The Neurobiology of Memory for Time

Overview

A fundamental aspect episodic memory is the ability to remember when events occurred (Allen & Fortin, 2013, PNAS). In the brain, the temporal organization of memory relies on the medial prefrontal cortex (mPFC), the hippocampus (HC), and mPFC-HC interactions. Notably, temporal abilities in memory are devastated in several disorders including Alzheimer’s disease, schizophrenia, epilepsy, and in typical aging (Allen et al., 2015, LearnMem). In the lab we address these issues in studies focusing on memory for sequences of events, memory for elapsed times, and on the fundamental neurobiological mechanisms of mPFC-HC interactions that facilitate memory for time. These studies are funded, in part, by NIH grant R01 MH113626.

mPFC-HC Interactions in Memory for Sequence of Events in Rats

In rats, the mPFC is ideally situated to influence memory retrieval through its many projections to the thalamus and cortex. We recently explored the hypothesis that the mPFC may be able to bias different sequence retrieval strategies through its top-down projection pathways that mediate interactions with the HC. To do this, we used a cutting-edge projection specific synaptic silencing approach (AAV-hM4Di) to compare the role of two mPFC pathways in an odor sequence memory task (Jayachandran et al., 2019, Cell Reports). We found that projections to both the nucleus reuniens of the thalamus (RE) and perirhinal cortex (PER) were critical to remembering sequences, but that the RE contributed to a working memory strategy and PER to a temporal context strategy.

We’re continuing experiments studying the neural mechanisms of memory for sequences of events. In these experiments we use chronic silicon probes and tetrode hyperdrives to record neural activity in combination with optogenetic manipulations (Allen*, Jayachandran* et al., 2020, eNeuro) in mPFC, RE, PER and HC during memory for sequences of events (Allen et al., 2016, JNeurosci; Ng et al., 2017, BehavBrainRes). The long-term goals are (1) to deliver a detailed anatomically-based framework for understanding mPFC-HC circuit contributions to sequence memory, and (2) apply this framework to preclinical (rodent) studies of mental health disorders. Integrating the results will provide a foundation for understanding the role of mPFC-HC interactions in the sequential organization of events in memory, and the role for top-down modulations of memory.

mPFC-HC Interactions in Memory for Sequence of Events in Humans

Just like in rats, the mPFC-HC system is critical to  memory for sequences of events in humans. Our lab uses a variety of approaches in order to bridge and extend the neurobiological and behavioral findings from animals to humans (Allen et al., 2014, Hippocampus). In a recent study using fMRI, we tested the roles of mPFC and HC probing multiple sequence memory strategies (Reeders et al., 2020, LearnMem; Reeders et al., 2018, bioRxiv). After studying the sequences, participants indicated whether items were in sequence or out of sequence in subsequent memory tests.

In this task the use of temporal context strategies, a form of item-item associations, should result in graded behavioral performance as a function of temporal distance. We predicted graded impairment across lag distance for items that skipped ahead in the sequence (Skips, e.g., ABD), with short lags being most affected. Subjects had more difficulty identifying out of sequence items that skipped ahead short distances, compared with longer distances. In the human brain, we found that the right anterior HC increased in activity as the forward lags increased, suggesting that the HC supports sequence memory with a temporal context.

We tested ordinal-position based strategies by using items were transferred from one sequence to another, but that retained their position (Ordinal Transfers; e.g., AB3). We found that performance on these Ordinal Transfer trials was comparatively worse than other memory probes, but were still performed above chance levels. In the brain, Ordinal Transfers that were incorrectly identified as in sequence were more strongly associated with high mPFC activity, suggesting that the activity in the mPFC is related to the use of an ordinal strategy during sequence memory.

mPFC-HC Interactions in Memory for Elapsed Time

Another critical aspect of the temporal organization of memory is the ability to remember how long ago an event occurred (Allen & Fortin, 2013, PNAS). Memory for elapsed time allows us to segregate memories and keep track of events with similar, or even identical, information content. We’ve shown that detailed temporal memories of this type critically depend on the HC using a fluophore-conjugated muscimol approach (Allen et al., 2008; Jacobs, et al., 2013, JNeurosci).

In a recent series of experiments, we tested the role of mPFC-HC circuits underlying memory for elapsed time in detail by using a projection-specific synaptic silencing approach (AAV-hM4Di) targeting cells of RE that project to ventral HC and mPFC (Linley et al., 2019, SfN). We found that RE projection to both the vHC and mPFC are critical for detailed elapsed time memory, just like HC, but that silencing RE projections to the vHC led to random memory errors, whereas silencing RE projections to mPFC led to impairments in the flexible use of elapsed-time memory. The studies contribute to a growing literature in humans showing elapsed-time memory deficits in hippocampal amnesics, schizophrenia, and dementia.

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