Hippocampal representations as a function of time, subregion, and brain state
Introduction
It has been over half a century since patient HM’s surgery first demonstrated the critical role of the hippocampus in memory formation (Scoville & Milner, 1957), and seemingly countless researchers are still enthralled by this complex, mysterious structure. Indeed, we learn about new and important hippocampal functions every day; in addition to memory formation and retrieval, new findings suggest its role in flexible cognition more broadly, including navigation (Astur et al., 2002, Hirshhorn et al., 2012), reasoning (Sheldon et al., 2011, Zeithamova et al., 2012), decision making (Barron et al., 2013, Palombo et al., 2015, Shohamy and Daw, 2015), and imagination (Addis and Schacter, 2011, Mullally and Maguire, 2014)—to name just a few. How does the hippocampus support such diverse behaviours? One possible answer is in its apparent ability to represent our experiences at multiple levels of abstraction, allowing our memories to be simultaneously high fidelity and flexible.
Theoretical and computational modeling of these hippocampal representational schemes have guided memory research since the 1970’s (Marr, 1971). These ideas, however, have only recently become the subject of empirical investigation, in part due to prior barriers in ‘reading out’ the structure of hippocampal representations. The recent wellspring of machine learning and pattern analysis approaches in both human (Kriegeskorte, Mur, & Bandettini, 2008) and rodent (McKenzie et al., 2016) neuroscience combined with advances in data acquisition methods finally enable the characterization of memory-specific neural patterns required to test these entrenched theories (Box 1). In this review, we provide a high-level overview of different theoretical representational schemes along with recent evidence from rodent and human literatures. Throughout, we focus on how hippocampal contributions to memory are shaped by the nature of its representations and memory traces, terms we use to refer to any pattern of neural activity that encodes a specific memory and enables subsequent retrieval.
As we review below, however, the answers emerging from representational investigations are not always straightforward. Rather than supporting the simple dominance of one scheme over the others, data suggest that the hippocampus may employ multiple schemes. Without organizing principles or the identification of key regulatory factors, this could be a theoretical calamity for memory research. Here, we focus on two factors that determine the representational code employed within a hippocampal network: (1) location within the hippocampus, as different subregions are biased toward different kinds of representations and may have separate outputs; (2) the state of neurons leading up to a given experience, including their excitability levels and the surrounding concentrations of specific neuromodulators.
Section snippets
Making memories for related events
In the lab, we often engineer to-be-remembered events to be as distinct as possible. However, such distinctiveness is supremely artificial. In the real world, so many of our experiences are interconnected via familiar people, places, and things. How do we store memories for such interrelated events? This review will focus on three prominent types of codes—pattern separation, integration, and differentiation—which are defined by the representational transformations they perform, alternatively
The emergence of complementary codes across hippocampal subregions
How might the hippocampus simultaneously maintain these different kinds of representations? One answer may lie in the heterogeneity of hippocampal structure and function across the transverse, longitudinal and radial planes. Here, we focus on heterogeneity in the transverse plane, reviewing both classic models and recent evidence for representational differences across subfields, beginning in the dentate gyrus (DG) then moving through the cornu ammonis fields (CA) 3 and 1. See Box 3 for
Time windows for memory integration and separation
So far, we have treated hippocampal neurons and networks as though they always operate in the same state—i.e., the same two related experiences will always be integrated or separated, with the coding scheme automatically determined by the fixed wiring properties of the hippocampus. Here, we will introduce an essential layer of complexity by considering dynamic molecular mechanisms. Specifically, we propose that shifting concentrations of key molecules open what we call integration or separation
Conclusions
A major theoretical challenge is facing memory researchers today—we do not have a clear model of how the hippocampus represents information in memory. At first blush, this statement may seem shocking. How could such a fundamental property of one of the most investigated brain regions remain unknown? Moreover, longstanding models are so entrenched in our work that they can give the false sense of consensus. Some researchers may believe that the hippocampus performs pattern separation and
Acknowledgements
This work was supported by NSERC Discovery Grant 500491 and CFI/ORF Project #34479 to KD. The authors declare no competing interests.
References (210)
- et al.
Reward-motivated learning: mesolimbic activation precedes memory formation
Neuron
(2006) - et al.
Neurons, numbers and the hippocampal network
Progress in Brain Research
(1990) - et al.
Humans with hippocampus damage display severe spatial memory impairments in a virtual Morris water task
Behavioural Brain Research
(2002) - et al.
The human dentate gyrus plays a necessary role in discriminating new memories
Current Biology
(2016) - et al.
Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture
Cell
(2002) - et al.
Cholinergic stimulation enhances long-term potentiation in the CA1 region of rat hippocampus
Neuroscience Letters
(1990) - et al.
Spontaneous miniature synaptic potentials in hippocampal neurons
Brain Research
(1979) - et al.
Muscarinic receptor activation facilitates the induction of long-term potentiation (LTP) in the rat dentate gyrus
Neuroscience Letters
(1990) - et al.
Spatial organization of direct hippocampal field CA1 axonal projections to the rest of the cerebral cortex
Brain Research Reviews
(2007) - et al.
