Boyer D. Winters

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.

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.

Glutamate Receptors in Perirhinal Cortex Mediate Encoding, Retrieval, and Consolidation of Object Recognition Memory

Object recognition is consistently impaired in human amnesia and animal models thereof. Results from subjects with permanent brain damage have revealed the importance of the perirhinal cortex to object recognition memory. Here, we report evidence from rats for interdependent but distinct stages in object recognition memory (encoding, retrieval, and consolidation), which require glutamate receptor activity within perirhinal cortex. Transient blockade of AMPA receptor-mediated synaptic transmission within perirhinal cortex disrupted encoding for short- and long-term memory as well as retrieval and consolidation. In contrast, transient NMDA receptor blockade during encoding affected only long-term object recognition memory; NMDA receptor activity was also necessary for consolidation but not retrieval. These results further demonstrate the importance of perirhinal cortex for object recognition memory and suggest that, as in the hippocampus, AMPA and NMDA receptors mediate synaptic transmission and activity-dependent synaptic plasticity, respectively, in several stages of memory processing.

The touchscreen cognitive testing method for rodents: How to get the best out of your rat

The touchscreen testing method for rodents is a computer-automated behavioral testing method that allows computer graphic stimuli to be presented to rodents and the rodents to respond to the computer screen via a nose-poke directly to the stimulus. The advantages of this method are numerous; however, a systematic study of the parameters that affect learning has not yet been conducted. We therefore sought to optimize stimuli and task parameters in this method. We found that when parameters were optimized, Lister Hooded rats could learn rapidly using this method, solving a discrimination of two-dimensional stimuli to a level of 80% within five to six sessions lasting approximately 30 min each. In a final experiment we tested both male and female rats of the albino Sprague-Dawley strain, which are often assumed to have visual abilities far too poor to be useful for studies of visual cognition. The performance of female Sprague-Dawley rats was indistinguishable from that of their male counterparts. Furthermore, performance of male Sprague-Dawley rats was indistinguishable from that of their Lister Hooded counterparts. Finally, Experiment 5 examined the ability of Lister Hooded rats to learn a discrimination between photographic stimuli. Under conditions in which parameters were optimized, rats were remarkably adept at this discrimination. Taken together, these experiments served to optimize the touchscreen method and have demonstrated its usefulness as a high-throughput method for the cognitive testing of rodents.

Perceptual Functions of Perirhinal Cortex in Rats: Zero-Delay Object Recognition and Simultaneous Oddity Discriminations

The perirhinal cortex (PRh) is widely accepted as having an important role in object recognition memory in humans and animals. Contrary to claims that PRh mediates declarative memory exclusively, previous evidence suggests that PRh has a role in the perceptual processing of complex objects. In the present study, we conducted an examination of the possible role of PRh in perceptual function in rats. We examined whether bilateral excitotoxic lesions of PRh or PPRh (perirhinal plus postrhinal cortices) in the rat would cause deficits in a zero-delay object-recognition task and a simultaneous oddity discrimination task. Both of these tasks measured spontaneous (untrained, unrewarded) behavior, and the stimuli in these experiments were manipulated to produce varying levels of perceptual difficulty. As predicted by simulations using a computational model, rats with PPRh lesions were impaired in object recognition when the stimuli to be discriminated were manipulated to share many features in common. Furthermore, rats with PPRh and PRh lesions were impaired in a simultaneous oddity discrimination task when the stimuli to be discriminated were manipulated explicitly to be more perceptually similar. These findings provide support for the idea that PRh in the rat is important for the perceptual processing of complex objects, in addition to its well established role in memory.

Paradoxical False Memory for Objects After Brain Damage

Novel or Familiar? Amnesia is characterized by a number of memory deficits, including the apparent inability to distinguish between novel and familiar stimuli. McTighe et al. (p. 1408; see the Perspective by Eichenbaum) observed that the recognition memory of brain-damaged rats in a standard model of amnesia was impaired not because previously experienced objects seemed to be novel, but because objects not previously experienced seemed to be familiar. Furthermore, simply placing the animal in a visually deprived environment during the delay, reducing visual interference, completely rescued the impairment. This counterintuitive finding contradicts the predominant “multiple memory systems” model in which amnesia is usually considered and forces a reconsideration of fundamental assumptions underlying our understanding of amnesia. Impaired recognition may be due to treating novel objects as familiar, rather than treating familiar objects as novel. Poor memory after brain damage is usually considered to be a result of information being lost or rendered inaccessible. It is assumed that such memory impairment must be due to the incorrect interpretation of previously encountered information as being novel. In object recognition memory experiments with rats, we found that memory impairment can take the opposite form: a tendency to treat novel experiences as familiar. This impairment could be rescued with the use of a visual-restriction procedure that reduces interference. Such a pattern of data can be explained in terms of a recent representational-hierarchical view of cognition.

