Evolutionarily divergent mTOR remodels the translatome to drive rapid wound closure and regeneration

An outstanding mystery in biology is why some species, such as the axolotl, can scarlessly heal and regenerate tissues while most mammals cannot. Here, we demonstrate that rapid activation of protein synthesis is a unique, and previously uncharacterized, feature of the injury response critical for limb regeneration in the axolotl (A. mexicanum). By applying polysome sequencing, we identify hundreds of transcripts, including antioxidants and ribosome components, which do not change in their overall mRNA abundance but are selectively activated at the level of translation from pre-existing mRNAs in response to injury. In contrast, we show that protein synthesis is not activated in response to digit amputation in the non-regenerative mouse. We further identify the mTORC1 pathway as a key upstream signal that mediates this regenerative translation response in the axolotl. Inhibition of this pathway is sufficient to suppress translation and axolotl regeneration. Surprisingly, although mTOR is highly evolutionarily conserved, we discover unappreciated expansions in mTOR protein sequence among urodele amphibians. By engineering an axolotl mTOR in human cells, we demonstrate that this change creates a hypersensitive kinase that may allow axolotls to maintain this pathway in a highly labile state primed for rapid activation. This may underlie metabolic differences and nutrient sensing between regenerative and non-regenerative species that are key to regeneration. Together, these findings highlight the unanticipated impact of the translatome on orchestrating the early steps of wound healing in highly regenerative species and provide a missing link in our understanding of vertebrate regenerative potential.

Modulating amygdala activation to traumatic memories with a single ketamine infusion

NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be stored in an altered form. This concept might have significant clinical implications in treating PTSD. Using amygdala activity as a major biomarker of fear response, we tested the potential of a single subanesthetic intravenous infusion of ketamine (NMDA receptor antagonist) to enhance post-retrieval extinction of PTSD trauma memories. Post-extinction, ketamine recipients (vs midazolam) showed a lower amygdala and hippocampus reactivation to trauma memories. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus, with no change in amygdala-vmPFC connectivity, which suggests that ketamine may enhance post-retrieval extinction of PTSD trauma memory in humans. These findings demonstrate the capacity to rewrite human traumatic memories and to modulate the fear response for at least 30 days post-extinction.

NON-LINEAR SUSCEPTIBILITY TO INTERFERENCES IN DECLARATIVE MEMORY FORMATION

After encoding, memories go through a labile state followed by a stabilization process known as consolidation. Once consolidated they can enter a new labile state after the presentation of a reminder of the original memory, followed by a period of re-stabilization (reconsolidation). During these periods of lability the memory traces can be modified. Currently, there are studies that show a rapid stabilization after 30 min, while others show that stabilization occurs after longer periods (e.g. 6 h). Here we investigate the effect of an interference treatment on declarative memory consolidation, comparing distinct time intervals after acquisition. On day 1, participants learned a list of non- syllable pairs (List 1). Immediately after, 30 min, 3 h or 8 h later, they received an interference list (List 2) that acted as an amnesic agent. On day 2 (48 h after training) participants had to recall List 1 first, followed by List 2. We found that the List 1 memory was susceptible to interference when the List 2 was administered immediately or 3 h after learning; however, shortly after acquisition (e.g. 30 min) the List 1 memory becomes transiently protected against interference. We propose the possibility that this rapid memory protection could be induced by a fast and transient neocortical integration (where the memory is transiently protected) becoming partially independent from the hippocampus followed by a hippocampal re-engagement where the memory becomes susceptible to interferences again. Our results open a discussion about the contribution of molecular and systemic aspects to memory consolidation.

Investigating the efficacy of the reminder-extinction procedure to disrupt contextual threat memories in humans using immersive Virtual Reality

Upon reactivation, consolidated memories can enter a temporary labile state and require restabilisation, known as reconsolidation. Interventions during this reconsolidation period can disrupt the reactivated memory. However, it is unclear whether different kinds of memory that depend on distinct brain regions all undergo reconsolidation. Evidence for reconsolidation originates from studies assessing amygdala-dependent memories using cue-conditioning paradigms in rodents, which were subsequently replicated in humans. Whilst studies providing evidence for reconsolidation of hippocampus-dependent memories in rodents have predominantly used context conditioning paradigms, studies in humans have used completely different paradigms such as tests for wordlists or stories. Here our objective was to bridge this paradigm gap between rodent and human studies probing reconsolidation of hippocampus-dependent memories. We modified a recently developed immersive Virtual Reality paradigm to test in humans whether contextual threat-conditioned memories can be disrupted by a reminder-extinction procedure that putatively targets reconsolidation. In contrast to our hypothesis, we found comparable recovery of contextual conditioned threat responses, and comparable retention of subjective measures of threat memory, episodic memory and exploration behaviour between the reminder-extinction and standard extinction groups. Our result provide no evidence that a reminder before extinction can prevent the return of context conditioned threat memories in humans.