Functional magnetic resonance imaging (fMRI) “brain reading”: Detecting and classifying distributed patterns of fMRI activity in human visual cortex
NeuroImage
(2003)
Diffuse transmission by acetylcholine in the CNS
Progress in Neurobiology
Moderate levels of activation lead to forgetting in the think/no-think paradigm
Neuropsychologia
A specific role for septohippocampal acetylcholine in memory?
Neuropsychologia
Hippocampus
Neuron
The hippocampus, memory, and place cells: is it spatial memory or a memory space?
Neuron
Searchlight analysis: Promise, pitfalls, and potential
NeuroImage
Are the dorsal and ventral hippocampus functionally distinct structures?
Neuron
Anterograde and retrograde tracing of projections from the ventral tegmental area to the hippocampal formation in the rat
Brain Research Bulletin
Post-learning hippocampal dynamics promote preferential retention of rewarding events
Neuron
Expected reward modulates encoding-related theta activity before an event
NeuroImage
Ensemble dynamics of hippocampal regions CA3 and CA1
Neuron
Neuromodulation: acetylcholine and memory consolidation
Trends in Cognitive Sciences
High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation
Program of Brain Research
A primer on pattern-based approaches to fmri: principles, pitfalls, and perspectives
Neuron
Bidirectional synaptic plasticity induced by a single burst during cholinergic theta oscillation in CA1 in vitro
Neuron
The cholinergic system, circadian rhythmicity, and time memory
Behavioural Brain Research
Acetylcholine and attention
Behavioural Brain Research
Tracking the flow of hippocampal computation: Pattern separation, pattern completion, and attractor dynamics
Neurobiology of Learning and Memory
Matching categorical object representations in inferior temporal cortex of man and monkey
Neuron
The hippocampus and imagining the future: Where do we stand?
Frontiers in Human Neuroscience
Attention promotes episodic encoding by stabilizing hippocampal representations
Proceedings of the National Academy of Sciences
How Hippocampal Memory Shapes, and Is Shaped by, Attention
Integration as a general boundary condition on retrieval-induced forgetting
Journal of Experimental Psychology: Learning, Memory, and Cognition
Blockade of central cholinergic receptors impairs new learning and increases proactive interference in a word paired-associate memory task
Behavioral Neuroscience
Contributions of human hippocampal subfields to spatial and temporal pattern separation
Hippocampus
Pattern separation in the human hippocampal CA3 and dentate gyrus
Science (New York, N.Y.)
Online evaluation of novel choices by simultaneous representation of multiple memories
Nature Neuroscience
Repetition suppression: A means to index neural representations using BOLD?
Philosophical Transactions of the Royal Society B: Biological Sciences
Strong evidence for pattern separation in human dentate gyrus
Journal of Neuroscience
Dopamine and memory: modulation of the persistence of memory for novel hippocampal NMDA receptor-dependent paired associates
Journal of Neuroscience
Voltage-clamp analysis of mossy fiber synaptic input to hippocampal neurons
Journal of Neurophysiology
A shared neural ensemble links distinct contextual memories encoded close in time
Nature
Endocannabinoids facilitate the induction of LTP in the hippocampus
Nature Neuroscience
Hippocampal replay in the awake state: A potential substrate for memory consolidation and retrieval
Nature Neuroscience
Overlap among spatial memories triggers repulsion of hippocampal representations article overlap among spatial memories triggers repulsion of hippocampal representations
Current Biology
Associative retrieval processes in the human medial temporal lobe: hippocampal retrieval success and CA1 mismatch detection
Learning & Memory (Cold Spring Harbor, N.Y.)
Similarity-based fusion of MEG and fMRI reveals spatio-temporal dynamics in human cortex during visual object recognition
Cerebral Cortex
A light and electron microscopic analysis of the mossy fibers of the rat dentate gyrus
The Journal of Comparative Neurology
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2023, NeuroImageCitation Excerpt :Interestingly, we found that while control participants exhibited a significant increase in representational dissimilarity for linked events from pre to post insight in the right anterior hippocampus, stress abolished this insight-related change in anterior hippocampal representations (group × time × link interaction: F(1, 53) = 6.20, pcorr = .032, ηG = .017; Fig. 7C). For the posterior hippocampus, there was no such change (group x time × link interaction: F(1, 56) = 1.03, pcorr = .626, ηG = .002; Fig. S3), in line with previous studies suggesting that the anterior but not the posterior part of the hippocampus is involved in mnemonic integration (Collin et al., 2015; Dandolo and Schwabe, 2018; De Shetler and Rissman, 2017; Duncan and Schlichting, 2018; Morton et al., 2017; Robin and Moscovitch, 2017). We performed a follow-up analysis of the interaction in the anterior hippocampus and found that controls showed a significant increase in representational dissimilarity from pre to post specifically for linked events (t(26) = -2.13, p = .043, drepeated measures = .41; Fig. 7C) but no increase in representational dissimilarity from pre to post for non-linked events (t(26) = .05, p = .620, drepeated measures = -.10; time × link interaction: F(1, 26) = 4.51, p = .043, ηG = .027).
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Equal contributions.