Projections from neocortex mediate top-down control of memory retrieval
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Top-down prefrontal cortex inputs to the hippocampus have been hypothesized to be important in memory consolidation, retrieval, and the pathophysiology of major psychiatric diseases; however, no such direct projections have been identified and functionally described. Here we report the discovery of a monosynaptic prefrontal cortex (predominantly anterior cingulate) to hippocampus (CA3 to CA1 region) projection in mice, and find that optogenetic manipulation of this projection (here termed AC-CA) is capable of eliciting contextual memory retrieval. To explore the network mechanisms of this process, we developed and applied tools to observe cellular-resolution neural activity in the hippocampus while stimulating AC-CA projections during memory retrieval in mice behaving in virtual-reality environments. Using this approach, we found that learning drives the emergence of a sparse class of neurons in CA2/CA3 that are highly correlated with the local network and that lead synchronous population activity events; these neurons are then preferentially recruited by the AC-CA projection during memory retrieval. These findings reveal a sparsely implemented memory retrieval mechanism in the hippocampus that operates via direct top-down prefrontal input, with implications for the patterning and storage of salient memory representations.
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Strong multi-synaptic (indirect pathway) connections between the mPFC and hippocampus exist, but monosynaptic projections (direct pathway) also exist.
“There are strong multi-synaptic (indirect pathway) connections between the mPFC and hippocampus, but monosynaptic projections (direct pathway) also exist”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Rajasethupathy et al., 2015
Light-stimulation of the axonal terminals of ACC was sufficient to incur EPSC and evoked action potentials in CA1 and CA3 neurons but not the dentate gyrus.
“light-stimulation of the axonal terminals of ACC was sufficient to incur EPSC and evoked action potentials in the CA1 and CA3 neurons, but not the dentate gyrus”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Rajasethupathy et al., 2015
A projection from the prefrontal cortical ACC to the dorsal hippocampal CA1 and CA3 regions in mice was found through viral vector tracing.
“a projection from the prefrontal cortical ACC to the dorsal hippocampal CA1 and CA3 regions in mice was found through viral vector tracing”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Rajasethupathy et al., 2015
This monosynaptic projection is functionally essential for memory retrieval, as assessed by contextual fear conditioning.
“This monosynaptic projection is also functionally essential for memory retrieval, as assessed by contextual fear conditioning”
From The medial prefrontal cortex - hippocampus circuit that integrates information of object, place and time to construct episodic memory in rodents: Behavioral, anatomical and neurochemical properties (2020) · cites this paper as Rajasethupathy et al., 2015
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- Authors
- Rajasethupathy, P., Sankaran, S., Marshel, J. H., Kim, C. K., Ferenczi, E., Lee, S. Y., Berndt, A., Ramakrishnan, C., Jaffe, A., Lo, M., Liston, C., & Deisseroth, K.
- Affiliations
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Deisseroth, Karl
- ORCID
- Venue
- Nature
- Published
- 2015-10
- Volume
- 526
- Issue
- 7575
- Pages
- 653-659
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4825678
- OpenAlex
- W1829380695
- Cited by
- 509
- References
- 67
- Citations by year
- 2026: 36 · 2025: 53 · 2024: 46 · 2023: 52 · 2022: 59 · 2021: 52 · 2020: 40 · 2019: 33 · 2018: 42 · 2017: 64 · 2016: 25 · 2015: 6
- FWCI
- 27.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (R00MH097822, R01MH075957)
- National Institute on Drug Abuse (R37DA035377)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- top-down control, memory retrieval, prefrontal cortex, anterior cingulate cortex, hippocampus, contextual memory, neuronal ensembles, virtual reality, optogenetics, memory consolidation
- MeSH terms
- Animals, Conditioning, Psychological, Fear, Gyrus Cinguli, Hippocampus, Learning, Male, Memory, Mice, Inbred C57BL, Models, Neurological, Neural Pathways, Neurons, User-Computer Interface, Prefrontal Cortex, Neocortex, Mice, Optogenetics
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