Epigenomic (re)programming of the brain and behavior by ovarian hormones
Rhythmic changes in sex hormone levels across the ovarian cycle exert powerful effects on the brain and behavior, and confer female-specific risks for neuropsychiatric conditions. In this talk, Dr. Kundakovic will discuss the role of fluctuating ovarian hormones as a critical biological factor contributing to the increased depression and anxiety risk in women. Cycling ovarian hormones drive brain and behavioral plasticity in both humans and rodents, and the talk will focus on animal studies in Dr. Kundakovic’s lab that are revealing the molecular and receptor mechanisms that underlie this female-specific brain dynamic. She will highlight the lab’s discovery of sex hormone-driven epigenetic mechanisms, namely chromatin accessibility and 3D genome changes, that dynamically regulate neuronal gene expression and brain plasticity but may also prime the (epi)genome for psychopathology. She will then describe functional studies, including hormone replacement experiments and the overexpression of an estrous cycle stage-dependent transcription factor, which provide the causal link(s) between hormone-driven chromatin dynamics and sex-specific anxiety behavior. Dr. Kundakovic will also highlight an unconventional role that chromatin dynamics may have in regulating neuronal function across the ovarian cycle, including in sex hormone-driven X chromosome plasticity and hormonally-induced epigenetic priming. In summary, these studies provide a molecular framework to understand ovarian hormone-driven brain plasticity and increased female risk for anxiety and depression, opening new avenues for sex- and gender-informed treatments for brain disorders.
Nr4a1-mediated morphological adaptations in Ventral Pallidal projections to Mediodorsal Thalamus support cocaine intake and relapse-like behaviors
Growing evidence suggests the ventral pallidum (VP) is critical for drug intake and seeking behaviors. Receiving dense projections from the nucleus accumbens as well as dopamine inputs from the midbrain, the VP plays a central role in the control of motivated behaviors. Repeated exposure to cocaine is known to alter VP neuronal firing and neurotransmission. Surprisingly, there is limited information on the molecular adaptations occurring in VP neurons following cocaine intake.To provide insights into cocaine-induced transcriptional alterations we performed RNA-sequencing on VP of mice following cocaine self-administration. Gene Ontology analysis pointed toward alterations in dendrite- and spinerelated genes. Subsequent transcriptional regulator analysis identified the transcription factor Nr4a1 as a common regulator for these sets of morphology-related genes.Consistent with the central role of the VP in reward, its neurons project to several key regions associated with cocaine-mediated behaviors. We thus assessed Nr4a1 expression levels in various projection populations.Following cocaine self-administration, VP neurons projecting to the mediodorsal thalamus (MDT) showed significantly increased Nr4a1 levels. To further investigate the role of Nr4a1 in cocaine intake and relapse, we bidirectionally manipulated its expression levels selectively in VP neurons projecting to the MDT. Increasing Nr4a1 levels resulted in enhanced relapse-like behaviors accompanied by a blockage of cocaine-induced spinogenesis.However, decreasing Nr4a1expression levels completely abolished cocaine intake and consequential relapse-like behaviors. Together, our preliminary findings suggest that drug-induced neuronal remodeling in pallido-thalamic circuits is critical for cocaine intake and relapse-like behaviors.