Removal of cholinergic input to perirhinal cortex disrupts object recognition but not spatial working memory in the rat

The perirhinal cortex of the temporal lobe has a crucial role in object recognition memory. Cholinergic transmission within perirhinal cortex also seems to be important for this function, as the muscarinic receptor antagonist scopolamine disrupts object recognition performance when administered systemically or directly into perirhinal cortex. In the present study, we directly assessed the contribution of cholinergic basal forebrain input to perirhinal cortex in object recognition. Selective bilateral removal of the cholinergic basal forebrain inputs to perirhinal cortex was accomplished by injecting the immunotoxin 192 IgG‐saporin directly into perirhinal cortex in rats. These animals were significantly impaired relative to vehicle‐injected controls in a spontaneous object recognition task despite intact spatial alternation performance. These results are consistent with recent reports of object recognition impairment following acute cholinergic receptor blockade and extend these findings by demonstrating that chronic removal of cholinergic basal forebrain input to an otherwise intact perirhinal cortex causes a severe object recognition deficit similar to that associated with more extensive cell body lesions of perirhinal cortex.

Older and stronger object memories are selectively destabilized by reactivation in the presence of new information

Reactivation can destabilize previously consolidated memories, rendering them vulnerable to disruption and necessitating a process of reconsolidation in order for them to be maintained. This process of destabilization and reconsolidation has commonly been cited as a means by which established memories can be updated or modified. However, little direct evidence exists to support this view. The present study addressed this issue by analyzing the influence of novel salient information present at the time of memory reactivation on the likelihood of the reactivated memory to become destabilized and vulnerable to disruption. Rats explored sample objects and, some time later, received systemic injections of the N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 or saline prior to memory reactivation. When object memories were relatively young or weakly encoded, MK-801 significantly disrupted reconsolidation regardless of the reactivation conditions. However, increasing the amount of sample object exploration or the interval between the sample phase and reactivation abolished the effect of MK-801 on reconsolidation unless salient novel contextual information was present during memory reactivation. These results highlight the dynamic nature of memory storage and retrieval and indicate an important interaction between the age and strength of a memory, its probability of being destabilized upon reactivation, and the stimulus conditions during reactivation. The essential involvement of novel encoding in destabilizing certain memories supports the idea that the reconsolidation process enables modification of existing memories.

Paradoxical Facilitation of Object Recognition Memory after Infusion of Scopolamine into Perirhinal Cortex: Implications for Cholinergic System Function

The cholinergic system has long been implicated in learning and memory, yet its specific function remains unclear. In the present study, we investigated the role of cortical acetylcholine in a rodent model of declarative memory by infusing the cholinergic muscarinic receptor antagonist scopolamine into the rat perirhinal cortex during different stages (encoding, storage/consolidation, and retrieval) of the spontaneous object recognition task. Presample infusions of scopolamine significantly impaired object recognition compared with performance of the same group of rats on saline trials; this result is consistent with previous reports supporting a role for perirhinal acetylcholine in object information acquisition. Scopolamine infusions directly before the retrieval stage had no discernible effect on object recognition. However, postsample infusions of scopolamine with sample-to-infusion delays of up to 20 h significantly facilitated performance relative to postsample saline infusion trials. Additional analysis suggested that the infusion episode could cause retroactive or proactive interference with the sample object trace and that scopolamine blocked the acquisition of this interfering information, thereby facilitating recognition memory. This is, to our knowledge, the first example of improved recognition memory after administration of scopolamine. The overall pattern of results is inconsistent with a direct role for cortical acetylcholine in declarative memory consolidation or retrieval. Rather, the cholinergic input to the perirhinal cortex may facilitate acquisition by enhancing the cortical processing of incoming stimulus information.