The Miller Lab is working to develop new medications for the treatment of disorders marked by persistent, unwanted memories – specifically substance use disorder (SUD; addiction) and posttraumatic stress disorder (PTSD). Mechanistically, our efforts are large focused on epigenetic and synaptic structural players.
DEVELOPMENT OF THERAPEUTICS TO PREVENT ADDICTION RELAPSE
Dr. Miller has long been interested in ways to selectively disrupt drug-associated memories (Reconsolidation; Miller and Marshall, Neuron, 2005) and the mechanisms that contribute to the persistence of memory (DNA methylation; Miller et al, Nature Neuroscience, 2010). In bringing these two areas together, the Miller Lab made the surprising discovery that memories associated with the commonly abused stimulant, methamphetamine, employ a unique, actin-based storage mechanism in the brain’s emotional memory center, the amygdala, that allows for their selective disruption (Young et al, Biological Psychiatry, 2014). This was followed by identification of nonmuscle myosin II (NMII) as a viable therapeutic target (Young et al, Molecular Psychiatry, 2015) and we are now in the middle of a drug development program supported by the NIH’s Blueprint Neurotherapeutics Network to develop a clinically safe NMII inhibitor. The goal is to enter a Phase 1a safety trial in 2020.
REGULATION OF TRAUMATIC MEMORY RELATED TO PTSD
We recently developed an animal model with PTSD-like features, including differential susceptibility, which has been replicated by other groups. The stress susceptible subgroup displays persistent, stress-enhanced fear memory, hyperarousal, amygdala hyperactivation and differential expression of genes with known polymorphisms in human PTSD genomic studies (Sillivan et al, Biological Psychiatry, 2017). Importantly, the stress susceptible population can be identified by training behavior, removing the need for additional phenotyping that introduces a molecular confound. Because the model was developed in an inbred mouse line (c57’s), it’s an excellent opportunity to investigate epigenetic mechanisms. To date we have largely focused on noncoding RNAs, including miRNAs. Small RNA-sequencing integrated with quantitative proteomics revealed a panel of miRNAs persistently upregulated in the amygdala of stress susceptible mice. We recently completed a study demonstrating a functional role for one of these miRNAs, which is also expressed in the human amygdala. Working with our collaborators, we also discovered the miRNA’s passenger strand is elevated in serum of a Dutch military cohort diagnosed with PTSD six months after a combat deployment to Afghanistan, indicating this miRNA may be a therapeutic target and biomarker for PTSD. Efforts are now shifting to in vivo calcium imaging and manipulation of the activity-dependent neuronal ensembles regulating differential susceptibility to stress.