Where and how are fear memories stored in the brain?

When we experience fear, what happens to the memory of the fear in our brain? What happens in our brains when we recall the fear? Why might the fear then be later experienced as part of post-traumatic disorder in a perfectly safe environment? These intriguing questions are being addressed by researchers in Paris, France, and Professor Gisella Vetere presented results of their investigations at ECNP2021.

Where and how are fear memories stored in the brain?

Memory results from connectivity between the hippocampus, thalamus, and cortex

Memories can be classified as either recent or remote (ie, in the past).

Analysis of remote memory in mice has revealed strong connectivity between the hippocampus, thalamus, and cortex, said Professor Vetere, and these subregions of the brain are strongly connected to fear memory.1

Subsequent “generalization” of remote memory results in the expression of fear behavior in a different context to that of the original fear memory,1 said Professor Vetere. This is also seen in people with post-traumatic stress disorder (PTSD) who can recall the fear even in completely safe environments.

“Generalization” of remote fear memory leads to fear behavior in a different context to that of the original fear memory

So where does the spatial information that provides the original context for the memory go?

 

Key roles for the anterodorsal and laterodorsal thalamic nuclei

Experiments in mice by Professor Vetere and her colleagues have recently shown that an inhibitory projection from the CA3 region of the hippocampus to the anterodorsal thalamic nucleus is necessary for retrieving fear memories remotely in the future, but not close in time to the event.2

As a result, Professor Vetere and her colleagues hypothesize that the inhibitory projection from the CA3 region of the hippocampus to the anterodorsal thalamic nucleus is not functionally active at recent timepoints after a fear memory.

Inactivation of the inhibitory projection from the CA3 region of the hippocampus to the anterodorsal thalamic nucleus impairs remote memory

Professor Vetere explained that this means:

  • The anterodorsal thalamic nucleus is active for acquiring recent fear and spatial memory
  • Activation of both inhibitory and excitatory projections from the CA3 region of the hippocampus to the anterodorsal thalamic nucleus leading to inactivation and active inactivation of the anterodorsal thalamic nucleus is necessary to recall remote memory
  • Inactivation of the inhibitory projection from the CA3 region of the hippocampus to the anterodorsal thalamic nucleus impairs memory performance, but only at remote timepoints — such inactivation leads to increased activity in the anterodorsal thalamic nucleus.2

Inactivation of the laterodorsal thalamus during memory consolidation impairs remote memory

In contrast to the lowered activity of the anterodorsal thalamic nucleus when experiencing remote memory, the laterodorsal thalamus is more active and has a stronger connectivity with the rest of the network related to recent timepoints.3

Inactivation of the laterodorsal thalamus during the memory consolidation period (when there is a rearrangement of circuits) leads to memory impairment at remote timepoints.3

Professor Vetere concluded that:

  • Both the anterodorsal and laterodorsal thalamic nuclei are required for recall of recent memory
  • Memory consolidation leads to active inhibition of the anterodorsal thalamic nucleus and activation of the laterodorsal thalamic nucleus

 

Why activation of the anterodorsal and laterodorsal thalamic nuclei have different effects on fear memory

Identification of the molecular and cellular mechanisms responsible for fear memory will reveal new therapeutic targets for anxiety, depression, and PTSD

Professor Vetere and her colleagues believe the different effects on fear memory when the anterodorsal and laterodorsal thalamic nuclei are activated has to do with the spatial detail, and therefore the experience of remote fear memory in safe environments. They are therefore now investigating individual cells within the anterodorsal and laterodorsal thalamic nuclei.

It is hoped that future identification of the molecular and cellular mechanisms through which fear influences the formation, storage, and retrieval of memories will reveal new therapeutic targets for the treatment of anxiety, depression, and PTSD.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References
  1. Wheeler AL, et al. Identification of a functional connectome for long-term fear memory in mice. PLOS Computational Biology 2013;9(1):e1002853.
  2. Vetere G, et al. An inhibitory hippocampal-thalamic pathway modulates remote memory retrieval. Nat Neurosci. 2021;24(5):685–693.
  3. Vetere G, et al. Chemogenetic interrogation of a brain-wide fear memory network in mice. Neuron 2017
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