The hippocampus, prefrontal cortex, and perirhinal cortex are critical to incidental order memory.

Considerable research in rodents and humans indicates the hippocampus and prefrontal cortex are essential for remembering temporal relationships among stimuli, and accumulating evidence suggests the perirhinal cortex may also be involved. However, experimental parameters differ substantially across studies, which limits our ability to fully understand the fundamental contributions of these structures. In fact, previous studies vary in the type of temporal memory they emphasize (e.g., order, sequence, or separation in time), the stimuli and responses they use (e.g., trial-unique or repeated sequences, and incidental or rewarded behavior), and the degree to which they control for potential confounding factors (e.g., primary and recency effects, or order memory deficits secondary to item memory impairments). To help integrate these findings, we developed a new paradigm testing incidental memory for trial-unique series of events, and concurrently assessed order and item memory in animals with damage to the hippocampus, prefrontal cortex, or perirhinal cortex. We found that this new approach led to robust order and item memory, and that hippocampal, prefrontal and perirhinal damage selectively impaired order memory. These findings suggest the hippocampus, prefrontal cortex and perirhinal cortex are part of a broad network of structures essential for incidentally learning the order of events in episodic memory

Flexible Bayesian Dynamic Modeling of Correlation and Covariance Matrices

Modeling correlation (and covariance) matrices can be challenging due to the positive-definiteness constraint and potential high-dimensionality. Our approach is to decompose the covariance matrix into the correlation and variance matrices and propose a novel Bayesian framework based on modeling the correlations as products of unit vectors. By specifying a wide range of distributions on a sphere (e.g. the squared-Dirichlet distribution), the proposed approach induces flexible prior distributions for covariance matrices (that go beyond the commonly used inverse-Wishart prior). For modeling real-life spatio-temporal processes with complex dependence structures, we extend our method to dynamic cases and introduce unit-vector Gaussian process priors in order to capture the evolution of correlation among components of a multivariate time series. To handle the intractability of the resulting posterior, we introduce the adaptive $\Delta$-Spherical Hamiltonian Monte Carlo. We demonstrate the validity and flexibility of our proposed framework in a simulation study of periodic processes and an analysis of rat's local field potential activity in a complex sequence memory task.Comment: 49 pages, 15 figure

Nonspatial sequence coding in CA1 neurons

The hippocampus is critical to the memory for sequences of events, a defining feature of episodic memory. However, the fundamental neuronal mechanisms underlying this capacity remain elusive. While considerable research indicates hippocampal neurons can represent sequences of locations, direct evidence of coding for the memory of sequential relationships among nonspatial events remains lacking. To address this important issue, we recorded neural activity in CA1 as rats performed a hippocampus-dependent sequencememory task. Briefly, the task involves the presentation of repeated sequences of odors at a single port and requires rats to identify each item as “in sequence” or “out of sequence”. We report that, while the animals’ location and behavior remained constant, hippocampal activity differed depending on the temporal context of items—in this case, whether they were presented in or out of sequence. Some neurons showed this effect across items or sequence positions (general sequence cells), while others exhibited selectivity for specific conjunctions of item and sequence position information (conjunctive sequence cells) or for specific probe types (probe-specific sequence cells). We also found that the temporal context of individual trials could be accurately decoded from the activity of neuronal ensembles, that sequence coding at the single-cell and ensemble level was linked to sequence memory performance, and that slow-gamma oscillations (20–40 Hz) were more strongly modulated by temporal context and performance than theta oscillations (4–12 Hz). These findings provide compelling evidence that sequence coding extends beyond the domain of spatial trajectories and is thus a fundamental function of the hippocampus

The neurobiology of memory based predictions

Recent findings indicate that, in humans, the hippocampal memory system is involved in the capacity to imagine the future as well as remember the past. Other studies have suggested that animals may also have the capacity to recall the past and plan for the future. Here, we will consider data that bridge between these sets of findings by assessing the role of the hippocampus in memory and prediction in rats. We will argue that animals have the capacity for recollection and that the hippocampus plays a central and selective role in binding information in the service of recollective memory. Then we will consider examples of transitive inference, a paradigm that requires the integration of overlapping memories and flexible use of the resulting relational memory networks for generating predictions in novel situations. Our data show that animals have the capacity for transitive inference and that the hippocampus plays a central role in the ability to predict outcomes of events that have not yet occurred

The hippocampus and disambiguation of overlapping sequences.

