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Until now, nobody has known how the hippocampus supports these functions and if there was any relationship between the two. Credit: Neuroscience News

Unlocking the Dual Memory Codes of the Hippocampus

Summary: Researchers have distinguished between two vital memory tasks housed in the hippocampus: one that remembers associations and another that predicts based on past events. The study used optogenetics to isolate one memory function without affecting the other.

The researchers revealed two distinct neural codes for these functions, aiding our understanding of dementia and Alzheimer’s. This discovery holds potential for more targeted interventions in treating memory and navigational deficits.

Key Facts:

  1. The hippocampus is responsible for two distinct memory functions: associative memory and predictive memory based on past experiences.
  2. Using advanced optogenetic techniques, researchers could isolate and manipulate one memory function while leaving the other intact in rats.
  3. The study’s findings could guide more specific treatments for dementia and Alzheimer’s disease by targeting the disrupted neural mechanism.

Source: Cornell University

For the first time, a Cornell University-led study in rats teases apart the role of the hippocampus in two functions of memory – one that remembers associations between time, place and what one did, and another that allows one to predict or plan future actions based on past experiences.

The breakthrough reveals that these two memory tasks, both coded in the hippocampus, can be separated. The finding has important implications for one day treating memory and learning issues found in dementia and Alzheimer’s disease.

The study, published in Science, used advanced optogenetic techniques to disable one type of memory while maintaining the other.

“We uncovered that two different neural codes support these very important aspects of memory and cognition, and can be dissociated, as we did experimentally,” said Antonio Fernandez-Ruiz, assistant professor of neurobiology and behavior.

One type of neural code controls the ability to make associations, such as remembering that apples are sold at the neighborhood grocery store. The other type is predictive and involves the ability to flexibly use memory to plan a new behavior; for example, if you always travel the same route to the store, but one day the road is closed, you can use an internal memorized map of the neighborhood to make a prediction of a new route.

Until now, nobody has known how the hippocampus supports these functions and if there was any relationship between the two.

In the study, rats with perturbed hippocampi had to explore a maze and find a new path every day to collect a reward. With the manipulation, the rats could not remember how to get the reward.

In a second experiment, the rats had to learn to associate a particular location in the environment with a reward. When the predictive capabilities were impaired, this associative memory remained intact. The researchers proved they could decouple these two types of memory.

The findings have implications for treating Alzheimer’s disease and other forms of dementia, where patients experience neural degeneration in the hippocampus as well as memory and navigation problems.

“By looking at which type of memory deficits occur in a patient,” Fernandez-Ruiz said, “we can try to infer what type of underlying neuronal mechanism has been compromised, which will help us develop more targeted interventions.

About this memory research news

Author: Becka Bowyer
Source: Cornell University
Contact: Becka Bowyer – Cornell University
Image: The image is credited to Neuroscience News

Original Research: Closed access.
Associative and predictive hippocampal codes support memory-guided behaviors” by Antonio Fernandez-Ruiz et al. Science


Associative and predictive hippocampal codes support memory-guided behaviors


The brain generates models of the environment that are used to guide flexible behaviors. This process requires learning the states of the world (such as specific locations) as well as the transitional relationships between those states (e.g., successive locations along often-traveled trajectories).

The hippocampal cognitive map is believed to be one such internal model, supporting a variety of behaviors, including associative learning, navigational planning, and inference. It remains unknown which facets of hippocampal coding are required for these different behaviors and how they support both associative and predictive memory functions.


We hypothesize that two modes of hippocampal activity support learning of world states and state transitions, respectively. On one hand, the synchronous coactivity of groups of hippocampal neurons—cell assemblies—may encode features of individual states, formingan associative code.

On the other hand, the ordered activation of these cell assemblies into behaviorally relevant sequences may encode the relational structure between states, forming a predictive code.

Previous research has not been able to dissociate these two dynamic codes or provide evidence of their specific functions.

We leveraged an optogenetic approach to dissociate these two coding schemes, with the goal of disrupting the predictive code (hippocampal sequences) while preserving the associative code (rate coding and coactivity dynamics) in behaving rats. This dissociation allowed us to examine the different memory functions of these two codes.


We optogenetically perturbed the fine temporal coordination of hippocampal place cell firing as rats navigated specific spatial trajectories in a novel maze. This manipulation disrupted properties of the predictive code (such as temporally compressed place cell sequences and anticipatory place field shifts), but global network dynamics and single-cell spatial tuning and rate coding properties were preserved.

During sleep after the novel experience, we observed that task-related cell assemblies encoding discrete maze locations were reactivated in sharp wave–ripples (SWRs), unaffected by the manipulation.

However, their sequential structure did not reproduce the order in which they were active in the task, resulting in impaired sequential replay for the perturbed trajectories. This result shows a dissociation between assembly reactivation and sequence replay, two phenomena previously assumed to reflect the same underlying process.

The same manipulation did not disrupt replay of familiar trajectories, suggesting that the precise temporal coordination of place cell firing during learning mediates initial plasticity required for subsequent replay. Computational simulations suggest that distinct Hebbian plasticity mechanisms mediate assembly reactivation and sequence replay.

We tested the functional role of the predictive code by deploying our optogenetic manipulation in two different hippocampal-dependent memory tasks. Context-reward associative learning in a conditioned place preference task was unaffected and thus does not require a predictive map or memory replay. On the other hand, flexible memory–guided navigation in a foraging task was perturbed by the manipulation and thus depends on hippocampal predictive coding.


Our results provide a mechanistic and functional dissociation between coactivity and sequence codes in the hippocampus.

Hippocampal cells with similar responses to behavioral variables fire together, forming functional assemblies during learning, which are reactivated in SWRs during subsequent sleep. These cell assemblies encode discrete states in the environment, an associative code that is sufficient for some types of episodic memories. As these cell assemblies are activated in a specific order during behavior, they form temporally compressed hippocampal sequences and promote Hebbian plasticity.

This process enables the replay of behaviorally relevant sequences during SWRs. Hippocampal sequences thus encode transitional structures of world states, generating a predictive model on top of the associative code of individual assemblies.

This new framework contributes to our understanding of how memory associations develop into predictive representations of the world and helps reconcile previously disparate views on hippocampal function.

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