Generalising reconsolidation: Spatial context and prediction error

Activating a previously consolidated memory trace brings it back into a labile state where it must then undergo a re-stabilisation process known as reconsolidation. During this process memories are susceptible to interference and may be updated with new information. In the studies showing this effect in human episodic memory, the reconsolidation process has been triggered primarily using spatial context or prediction error manipulations to reactivate an established memory. However, these studies have produced conflicting results, showing both that spatial context is necessary and sufficient to trigger reconsolidation and that prediction error is necessary and sufficient to trigger the process. We examined this conflict in two experiments, one investigating the role of context cues and another investigating the role of prediction error. In Experiment 1, spatial context triggered a reconsolidation process and prediction error was irrelevant. In Experiment 2, prediction error triggered reconsolidation, and spatial context cues were irrelevant. These findings replicate prior research but add to the puzzle concerning the roles of these two means of triggering reconsolidation.

Generalizing Reconsolidation: Spatial Context and Prediction Error

Activating a previously consolidated memory trace brings it back into a labile state where it mustthen undergo a re-stabilization process known as reconsolidation. During this process memoriesare susceptible to interference and may be updated with new information. In the studies showingthis effect in human episodic memory, the reconsolidation process has been triggered primarilyby using spatial context or prediction error manipulations to reactivate an established memory.However, these studies have produced conflicting results, showing both that spatial context isnecessary and sufficient to trigger reconsolidation and that prediction error is necessary andsufficient to trigger the process. We examined this conflict in two experiments, one investigatingthe role of context cues and another investigating the role of prediction error. In Experiment 1,spatial context triggered a reconsolidation process and prediction error was irrelevant. InExperiment 2, prediction error triggered reconsolidation, and spatial context cues were irrelevant.These findings replicate prior research but add to the puzzle concerning the roles of these twomeans of triggering reconsolidation.

The surprising subtleties of changing fear memory: a challenge for translational science

Current pharmacological and psychological treatments for disorders of emotional memory only dampen the affective response while leaving the original fear memory intact. Under adverse circumstances, these original memories regain prominence, causing relapses in many patients. The (re)discovery in neuroscience that after reactivation consolidated fear memories may return to a transient labile state, requiring a process of restabilization in order to persist, offers a window of opportunity for modifying fear memories with amnestic agents. This process, known as memory reconsolidation, opens avenues for developing a revolutionary treatment for emotional memory disorders. The reconsolidation intervention challenges the dominant pharmacological and psychological models of treatment: it is only effective when the amnestic drug is given in conjunction with memory reactivation during a specific time window, and a modification of cognitive processes is a boundary condition for changing fear. Notwithstanding the dramatic effects of targeting memory reconsolidation in the laboratory (i.e. proof of principle), the greatest hurdle to overcome is that the success of the manipulation depends on subtle differences in the reactivation procedure. These experimental parameters cannot be easily controlled in clinical practice. In harnessing the clinical potential of memory reconsolidation, a heuristic for bi-directionally translating behavioural neuroscience and clinical science is proposed. This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.

Transient acidosis while retrieving a fear-related memory enhances its lability

Attenuating the strength of fearful memories could benefit people disabled by memories of past trauma. Pavlovian conditioning experiments indicate that a retrieval cue can return a conditioned aversive memory to a labile state. However, means to enhance retrieval and render a memory more labile are unknown. We hypothesized that augmenting synaptic signaling during retrieval would increase memory lability. To enhance synaptic transmission, mice inhaled CO2 to induce an acidosis and activate acid sensing ion channels. Transient acidification increased the retrieval-induced lability of an aversive memory. The labile memory could then be weakened by an extinction protocol or strengthened by reconditioning. Coupling CO2 inhalation to retrieval increased activation of amygdala neurons bearing the memory trace and increased the synaptic exchange from Ca2+-impermeable to Ca2+-permeable AMPA receptors. The results suggest that transient acidosis during retrieval renders the memory of an aversive event more labile and suggest a strategy to modify debilitating memories.