Lisa M. Saksida

A Functional Role for Adult Hippocampal Neurogenesis in Spatial Pattern Separation

Neurogenesis and Spatial Memory The dentate gyrus of the hippocampus is one of two sites in the brain where new neurons are produced throughout life. Adult-born neurons integrate into the dentate gyrus circuitry and are thought to play a role in learning and memory. However, their contribution to hippocampal function remains unclear. Clelland et al. (p. 210) disrupted neurogenesis in mice and used two behavioral tasks to test for impairment in the formation of uncorrelated episodic memory representations. In one task, two arms were presented and the mice were rewarded for choosing the most recently visited arm in an earlier sequence; in the second task, animals were rewarded for choosing a certain location on a touch screen. Ablation of neurogenesis affected discrimination performance in both tasks but only when the arms or screen locations were close to one another. Neurogenesis is thus necessary for spatial pattern separation in the dentate gyrus. Disruption of neurogenesis in a neuron-forming site in the brain impairs spatial memory functions in mice. The dentate gyrus (DG) of the mammalian hippocampus is hypothesized to mediate pattern separation—the formation of distinct and orthogonal representations of mnemonic information—and also undergoes neurogenesis throughout life. How neurogenesis contributes to hippocampal function is largely unknown. Using adult mice in which hippocampal neurogenesis was ablated, we found specific impairments in spatial discrimination with two behavioral assays: (i) a spatial navigation radial arm maze task and (ii) a spatial, but non-navigable, task in the mouse touch screen. Mice with ablated neurogenesis were impaired when stimuli were presented with little spatial separation, but not when stimuli were more widely separated in space. Thus, newborn neurons may be necessary for normal pattern separation function in the DG of adult mice.

Double Dissociation between the Effects of Peri-Postrhinal Cortex and Hippocampal Lesions on Tests of Object Recognition and Spatial Memory: Heterogeneity of Function within the Temporal Lobe

It is widely believed that declarative memory is mediated by a medial temporal lobe memory system consisting of several distinct structures, including the hippocampus and perirhinal cortex. The strong version of this view assumes a high degree of functional homogeneity and serial organization within the medial temporal lobe, such that double dissociations between individual structures should not be possible. In the present study, we tested for a functional double dissociation between the hippocampus and peri-postrhinal cortex in a single experiment. Rats with bilateral excitotoxic lesions of either the hippocampus or peri-postrhinal cortex were assessed in tests of spatial memory (radial maze) and object recognition memory. For the latter, the spontaneous object recognition task was conducted in a modified apparatus designed to minimize the potentially confounding influence of spatial and contextual factors. A clear functional double dissociation was observed: rats with hippocampal lesions were impaired relative to controls and those with peripostrhinal cortex lesions on the spatial memory task, whereas rats with peri-postrhinal lesions were impaired relative to the hippocampal and control groups in object recognition. These results provide strong evidence in favor of heterogeneity and independence of function within the temporal lobe.

Object recognition memory: neurobiological mechanisms of encoding, consolidation and retrieval.

Tests of object recognition memory, or the judgment of the prior occurrence of an object, have made substantial contributions to our understanding of the nature and neurobiological underpinnings of mammalian memory. Only in recent years, however, have researchers begun to elucidate the specific brain areas and neural processes involved in object recognition memory. The present review considers some of this recent research, with an emphasis on studies addressing the neural bases of perirhinal cortex-dependent object recognition memory processes. We first briefly discuss operational definitions of object recognition and the common behavioural tests used to measure it in non-human primates and rodents. We then consider research from the non-human primate and rat literature examining the anatomical basis of object recognition memory in the delayed nonmatching-to-sample (DNMS) and spontaneous object recognition (SOR) tasks, respectively. The results of these studies overwhelmingly favor the view that perirhinal cortex (PRh) is a critical region for object recognition memory. We then discuss the involvement of PRh in the different stages--encoding, consolidation, and retrieval--of object recognition memory. Specifically, recent work in rats has indicated that neural activity in PRh contributes to object memory encoding, consolidation, and retrieval processes. Finally, we consider the pharmacological, cellular, and molecular factors that might play a part in PRh-mediated object recognition memory. Recent studies in rodents have begun to indicate the remarkable complexity of the neural substrates underlying this seemingly simple aspect of declarative memory.

Running enhances spatial pattern separation in mice

Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of newly born neurons may bolster dentate gyrus-mediated encoding of fine spatial distinctions.

Perirhinal cortex resolves feature ambiguity in complex visual discriminations

The present experiment tested predictions of a ‘perceptual–mnemonic/feature conjunction’ (PMFC) model of perirhinal cortex function. The model predicts that lesions of perirhinal cortex should disrupt complex visual discriminations with a high degree of ‘feature ambiguity’, a property of visual discrimination problems that can emerge when features of an object are rewarded when they are part of one object, but not when part of another. As feature ambiguity is thought to be the critical factor, such effects should be independent of the number of objects to be discriminated. This was tested directly, by assessing performance of control monkeys and monkeys with aspiration lesions of perirhinal cortex on a series of concurrent discriminations in which the number of object pairs was held constant, but the degree of feature ambiguity was varied systematically. Monkeys were tested in three conditions: Maximum Feature Ambiguity, in which all features were explicitly ambiguous (AB+, CD+, BC–, AD–; the biconditional problem); Minimum Feature Ambiguity, in which no features were explicitly ambiguous (AB+, CD+, EF–, GH–); and Intermediate Feature Ambiguity, in which half the features were explicitly ambiguous (AB+, CD+, CE–, AF–). The pattern of results closely matched that predicted by simulations using a connectionist network: monkeys with perirhinal cortex lesions were unimpaired in the Minimum Feature Ambiguity condition, mildly impaired in the Intermediate Feature Ambiguity condition and severely impaired in the Maximum Feature Ambiguity condition. These results confirm the predictions of the PMFC model, and force a reconsideration of prevailing views regarding perirhinal cortex function.

Perceptual deficits in amnesia: challenging the medial temporal lobe 'mnemonic' view

Recent animal studies suggest that the medial temporal lobe (MTL), which is thought to subserve memory exclusively, may support non-mnemonic perceptual processes, with the hippocampus and perirhinal cortex contributing to spatial and object perception, respectively. There is, however, no support for this view in humans, with human MTL lesions causing prominent memory deficits in the context of apparently normal perception. We assessed visual discrimination in amnesic cases to reveal that while selective hippocampal damaged patients could discriminate faces, objects, abstract art and colour, they were significantly poorer in discriminating spatial scenes. By contrast, patients with MTL damage, including perirhinal cortex, were significantly impaired in discriminating scenes, faces, and to a lesser extent objects, with relatively intact discrimination of art and colour. These novel observations imply that the human MTL subserves both perceptual and mnemonic functions, with the hippocampus and perirhinal cortex playing distinct roles in spatial and object discrimination, respectively.

The organization of visual object representations: a connectionist model of effects of lesions in perirhinal cortex

We have developed a simple connectionist model based on the idea that perirhinal cortex has properties similar to other regions in the ventral visual stream, or ‘what’ pathway. The model is based on the assumption that representations in the ventral visual stream are organized hierarchically, such that representations of simple features of objects are stored in caudal regions of the ventral visual stream, and representations of the conjunctions of these features are stored in more rostral regions. We propose that a function of these feature conjunction representations is to help to resolve ‘feature ambiguity’, a property of visual discrimination problems that can emerge when features of an object predict a given outcome (e.g. reward) when part of one object, but predict a different outcome when part of another object. Several recently reported effects of lesions of perirhinal cortex in monkeys have provided key insights into the functions of this region. In the present study these effects were simulated by comparing the performance of connectionist networks before and after removal of a layer of units corresponding to perirhinal cortex. The results of these simulations suggest that effects of lesions in perirhinal cortex on visual discrimination may be due not to the impairment of a specific type of learning or memory, such as declarative or procedural, but to compromising the representations of visual stimuli. Furthermore, we propose that attempting to classify perirhinal cortex function as either ‘perceptual’ or ‘mnemonic’ may be misguided, as it seems unlikely that these broad constructs will map neatly onto anatomically defined regions of the brain.

Functional specialization in the human medial temporal lobe

Investigations of memory in rats and nonhuman primates have demonstrated functional specialization within the medial temporal lobe (MTL), a set of heavily interconnected structures including the hippocampal formation and underlying entorhinal, perirhinal, and parahippocampal cortices. Most studies in humans, however, especially in patients with brain damage, suggest that the human MTL is a unitary memory system supporting all types of declarative memory, our conscious memory for facts and events. To resolve this discrepancy, amnesic patients with either selective hippocampal damage or more extensive MTL damage were tested on variations of an object discrimination task adapted from the nonhuman primate literature. Although both groups were equally impaired on standard recall-based memory tasks, they exhibited different profiles of performance on the object discrimination test, arguing against a unitary view of MTL function. Cases with selective hippocampal damage performed normally, whereas individuals with broader MTL lesions were impaired. Furthermore, deficits in this latter group were related not to the number of discriminations to be learned and remembered, but to the degree of “feature ambiguity,” a property of visual discriminations that can emerge when features are part of both rewarded and unrewarded stimuli. These findings resolve contradictions between published studies in humans and animals and introduce a new way of characterizing the impairments that arise after damage to the MTL.

Impaired Fear Extinction Learning and Cortico-Amygdala Circuit Abnormalities in a Common Genetic Mouse Strain

Fear extinction is a form of new learning that results in the inhibition of conditioned fear. Trait deficits in fear extinction are a risk factor for anxiety disorders. There are few examples of naturally occurring animal models of impaired extinction. The present study compared fear extinction in a panel of inbred mouse strains. This strain survey revealed an impairment in fear extinction in 129/SvImJ (129S1). The phenotypic specificity of this deficit was evaluated by comparing 129S1 and C57BL/6J for one-trial and multitrial fear conditioning, nociception, and extinction of conditioned taste aversion and an appetitive instrumental response. 129S1 were tested for sensitivity to the extinction-facilitating effects of extended training, as well as d-cycloserine and yohimbine treatment. To elucidate the neural basis of impaired 129S1 fear extinction, c-Fos and Zif268 expression was mapped after extinction recall. Results showed that impaired fear extinction in 129S1 was unrelated to altered fear conditioning or nociception, and was dissociable from intact appetitive extinction. Yohimbine treatment facilitated extinction in 129S1, but neither extended extinction training nor d-cycloserine treatment improved 129S1 extinction. After extinction recall, 129S1 showed reduced c-Fos and Zif268 expression in the infralimbic cortex and basolateral amygdala, and elevated c-Fos or Zif268 expression in central nucleus of the amygdala and medial paracapsular intercalated cell mass, relative to C57BL/6J. Collectively, these data demonstrate a deficit in fear extinction in 129S1 associated with a failure to properly engage corticolimbic extinction circuitry. This common inbred strain provides a novel model for studying impaired fear extinction in anxiety disorders.

Impairments in visual discrimination after perirhinal cortex lesions: testing 'declarative'vs. 'perceptual-mnemonic'views of perirhinal cortex function

Two experiments tested the predictions of ‘declarative’ vs. ‘perceptual‐mnemonic’ views of perirhinal cortex function. The former view predicts that perirhinal cortex lesions should impair rapidly learned, but not more slowly learned, visual discriminations, whereas the latter view predicts that impairments should be related not to speed of learning but to perceptual factors. It was found that monkeys with perirhinal cortex lesions were impaired in the acquisition and performance of slowly learned, perceptually difficult greyscale picture discriminations, but were not impaired in the acquisition of rapidly learned, perceptually easier discriminations. In addition, these same monkeys were not impaired in the acquisition or performance of difficult colour or size discriminations, indicating that the observed pattern of impairments was not due to ceiling effects or difficulty per se. These findings, taken together, are consistent with the ‘perceptual‐mnemonic’ view that the perirhinal cortex is involved in both perception and memory, but are not consistent with the ‘declarative’ view that the perirhinal cortex is important exclusively for declarative memory, having little or no role in perception. Moreover, the results are consistent with the more specific proposal that the perirhinal cortex contributes to the solution of complex visual discriminations with a high degree of ‘feature ambiguity’, a property of visual discrimination problems that can emerge when features of an object are rewarded when part of one object, but not when part of another. These and other recent findings suggest the need for a revision of prevailing views regarding the neural organization of perception and memory.