Project Grant F31MH146119

THYROID HORMONE SIGNALING IN THE EPIGENETIC EMBEDDING OF EARLY-LIFE STRESS - PROJECT SUMMARY/ABSTRACT EARLY-LIFE STRESS (ELS) DRAMATICALLY ELEVATES LIFETIME RISK FOR DEPRESSION, ANXIETY, AND OTHER PSYCHIATRIC DISORDERS BY SENSITIZING INDIVIDUALS TO FUTURE STRESSORS, BUT THE PATHWAYS THROUGH WHICH CHILDHOOD ADVERSITY BECOMES BIOLOGICALLY EMBEDDED REMAIN UNCLEAR. RECENT EVIDENCE POINTS TO THYROID HORMONE SIGNALING AS AN UNUSUALLY ACCESSIBLE ENTRY POINT INTO THIS PROBLEM. IN MICE, ELS REDUCES THYROID HORMONE LEVELS DURING A CRITICAL POSTNATAL WINDOW, AND POST-ELS SUPPLEMENTATION WITH THE SYNTHETIC THYROID HORMONE LEVOTHYROXINE RESTORES BEHAVIORAL RESILIENCE. USING A WELL-ESTABLISHED MOUSE MODEL THAT REPRODUCES KEY MOLECULAR AND BEHAVIORAL FEATURES OF HUMAN CHILDHOOD ADVERSITY, THIS STUDY WILL TEST THE HYPOTHESIS THAT TRANSIENT ELS-INDUCED THYROID HORMONE SUPPRESSION IMPRINTS LASTING EPIGENETIC STATES ENCODING STRESS HYPERSENSITIVITY IN THE NEURONS OF THE BASOLATERAL AMYGDALA (BLA), A BRAIN REGION INVOLVED IN EMOTIONAL PROCESSING. AIM 1 WILL EMPLOY INTEGRATED SINGLE-NUCLEUS TRANSCRIPTOMIC AND CHROMATIN ACCESSIBILITY PROFILING TO IDENTIFY CELL-TYPE-SPECIFIC CHANGES TO GENE REGULATION ACROSS STANDARD-REARED CONTROLS, ELS-EXPOSED MICE, MICE WITH PHARMACOLOGICAL THYROID SUPPRESSION, AND ELS-EXPOSED MICE TREATED WITH LEVOTHYROXINE. THESE COMPARISONS WILL PINPOINT THYROID HORMONE-SPECIFIC MOLECULAR SIGNATURES OF ELS AND HIGHLIGHT TARGETS FOR DEEPER MECHANISTIC STUDY IN THE SUBEQUENT AIMS. AIM 2 WILL COMBINE TRANSGENIC NUCLEAR TAGGING OF EXCITATORY AND INHIBITORY NEURONS WITH PROTEIN-DNA INTERACTION PROFILING TO MAP THYROID HORMONE RECEPTOR BINDING, COFACTOR RECRUITMENT, AND ASSOCIATED HISTONE MODIFICATIONS ACROSS DEVELOPMENT. THIS WILL ESTABLISH THE DIRECT MECHANISTIC CHAIN LINKING DISRUPTED THYROID HORMONE SIGNALING TO DURABLE EPIGENETIC REMODELING AT SPECIFIC LOCI. AIM 3 WILL USE VIRAL- MEDIATED KNOCKDOWN AND OVEREXPRESSION OF KEY THYROID HORMONE SIGNALING PATHWAY COMPONENTS IN BLA NEURONS, PAIRED WITH DETAILED BEHAVIORAL ASSAYS BEFORE AND AFTER ADULT STRESS EXPOSURE, TO DETERMINE WHETHER SUPPRESSION OF THYROID HORMONE SIGNALING IN THE BLA IS SUFFICIENT TO GENERATE STRESS VULNERABILITY AND WHETHER RESTORING THIS SIGNALING RESCUES RESILIENCE. PRELIMINARY DATA STRONGLY SUPPORT THIS FRAMEWORK: LEVOTHYROXINE TREATMENT ROBUSTLY NORMALIZES ELS-ALTERED CHROMATIN SITES IN BLA NEURONS. BECAUSE THYROID DYSFUNCTION CAN BE DETECTED WITH ROUTINE BLOOD TESTS AND TREATED WITH RELATIVELY INEXPENSIVE MEDICATIONS, THE RESULTS OF THIS WORK HAVE IMMEDIATE TRANSLATIONAL POTENTIAL FOR SCREENING, PREVENTION, AND TREATMENT STRATEGIES FOR INDIVIDUALS WHO EXPERIENCED CHILDHOOD ADVERSITY.