Jena B. Hales

Medial Entorhinal Cortex Lesions Only Partially Disrupt Hippocampal Place Cells and Hippocampus-Dependent Place Memory

The entorhinal cortex provides the primary cortical projections to the hippocampus, a brain structure critical for memory. However, it remains unclear how the precise firing patterns of medial entorhinal cortex (MEC) cells influence hippocampal physiology and hippocampus-dependent behavior. We found that complete bilateral lesions of the MEC resulted in a lower proportion of active hippocampal cells. The remaining active cells had place fields, but with decreased spatial precision and decreased long-term spatial stability. In addition, MEC rats were as impaired in the water maze as hippocampus rats, while rats with combined MEC and hippocampal lesions had an even greater deficit. However, MEC rats were not impaired on other hippocampus-dependent tasks, including those in which an object location or context was remembered. Thus, the MEC is not necessary for all types of spatial coding or for all types of hippocampus-dependent memory, but it is necessary for the normal acquisition of place memory.

The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity

The superficial layers of the medial entorhinal cortex (MEC) are a major input to the hippocampus. The high proportion of spatially modulated cells, including grid cells and border cells, in these layers suggests that MEC inputs are critical for the representation of space in the hippocampus. However, selective manipulations of the MEC do not completely abolish hippocampal spatial firing. To determine whether other hippocampal firing characteristics depend more critically on MEC inputs, we recorded from hippocampal CA1 cells in rats with MEC lesions. Theta phase precession was substantially disrupted, even during periods of stable spatial firing. Our findings indicate that MEC inputs to the hippocampus are required for the temporal organization of hippocampal firing patterns and suggest that cognitive functions that depend on precise neuronal sequences in the hippocampal theta cycle are particularly dependent on the MEC.

Activity in the hippocampus and neocortical working memory regions predicts successful associative memory for temporally discontiguous events

Models of mnemonic function suggest that the hippocampus binds temporally discontiguous events in memory (Wallenstein, Eichenbaum, & Hasselmo, 1998), which has been supported by recent studies in humans. Less is known, however, about the involvement of working memory in bridging the temporal gap between to-be-associated events. In this study, subsequent memory for associations between temporally discontiguous stimuli was examined using functional magnetic resonance imaging. In the scanner, subjects were instructed to remember sequentially presented images. Occasionally, a plus-sign was presented during the interstimulus interval between two images, instructing subjects to associate the two images as a pair. Following the scan, subjects identified remembered images and their pairs. Images following the plus-sign were separated into trials in which items were later recognized and the pair remembered, recognized and the pair forgotten, or not recognized. Blood-oxygen-level-dependent responses were measured to identify regions where response amplitude predicted subsequent associative- or item memory. Distinct neocortical regions were involved in each memory condition, where activity in bilateral frontal and parietal regions predicted memory for associative information and bilateral occipital and medial frontal regions for item information. While activity in posterior regions of the medial temporal lobe showed an intermediate response predicting memory for both conditions, bilateral hippocampal activity only predicted associative memory.

Dissociation of frontal and medial temporal lobe activity in maintenance and binding of sequentially presented paired associates

Substructures of the prefrontal cortex (PFC) and the medial-temporal lobe are critical for associating objects presented over time. Previous studies showing frontal and medial-temporal involvement in associative encoding have not addressed the response specificity of these regions to different aspects of the task, which include instructions to associate and binding of stimuli. This study used a novel paradigm to temporally separate these two components of the task by sequential presentation of individual images with or without associative instruction; fMRI was used to investigate the temporal involvement of the PFC and the parahippocampal cortex in encoding each component. Although both regions showed an enhanced response to the second stimulus of a pair, only the PFC had increased activation during the delay preceding a stimulus when associative instruction was given. These findings present new evidence that prefrontal and medial-temporal regions provide distinct temporal contributions during associative memory formation.

Erratum: search-related suppression of hippocampus and default network activity during associative memory retrieval

Episodic memory retrieval involves the coordinated interaction of several cognitive processing stages such as mental search, access to a memory store, associative re-encoding, and post-retrieval monitoring. The neural response during memory retrieval is an integration of signals from multiple regions that may subserve supportive cognitive control, attention, sensory association, encoding, or working memory functions. It is particularly challenging to dissociate contributions of these distinct components to brain responses in regions such as the hippocampus, which lies at the interface between overlapping memory encoding and retrieval, and “default” networks. In the present study, event-related functional magnetic resonance imaging (fMRI) and measures of memory performance were used to differentiate brain responses to memory search from subcomponents of episodic memory retrieval associated with successful recall. During the attempted retrieval of both poorly and strongly remembered word pair associates, the hemodynamic response was negatively deflected below baseline in anterior hippocampus and regions of the default network. Activations in anterior hippocampus were functionally distinct from those in posterior hippocampus and negatively correlated with response times. Thus, relative to the pre-stimulus period, the hippocampus shows reduced activity during intensive engagement in episodic memory search. Such deactivation was most salient during trials that engaged only pre-retrieval search processes in the absence of successful recollection or post-retrieval processing. Implications for interpretation of hippocampal fMRI responses during retrieval are discussed. A model is presented to interpret such activations as representing modulation of encoding-related activity, rather than retrieval-related activity. Engagement in intensive mental search may reduce neural and attentional resources that are otherwise tonically devoted to encoding an individual’s stream of experience into episodic memory.

