E. Clea Warburton

Recognition Memory for Objects, Place, and Temporal Order: A Disconnection Analysis of the Role of the Medial Prefrontal Cortex and Perirhinal Cortex

Recognition memory requires judgments of the previous occurrence of stimuli made on the basis of the relative familiarity of individual objects, or by integrating information concerning objects and location, or by using recency information. The present study examined the role of the medial prefrontal cortex (mPFC) and perirhinal cortex (PRH) in these distinct recognition memory processes using a series of behavioral tests: a novel object preference task, an object-in-place task, and a temporal order memory task. Also, a disconnection procedure was used to test whether these regions form components of an integrated system for recognition memory. Male DA rats received bilateral lesions in the PRH or mPFC or unilateral lesions placed in both cortices in either the same (PRH–mPFC IPSI) or contralateral (PRH–mPFC CONTRA) hemispheres. A fifth group underwent sham surgery (SHAM). In the object-in-place and temporal order memory tasks, the PRH, mPFC, and PRH–mPFC CONTRA groups were significantly impaired. However, performance in the novel object preference task was only impaired in the PRH group. No group was impaired in the object location task. These results demonstrate that the mPFC and PRH are crucial for object-in-place associational and recency discriminations, whereas the PRH but not the mPFC is important for the discrimination of novel and familiar individual objects. Importantly, these results provide direct support for the hypothesis that to make discriminations based on associational or recency information, both cortical regions operate within an integrated neural network for recognition memory.

Cholinergic neurotransmission is essential for perirhinal cortical plasticity and recognition memory.

We establish the importance of cholinergic neurotransmission to both recognition memory and plasticity within the perirhinal cortex of the temporal lobe. The muscarinic receptor antagonist scopolamine impaired the preferential exploration of novel over familiar objects, disrupted the normal reduced activation of perirhinal neurones to familiar compared to novel pictures, and blocked production of long-term depression (LTD) but not long-term potentiation (LTP) of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for the involvement of cholinergic mechanisms in synaptic plastic processes within perirhinal cortex that are necessary for recognition memory.

Expression of Long-Term Depression Underlies Visual Recognition Memory

The modifications occurring in the brain during learning and memory are still poorly understood but may involve long-lasting changes in synaptic transmission (synaptic plasticity). In perirhinal cortex, a lasting decrement in neuronal responsiveness is associated with visual familiarity discrimination, leading to the hypothesis that long-term depression (LTD)-like synaptic plasticity may underlie recognition memory. LTD relies on internalization of AMPA receptors (AMPARs) through interaction between their GluR2 subunits and AP2, the clathrin adaptor protein required for endocytosis. We demonstrate that a peptide that blocks interactions between GluR2 and AP2 blocks LTD in perirhinal cortex in vitro. Viral transduction of this peptide in perirhinal cortex produced striking deficits in visual recognition memory. Furthermore, there was a deficit of LTD in perirhinal cortex slices from virally transduced, recognition memory-deficient animals. These results suggest that internalization of AMPA receptors, a process critical for the expression of LTD in perirhinal cortex, underlies visual recognition memory.

Findings from animals concerning when interactions between perirhinal cortex, hippocampus and medial prefrontal cortex are necessary for recognition memory.

Loss of recognition memory is a prominent feature of the human classical amnesic syndrome. Recognition memory requires judgments concerning prior occurrence. Such judgments can be made in a variety of ways using different types of information such as the relative familiarity of individual objects or locations, or the location of a previously encountered object, or when an object was previously encountered. We review findings of selective ablation studies which demonstrate that the perirhinal cortex, hippocampus and medial prefrontal cortex are differently involved in recognition memory processes involving these different types of information. This review also presents data from a series of disconnection analyses, which test whether the perirhinal cortex, hippocampus and medial prefrontal cortex form components of an integrated system for these recognition memory processes. These analyses reveal that it is necessary for the perirhinal cortex, medial prefrontal cortex and the hippocampus to interact, forming an integrated network, in recognition memory involving judgment of whether an object has been previously encountered in a particular place (object-in-place recognition memory) and in judging which of two objects was encountered longer ago (temporal order memory). In contrast, such interactions are not necessary when judgments are made concerning the prior occurrence of an individual item without positional information being necessary for the judgment (object memory) or concerning the prior occurrence of some item at a particular location without object information being necessary for the judgment (location memory).

NMDA Receptor Plasticity in the Perirhinal and Prefrontal Cortices Is Crucial for the Acquisition of Long-Term Object-in-Place Associative Memory

A key process for recognition memory is the formation of associations between an object and the place in which it was encountered, a process that has been shown to require the perirhinal (PRH) and medial prefrontal (mPFC) cortices. Here we demonstrate, for the first time, the importance of glutamatergic neurotransmission, within the PRH and mPFC, for object-in-place associative recognition memory. Unilateral blockade of AMPA receptors (by CNQX) in the PRH and mPFC in opposite hemispheres impaired an object-in-place task in rats, confirming that these cortical regions operate within a neural network for object-in-place recognition memory. Intra-mPFC infusions of AP5 (NMDA receptor antagonist) impaired short-term memory and the acquisition of long-term memory, but had no effect on retrieval. AP5 infusions into the PRH disrupted acquisition of long-term memory, but not short-term memory or retrieval. Significantly, crossed AP5 infusions into both the PRH and mPFC disrupted acquisition of long-term memory but were without effect on short-term memory. Finally a unilateral infusion of the selective kainate (GLUK5) receptor antagonist UBP302 [(S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-2,4-dione] into the PRH combined with a unilateral infusion of AP5 into the contralateral mPFC significantly impaired short-term object-in-place associative memory. These data show that the PRH and mPFC make distinct contributions to object-in-place associative memory and that the encoding of long-term but not short-term memory requires concurrent NMDA receptor activation in both cortical regions. In contrast, short-term object-in-place memory appears to be dependent on kainate receptor activation in the PRH and NMDA receptor activation in the mPFC.

cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

We established the importance of phosphorylation of cAMP responsive element-binding protein (CREB) to both the familiarity discrimination component of long-term recognition memory and plasticity within the perirhinal cortex of the temporal lobe. Adenoviral transduction of perirhinal cortex (and adjacent visual association cortex) with a dominant-negative inhibitor of CREB impaired the preferential exploration of novel over familiar objects at a long (24 h) but not a short (15 min) delay, disrupted the normal reduced activation of perirhinal neurons to familiar compared with novel pictures, and impaired long-term potentiation of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for involvement of CREB phosphorylation in synaptic plastic processes within perirhinal cortex necessary for long-term recognition memory.

Anterior thalamic lesions stop synaptic plasticity in retrosplenial cortex slices: expanding the pathology of diencephalic amnesia

Recent, convergent evidence places the anterior thalamic nuclei at the heart of diencephalic amnesia. However, the reasons for the severe memory loss in diencephalic amnesia remain unknown. A potential clue comes from the dense, reciprocal connections between the anterior thalamic nuclei and retrosplenial cortex, another region vital for memory. We now report a loss of synaptic plasticity [long-term depression (LTD)] in rat retrosplenial cortex slices months following an anterior thalamic lesion. The loss of LTD was lamina-specific, occurring only in superficial layers of the cortex and was associated with a decrease in GABA(A)-mediated inhibitory transmission. As retrosplenial cortex is itself vital for memory, this distal lesion effect will amplify the impact of anterior thalamic lesions. These findings not only provide novel insights into the functional pathology of diencephalic amnesia and have implications for the aetiology of the posterior cingulate hypoactivity in Alzheimers disease, but also show how distal changes in plasticity could contribute to diaschisis.

Hippocampal lesions halve immediate-early gene protein counts in retrosplenial cortex : distal dysfunctions in a spatial memory system

The present study examined whether hippocampal lesions disrupt retrosplenial cortex function. The immediate–early genesc‐fos and zif268 provided markers of cellular activity, and their levels were compared in different cytoarchitectonic subregions (dysgranular, granular a and granular b) and different layers (superficial or deep) within retrosplenial cortex. Experiments 1–3 examined the impact of hippocampal lesions on retrosplenial cortex function, with the variations in protocol (e.g. lesion method, rat strain, behaviour prior to gene activity measurement) testing the generality of the findings. Experiment 1 showed that radio‐frequency hippocampus lesions result in very striking losses of Fos and Zif268 activity in both superficial and deep laminae of all retrosplenial subregions. This pattern of results was repeated for Fos in experiments 2 and 3. Despite the loss of Fos and Zif268, there was no evidence of retrosplenial cortex atrophy as measured by Nissl counts (experiments 1–3) or NeuN‐positive cell counts (experiment 3). Likewise, there was little evidence of any overt changes in cellular size, shape or appearance. The specificity of these hippocampal lesion effects was confirmed in experiment 4 as entorhinal cortex lesions did not change retrosplenial Fos levels. These results provide strong support for the notion that the retrosplenial cortex is unusually sensitive to deafferentation from some of its inputs, so that hippocampal damage might produce permanent ‘covert pathology’ in the retrosplenial cortex. Such dysfunctions could contribute to the pattern of cognitive changes associated with hippocampal lesions and also help to explain the functional interdependency of these two structures.

Investigations into the involvement of NMDA mechanisms in recognition memory

This review will focus on evidence showing that NMDA receptor neurotransmission is critical for synaptic plasticity processes within brain regions known to be necessary for the formation of object recognition memories. The aim will be to provide evidence concerning NMDA mechanisms related to recognition memory processes and show that recognition memory for objects, places or associations between objects and places depends on NMDA neurotransmission within the perirhinal cortex, temporal association cortex medial prefrontal cortex and hippocampus. Administration of the NMDA antagonist AP5, selectively into each of these brain regions has revealed that the extent of the involvement NMDA receptors appears dependent on the type of information required to solve the recognition memory task; thus NMDA receptors in the perirhinal cortex are crucial for the encoding of long-term recognition memory for objects, and object-in-place associations, but not for short-term recognition memory or for retrieval. In contrast the hippocampus and medial prefrontal cortex are required for both long-term and short-term recognition memory for places or associations between objects and places, or for recognition memory tasks that have a temporal component. Such studies have therefore confirmed that the multiple brain regions make distinct contributions to recognition memory but in addition that more than one synaptic plasticity process must be involved. This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’.

Separate elements of episodic memory subserved by distinct hippocampal-prefrontal connections.

Episodic memory formation depends on information about a stimulus being integrated within a precise spatial and temporal context, a process dependent on the hippocampus and prefrontal cortex. Investigations of putative functional interactions between these regions are complicated by multiple direct and indirect hippocampal–prefrontal connections. Here application of a pharmacogenetic deactivation technique enabled us to investigate the mnemonic contributions of two direct hippocampal–medial prefrontal cortex (mPFC) pathways, one arising in the dorsal CA1 (dCA1) and the other in the intermediate CA1 (iCA1). While deactivation of either pathway impaired episodic memory, the resulting pattern of mnemonic deficits was different: deactivation of the dCA1→mPFC pathway selectively disrupted temporal order judgments while iCA1→mPFC pathway deactivation disrupted spatial memory. These findings reveal a previously unsuspected division of function among CA1 neurons that project directly to the mPFC. Such subnetworks may enable the distinctiveness of contextual information to be maintained in an episodic memory circuit.