Targeting anticipatory neurogenesis to maintain cognitive reserve

Memory imprecision is a hallmark of age-related cognitive decline and mild-cognitive impairment (MCI) and is characterized by increased memory interference and decreased stability of memory representations. Evidence from humans, non-human primates and rodents demonstrate reduced hippocampal neurogenesis, excitation-inhibition imbalance and inflexible hippocampal remapping during age-related cognitive decline and MCI. Developing strategies to reverse cognitive decline during aging and Mild Cognitive Impairment necessitates an understanding of molecular, cellular, circuit and network mechanisms that support memory functions of the hippocampus. Over the last decade we have built a multifaceted program grounded in basic neuroscience that is aimed at improving memory in aging and MCI. We have demonstrated how we can Rejuvenate the aged hippocampus by selectively increasing neurogenesis and how we can Re-engineer connectivity of aged inhibitory microcircuits to improve memory precision in aging. Ongoing efforts include strategies to Repairing neurogenic niche fitness by targeting intercellular communication in the aging hippocampus. In today’s talk I will present a fourth approach catalyzed by our discovery of the first transcriptional regulator of neural stem cell expansion in the adult hippocampus. We will present data in support of this claim and convey how this discovery may guide strategies to maintain cognitive reserve embodied in the pool of neural stem cells in the adult hippocampus.

Episodic memory enhancement versus impairment is determined by contextual similarity across events

For over a century, stability of spatial context across related episodes has been considered a source of memory interference, impairing memory retrieval. However, contemporary memory integration theory generates a diametrically opposite prediction. Here, we aimed to resolve this discrepancy by manipulating local context similarity across temporally disparate but related episodes and testing the direction and underlying mechanisms of memory change. A series of experiments show that contextual stability produces memory integration and marked reciprocal strengthening. Variable context, conversely, seemed to result in competition such that new memories become enhanced at the expense of original memories. Interestingly, these patterns were virtually inverted in an additional experiment where context was reinstated during recall. These observations 1) identify contextual similarity across original and new memories as an important determinant in the volatility of memory, 2) present a challenge to classic and modern theories on episodic memory change, and 3) indicate that the sensitivity of context-induced memory changes to retrieval conditions may reconcile paradoxical predictions of interference and integration theory.

Consolidation/reconsolidation therapies for the prevention and treatment of PTSD and re-experiencing: a systematic review and meta-analysis

Translational research highlights the potential of novel 'memory consolidation/reconsolidation therapies' to treat re-experiencing symptoms and post-traumatic stress disorder (PTSD). This systematic review and meta-analysis assessed the efficacy of so-called memory consolidation/reconsolidation therapies in randomised controlled trials (RCTs) for prevention and treatment of PTSD and symptoms of re-experiencing in children and adults (PROSPERO: CRD42020171167). RCTs were identified and rated for risk of bias. Available data was pooled to calculate risk ratios (RR) for PTSD prevalence and standardised mean differences (SMD) for PTSD/re-experiencing severity. Twenty-five RCTs met inclusion criteria (16 prevention and nine treatment trials). The methodology of most studies had a significant risk of bias. We found a large effect of reconsolidation interventions in the treatment of PTSD (11 studies, n = 372, SMD: −1.42 (−2.25 to −0.58), and a smaller positive effect of consolidation interventions in the prevention of PTSD (12 studies, n = 2821, RR: 0.67 (0.50 to 0.90). Only three protocols (hydrocortisone for PTSD prevention, Reconsolidation of Traumatic Memories (RTM) for treatment of PTSD symptoms and cognitive task memory interference procedure with memory reactivation (MR) for intrusive memories) were superior to control. There is some emerging evidence of consolidation and reconsolidation therapies in the prevention and treatment of PTSD and intrusive memories specifically. Translational research should strictly adhere to protocols/procedures describing precise reconsolidation conditions (e.g. MR) to both increase the likelihood of positive findings and more confidently interpret negative findings of putative reconsolidation agents.

Autophagy in DG engrams mediates Rac1-dependent forgetting during aging via microglia-mediated synapse elimination

Engrams are considered to be substrates for memory storage, and the functional dysregulation of the engrams leads to cognition impairment. However, the pathological changes of the engrams leading to forgetting, which typically involves a failure in memory retrieval, remains unclear. Here we found that the expression of autophagy protein 7 (Atg7) in dentate gyrus (DG) engrams was dramatically increased in aged mice, leading to the activation of surrounding microglia and impair retrieval of conditioned fear memory. Using transcriptomic and fluorescence in situ hybridization analyses, we demonstrated Toll-like receptor (TLR) pathway were upregulated in DG microglia by overexpressing ATG7 in DG engrams. TLR2/4 in the microglia mediates the excessive synapse elimination and impaired retrieval of fear memory induced by ATG7-depedent autophagy in DG engrams. The expression of Rac1, a Rho-GTPases which mediates active forgetting, was upregulated in aged engrams. Optogenetic activation of Rac1 in DG engrams promoted the expression of ATG7 and autophagy in the engrams, the activation of microglia, and thus impaired the retrieval of fear memory. Interference of the Atg7 expression in the engram and microglia activation prevented the impairment of fear memory retrieval induced by activation of Rac1 in DG engrams. Together, our findings revealed autophagy-dependent remodeling of DG engrams by microglia as a novel interference mechanism of memory retrieval.

Abrupt hippocampal remapping signals resolution of memory interference

Remapping refers to a decorrelation of hippocampal representations of similar spatial environments. While it has been speculated that remapping may contribute to the resolution of episodic memory interference in humans, direct evidence is surprisingly limited. We tested this idea using high-resolution, pattern-based fMRI analyses. Here we show that activity patterns in human CA3/dentate gyrus exhibit an abrupt, temporally-specific decorrelation of highly similar memory representations that is precisely coupled with behavioral expressions of successful learning. The magnitude of this learning-related decorrelation was predicted by the amount of pattern overlap during initial stages of learning, with greater initial overlap leading to stronger decorrelation. Finally, we show that remapped activity patterns carry relatively more information about learned episodic associations compared to competing associations, further validating the learning-related significance of remapping. Collectively, these findings establish a critical link between hippocampal remapping and episodic memory interference and provide insight into why remapping occurs.

Association of physical activity on memory interference: Boston Puerto Rican Health Study

Background: The objective of this study was to evaluate the association between habitual physical activity engagement on memory interference. The present analysis used cross-sectional data from the Boston Puerto Rican Health Study (n=1,241; mean age= 57.2; 72.1% female). Methods: Physical activity was evaluated via self-report. Memory interference was evaluated using a word-list paradigm. The memory task included learning a list of 16 words (List A; 5 trials), followed by a distractor list (List B), and then an immediate recall of List A. Proactive interference occurs when preceding stimuli (e.g., Trial 1 and Trial 5 of List A) interferes with performance on a subsequent stimuli (List B). Retroactive interference occurs when subsequent stimuli (List B) interferes with the recall of previously encoded stimuli (Trial 5). Results: For proactive interference, there was no association between physical activity and the difference between performance on List B and Trial 1 of List A (β=0.00001; P=0.96). Similarly, for retroactive interference, there was no association between physical activity and the difference between the short delay recall and Trial 5 of List A (β=0.0002; P=0.50). Conclusion: The present study did not observe an association between habitual physical activity on attenuating memory interference.

Adaptive Repulsion of Long-Term Memory Representations Is Triggered by Event Similarity

We tested whether similarity between events triggers adaptive biases in how those events are remembered. We generated pairs of competing objects that were identical except in color and varied the degree of color similarity for the competing objects. Subjects ( N = 123 across four experiments) repeatedly studied and were tested on associations between each of these objects and corresponding faces. As expected, high color similarity between competing objects created memory interference for object–face associations. Strikingly, high color similarity also resulted in a systematic bias in how the objects themselves were remembered: Competing objects with highly similar colors were remembered as being further apart (in color space) than they actually were. This repulsion of color memories increased with learning and served a clear adaptive purpose: Greater repulsion was associated with lower associative-memory interference. These findings reveal that similarity between events triggers adaptive-memory distortions that minimize interference.