The timing of associative memory formation: Frontal lobe and anterior medial temporal lobe activity at associative binding predicts memory

The process of associating items encountered over time and across variable time delays is fundamental for creating memories in daily life, such as for stories and episodes. Forming associative memory for temporally discontiguous items involves medial temporal lobe structures and additional neocortical processing regions, including prefrontal cortex, parietal lobe, and lateral occipital regions. However, most prior memory studies, using concurrently presented stimuli, have failed to examine the temporal aspect of successful associative memory formation to identify when activity in these brain regions is predictive of associative memory formation. In the current study, functional MRI data were acquired while subjects were shown pairs of sequentially presented visual images with a fixed interitem delay within pairs. This design allowed the entire time course of the trial to be analyzed, starting from onset of the first item, across the 5.5-s delay period, and through offset of the second item. Subjects then completed a postscan recognition test for the items and associations they encoded during the scan and their confidence for each. After controlling for item-memory strength, we isolated brain regions selectively involved in associative encoding. Consistent with prior findings, increased regional activity predicting subsequent associative memory success was found in anterior medial temporal lobe regions of left perirhinal and entorhinal cortices and in left prefrontal cortex and lateral occipital regions. The temporal separation within each pair, however, allowed extension of these findings by isolating the timing of regional involvement, showing that increased response in these regions occurs during binding but not during maintenance.

Hippocampus, perirhinal cortex, and complex visual discriminations in rats and humans.

Structures in the medial temporal lobe, including the hippocampus and perirhinal cortex, are known to be essential for the formation of long-term memory. Recent animal and human studies have investigated whether perirhinal cortex might also be important for visual perception. In our study, using a simultaneous oddity discrimination task, rats with perirhinal lesions were impaired and did not exhibit the normal preference for exploring the odd object. Notably, rats with hippocampal lesions exhibited the same impairment. Thus, the deficit is unlikely to illuminate functions attributed specifically to perirhinal cortex. Both lesion groups were able to acquire visual discriminations involving the same objects used in the oddity task. Patients with hippocampal damage or larger medial temporal lobe lesions were intact in a similar oddity task that allowed participants to explore objects quickly using eye movements. We suggest that humans were able to rely on an intact working memory capacity to perform this task, whereas rats (who moved slowly among the objects) needed to rely on long-term memory.

Hippocampal Infusion of Zeta Inhibitory Peptide Impairs Recent, but Not Remote, Recognition Memory in Rats

Spatial memory in rodents can be erased following the infusion of zeta inhibitory peptide (ZIP) into the dorsal hippocampus via indwelling guide cannulas. It is believed that ZIP impairs spatial memory by reversing established late-phase long-term potentiation (LTP). However, it is unclear whether other forms of hippocampus-dependent memory, such as recognition memory, are also supported by hippocampal LTP. In the current study, we tested recognition memory in rats following hippocampal ZIP infusion. In order to combat the limited targeting of infusions via cannula, we implemented a stereotaxic approach for infusing ZIP throughout the dorsal, intermediate, and ventral hippocampus. Rats infused with ZIP 3–7 days after training on the novel object recognition task exhibited impaired object recognition memory compared to control rats (those infused with aCSF). In contrast, rats infused with ZIP 1 month after training performed similar to control rats. The ability to form new memories after ZIP infusions remained intact. We suggest that enhanced recognition memory for recent events is supported by hippocampal LTP, which can be reversed by hippocampal ZIP infusion.

Consolidation of spatial memory in the rat: Findings using zeta-inhibitory peptide.

Whether or not spatial memories reorganize in the rodent brain is an unanswered question that carries the importance of whether the rodent provides a suitable animal model of human retrograde amnesia. The finding of equally impaired recent and remote spatial memory could reflect the continued importance of the hippocampus for spatial memory or a performance deficit (for example, hippocampal lesions may impair the rats ability to use distal spatial cues to navigate to a specific point in space). In the current study, we tested recent and remote spatial memory in rats following hippocampal ZIP (zeta-pseudosubstrate inhibitory peptide) infusion to inhibit PKMzeta. Hippocampal ZIP infusion has previously been shown to impair spatial and nonspatial memory soon after learning, presumably by reversing late-phase long-term potentiation, allowing us to disrupt memory without damaging hippocampal tissue. We used a stereotaxic approach for infusing ZIP throughout the dorsal, intermediate, and ventral hippocampus following spatial memory training. Although rats showed intact memory retrieval on the standard Morris watermaze task and trace fear conditioning, rats infused with ZIP 24h after training on the annular watermaze task exhibited impaired spatial memory compared to control rats (those infused with aCSF) and performed no different than chance. In contrast, rats infused with ZIP 1month after training performed similar to control rats and both groups performed above chance. Additionally, the ability to form new memories after ZIP infusions remained intact. Thus, ZIP infusions into the hippocampus after learning impaired retrieval of recently formed spatial memories while sparing remote spatial memories.

The path to memory is guided by strategy: Distinct networks are engaged in associative encoding under visual and verbal strategy and influence memory performance in healthy and impaired individuals

Given the diversity of stimuli encountered in daily life, a variety of strategies must be used for learning new information. Relating and encoding visual and verbal stimuli into memory has been probed using various tasks and stimulus types. Engagement of specific subsequent memory and cortical processing regions depends on the stimulus modality of studied material; however, it remains unclear whether different encoding strategies similarly influence regional activity when stimulus type is held constant. In this study, participants encoded object pairs using a visual or verbal associative strategy during fMRI, and subsequent memory was assessed for pairs encoded under each strategy. Each strategy elicited distinct regional processing and subsequent memory effects: middle/superior frontal, lateral parietal, and lateral occipital for visually associated pairs and inferior frontal, medial frontal, and medial occipital for verbally associated pairs. This regional selectivity mimics the effects of stimulus modality, suggesting that cortical involvement in associative encoding is driven by strategy and not simply by stimulus type. The clinical relevance of these findings, probed in a patient with a recent aphasic stroke, suggest that training with strategies utilizing unaffected cortical regions might improve memory ability in patients with brain damage.