Das, R. K. | Search bioRxiv

bioRxiv2018

Modulation of naturalistic maladaptive memories using behavioural and pharmacological reconsolidation-interfering strategies: A systematic review and meta-analysis of clinical and ‘sub-clinical’ studies

Consolidated memories can undergo enduring modification through retrieval-dependent treatments that modulate reconsolidation. This has been suggested to represent a potentially transformative clinical strategy for weakening or overwriting the maladaptive memories that underlie substance use and anxiety/trauma-related disorders. However, the ability to modulate naturalistic maladaptive memories may be limited by boundary conditions imposed on reconsolidation by the nature of these memories. As such, the true potential of reconsolidation therapy is currently unknown. Here, we report a meta-analyses of behavioural and pharmacological studies examining retrieval-dependent modulation of reward and threat memories in (sub)clinical substance use and anxiety/trauma respectively.\n\nOf 4936 publications assessed for eligibility, 7 studies of substance use, and 9 of anxiety (phobia) and trauma-related symptoms were included in the meta-analyses. Overall, the findings were in the predicted direction, with the majority of effect sizes favouring the Retrieval + Treatment condition. However, the magnitude of effects depended upon the nature of the treatment type, with pharmacological interventions (relative to behavioural strategies) showing a clearer beneficial effect in studies of phobia/trauma and post-retrieval behavioural strategies, a (significantly) larger effect in substance use studies. However, high levels of heterogeneity and small sample sizes limit the strength of conclusions that can be drawn at this stage of inquiry. We hope this review will provide an impetus to address these issues in future research.

neuroscience↗

bioRxiv2017

A deep mutational scan of an acidic activation domain

Transcriptional activation domains are intrinsically disordered peptides with little primary sequence conservation. These properties have made it difficult to identify the sequence features that define activation domains. For example, although acidic activation domains were discovered 30 years ago, we still do not know what role, if any, acidic residues play in these peptides. To address this question we designed a rational mutagenesis scheme to independently test four sequence features theorized to control the strength of activation domains: acidity (negative charge), hydrophobicity, intrinsic disorder, and short linear motifs. To test enough mutants to deconvolve these four features we developed a method to quantify the activities of thousands of activation domain variants in parallel. Our results with Gcn4, a classic acidic activation domain, suggest that acidic residues in particular regions keep two hydrophobic motifs exposed to solvent. We also found that the specific activity of the Gcn4 activation domain increases during amino acid starvation. Our results suggest that Gcn4 may have evolved to have low activity but high inducibility. Our results also demonstrate that high-throughput rational mutation scans will be powerful tools for unraveling the properties that control how intrinsically disordered proteins function.

systems biology↗