, whereas recollection is experienced when memories are stronger or involve more information.There is also compelling evidence indicating that recollection and familiarity may have distinct neural substrates, but the question of whether specific brain areas make qualitatively different contributions to recognition memory remains controversial 1 , 3 . Evidence from

Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness.