Timothy J. Bussey

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.

Perceptual–mnemonic functions of the perirhinal cortex

It is widely acknowledged that the perirhinal cortex, located in the ventromedial aspect of the temporal lobe, is essential for certain types of memory in macaque monkeys. For example, removal of the perirhinal cortex yields severe impairments on tests of stimulus recognition and stimulus-stimulus association. There is considerable disagreement, however, about the most accurate way to characterize the function of the perirhinal cortex; some views emphasize a role in perception whereas others posit a role exclusively in declarative memory. In this article, we review recent findings from anatomical, physiological and ablation studies in monkeys, and discuss related findings obtained in humans, in an attempt to identify not only the cognitive functions of the perirhinal cortex, but also the implications of these findings for theoretical views concerning the organization of memory.

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.

Transient Inactivation of Perirhinal Cortex Disrupts Encoding, Retrieval, and Consolidation of Object Recognition Memory

Damage to perirhinal cortex (PRh) impairs object recognition memory in humans, monkeys, and rats when tested in tasks such as delayed nonmatching to sample, visual paired comparison, and its rodent analog, the spontaneous object recognition task. In the present study, we have capitalized on the discrete one-trial nature of the spontaneous object recognition task to investigate the role of PRh in several distinct stages of object recognition memory. In a series of experiments, transient inactivation of PRh was accomplished with bilateral infusions of lidocaine directly into PRh immediately before the sample phase (encoding), immediately before the choice phase (retrieval), or within the retention delay after the sample phase (storage-consolidation). Compared with performance on trials in which they received saline infusions, rats were significantly impaired when lidocaine was infused before the sample phase, regardless of the length of the retention delay. Similarly, delay-independent deficits were observed after immediate pre-choice infusions of lidocaine. Finally, PRh inactivation immediately and 20 min after the sample phase, but not 40, 60, or 80 min after, also disrupted subsequent object recognition when the retention delay was sufficiently long to ensure the dissipation of the actions of lidocaine during the choice phase. The effects of pre-sample and pre-choice inactivation indicate involvement of PRh in encoding and retrieval stages of object recognition, and the time course of post-sample inactivation effects suggests a role for PRh in the maintenance of the object trace during memory consolidation.

Distinct patterns of behavioural impairments resulting from fornix transection or neurotoxic lesions of the perirhinal and postrhinal cortices in the rat

The present study provides evidence that lesions of the fornix (FNX) and of the perirhinal/postrhinal cortex (PPRH), which both disconnect the hippocampus from other brain regions, can lead to distinct patterns of behavioural impairments on tests of spatial memory and spontaneous object recognition. For example, whereas FNX lesions impaired allocentric spatial delayed alternation in a T-maze but generally spared a test of spontaneous object recognition, PPRH lesions produced the opposite pattern of results. Indeed, on the T-maze task PPRH animals significantly outperformed controls when the retention delay was increased to 60 s. In addition, some evidence was found that contributions from both the fornix and perirhinal/postrhinal cortex may be required when object and spatial information must be integrated. In an object-in-place test, for example, PPRH animals failed according to two measures, and FNX animals failed according to one measure, to discriminate objects that had remained in fixed locations from those that had exchanged locations with other objects. Neither lesion, however, affected performance of a visuospatial conditional task, a Pavlovian autoshaping task, or a one-pair pattern discrimination task. It is suggested that the perirhinal/postrhinal cortex, rather than being specialised for a particular type of associative learning, is important for processing complex visual stimuli.

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.