Editors' ChoiceNeuroscience

Fear memory erasure through neuronal transplantation

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Science Translational Medicine  04 Jan 2017:
Vol. 9, Issue 371, eaal4986
DOI: 10.1126/scitranslmed.aal4986

Abstract

Transplant of immature inhibitory neurons can erase fear memories in adult mice.

For many years, neuroscientists considered memory to be a stable and durable mental function, with emotional “flashbulb” memories (those tied to salient events such as major traumas) thought to last the lifetime of the organism. Memories were shown to be encoded by long-lasting molecular and structural changes in neurons within relevant brain regions and were considered susceptible to degradation only through processes like age-related memory loss or neurodegeneration. However, work over the past 15 years has shown that a variety of behavioral and pharmacological manipulations could render a seemingly stable memory suddenly labile—to the point where every known metric pointed to erasure of the memory trace itself. In practical terms, although it is difficult to know whether the neural trace of the memory was itself eliminated, erasure of a memory is demonstrated by the inability of a range of behavioral manipulations to drive its recall (termed reinstatement). These studies have often focused on fear memories, in which previously neutral discrete cues or environmental contexts come to predict an aversive event. For example, pairing a neutral tone with an aversive foot shock leads to defensive behavior (i.e., freezing) when the tone is later replayed alone. Fear memories are furthermore easy to elicit and measure, rapidly-learned, and long-lasting, and yet they remain susceptible to memory erasure.

Building on a large body of research demonstrating the developmental plasticity and functional importance of inhibitory neuronal circuits for information processing in the amygdala, a core region in the brain that encodes fear memories, Yang and colleagues tested whether introduction of immature inhibitory neurons could alter the formation, extinction, and erasure of fear memories by interacting with the established neural circuitry in the amygdalae of adult mice. The authors found that “brain transplantation” of inhibitory neurons from embryonic mice led to reactivation of a more juvenile and plastic state in the amygdalae of adult mice, driven by integration of these immature neurons into established circuits. This led to changes in the capacity for synaptic plasticity (the cellular basis of memory) and changes in proteins providing the scaffolding around neurons that help maintain structural changes involved in memory formation. Most importantly, two weeks after immature neurons were introduced into the amygdala, attempts at extinguishing previously encoded fear memories resulted instead in erasure of these memories. Extinction is normally the process by which new fear inhibitory memories are created, which suppress expression of the original fear memories but do not erase them. However, in animals that received neuronal transplants, memories could not be reinstated after extinction training, indicating that fear memory erasure had happened instead.

This work sheds important new light on the nature and malleability of fear memories. Could induction of a more juvenile and plastic state in patients’ amygdalae provide the route for long-lasting and highly effective treatment with extinction-like psychotherapy? Potential new approaches—likely pharmacological, rather than through direct neuronal transplantation—for the treatment of pathological fear-related disorders, such as post-traumatic stress disorder, should be considered.

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