Recent models of hippocampal function emphasize its potential role in disambiguating sequences of events that compose distinct episodic memories. In this study, rats were trained to distinguish two overlapping sequences of odor choices. The capacity to disambiguate the sequences was measured by the critical odor choice after the overlapping elements of the sequences. When the sequences were presented in rapid alternation, damage to the hippocampus, produced either by infusions of the neurotoxin ibotenic acid or by radiofrequency current, produced a severe deficit, although animals with radiofrequency lesions relearned the task. When the sequences were presented spaced apart and in random order, animals with radiofrequency hippocampal lesions could perform the task. However, they failed when a memory delay was imposed before the critical choice. These findings support the hypothesis that the hippocampus is involved in representing sequences of nonspatial events, particularly when interference between the sequences is high or when animals must remember across a substantial delay preceding items in a current sequence

Nonspatial Sequence Coding in CA1 Neurons.

The hippocampus is critical to the memory for sequences of events, a defining feature of episodic memory. However, the fundamental neuronal mechanisms underlying this capacity remain elusive. While considerable research indicates hippocampal neurons can represent sequences of locations, direct evidence of coding for the memory of sequential relationships among nonspatial events remains lacking. To address this important issue, we recorded neural activity in CA1 as rats performed a hippocampus-dependent sequence-memory task. Briefly, the task involves the presentation of repeated sequences of odors at a single port and requires rats to identify each item as "in sequence" or "out of sequence". We report that, while the animals' location and behavior remained constant, hippocampal activity differed depending on the temporal context of items-in this case, whether they were presented in or out of sequence. Some neurons showed this effect across items or sequence positions (general sequence cells), while others exhibited selectivity for specific conjunctions of item and sequence position information (conjunctive sequence cells) or for specific probe types (probe-specific sequence cells). We also found that the temporal context of individual trials could be accurately decoded from the activity of neuronal ensembles, that sequence coding at the single-cell and ensemble level was linked to sequence memory performance, and that slow-gamma oscillations (20-40 Hz) were more strongly modulated by temporal context and performance than theta oscillations (4-12 Hz). These findings provide compelling evidence that sequence coding extends beyond the domain of spatial trajectories and is thus a fundamental function of the hippocampus.Significance statementThe ability to remember the order of life events depends on the hippocampus, but the underlying neural mechanisms remain poorly understood. Here we addressed this issue by recording neural activity in hippocampal region CA1 while rats performed a nonspatial sequence memory task. We found that hippocampal neurons code for the temporal context of items (whether odors were presented in the correct or incorrect sequential position) and that this activity is linked with memory performance. The discovery of this novel form of temporal coding in hippocampal neurons advances our fundamental understanding of the neurobiology of episodic memory and will serve as a foundation for our cross-species, multitechnique approach aimed at elucidating the neural mechanisms underlying memory impairments in aging and dementia

Critical role of the hippocampus in memory for elapsed time.

Episodic memory includes information about how long ago specific events occurred. Since most of our experiences have overlapping elements, remembering this temporal context is crucial for distinguishing individual episodes. The discovery of timing signals in hippocampal neurons, including evidence of "time cells" and of gradual changes in ensemble activity over long timescales, strongly suggests that the hippocampus is important for this capacity. However, behavioral evidence that the hippocampus is critical for the memory of elapsed time is lacking. This is possibly because previous studies have used time durations in the range of seconds when assessing hippocampal dependence, a timescale known to require corticostriatal circuits. Here we developed a nonspatial paradigm to test the hypothesis that the hippocampus is critical for keeping track of elapsed time over several minutes. We report that rats have a robust ability to remember durations at this timescale. We then determined the role of the hippocampus using infusions of fluorophore-conjugated muscimol, a GABAA agonist. We found that the hippocampus was essential for discriminating smaller, but not larger, temporal differences (measured in log units), consistent with a role in temporal pattern separation. Importantly, this effect was observed at long (minutes) but not short (seconds) timescales, suggesting an interplay of temporal resolution and timescale in determining hippocampal dependence. These results offer compelling evidence that the hippocampus plays a critical role in remembering how long ago events occurred