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ACNP 58Th Annual Meeting: Poster Session I www.nature.com/npp ABSTRACTS COLLECTION ACNP 58th Annual Meeting: Poster Session I Neuropsychopharmacology (2019) 44:78–229; https://doi.org/10.1038/s41386-019-0545-y Sponsorship Statement: Publication of this supplement is sponsored by the ACNP. Presenting author disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting. M1 mutagenesis of Top2B, and imaging-based assays to detect the formation of stimulus-induced DSBs in cultured primary neurons. The Role of Activity-Induced DNA Breaks in Neuronal Results: Our ChIP-seq studies in vivo recapitulated our previous Physiology and Learning Behaviors observations in cultured primary neurons, and indicated that physiological learning behaviors also cause DSB formation within Ilse Delint Ramirez, Richard Rueda, Charlotte Marchioni, Ryan the promoters of neuronal IEGs. Interestingly however, we also Stott, Oleg Kritskiy, Jacob Jaffe, Li-Huei Tsai, Ram Madabhushi* observed DSB accumulation at many new loci that were not detected in cultured primary neurons. Gene ontology analysis revealed a significant enrichment of biological processes related University of Texas Southwestern Medical Center, Dallas, Texas, to synaptic transmission and synaptic function within loci that United States 1234567890();,: incur DSBs in the hippocampus following CFC. The formation of stimulus-induced DSBs in the hippocampus was attenuated in Background: Neuronal activity triggers the rapid expression of Top2bCKO mice, suggesting that Top2B also generates DSBs immediate early genes that play important roles in experience- in response to physiological neuronal activity in vivo. Furthermore, driven synaptic changes, learning, and memory. While immediate fi fi Top2bCKO mice showed signi cant defects in both contextual early genes are primed for rapid induction, the speci cimpediments and cued fear-conditioning tasks, indicating defects in long-term to their expression under basal conditions, and the mechanisms that memory formation. Finally, our targeted mass spectrometry relieve these constraints are still poorly understood. Recently, we experiments revealed that the activity of Top2B is modulated reported that activity-dependent stimulation of cultured primary through activity-dependent changes in Top2B phosphorylation. neurons triggers the formation of DNA double strand breaks (DSBs) Conclusions: Together, our results suggest that physiological in the promoters of a subset of immediate early genes, including learning behaviors trigger the formation of Top2B-mediated DSBs at Fos, Npas4, and Egr1. These activity-induced DSBs are generated by fi β speci c genomic locations, that the activity of Top2B is modulated the type II topoisomerase, topoisomerase II (Top2B), and we to generate DSBs, and that the formation of these DSBs is necessary showed surprisingly that Top2B-mediated DSBs facilitate the rapid for the activation of stimulus-dependent gene transcription induction of these aforementioned IEGs. Together, these results raise programs and for the development of adaptive behaviors. intriguing questions about the mechanisms that regulate the fi Keywords: Topoisomerase, Early Response Genes, Gene Tran- formation of stimulus-induced DSBs at speci c genomic loci and scription, DNA Double Strand Breaks whether the formation of these DSBs has a role in neuronal Disclosure: Nothing to disclose. functions, including in the development of adaptive behaviors. Methods: To assess whether stimulus-induced DSBs are also formed at specific genomic loci in vivo, we subjected two-month old C57BL/6 mice to a contextual fear conditioning (CFC) M2 paradigm, following which we dissected the hippocampi and performed ChIP-seq with antibodies against the DSB marker, Verubecestat-Induced Brain Volume Loss Occurs Rapidly and γH2AX. We have obtained a mouse model (Top2bf/f mice) in Only in Amyloid-Enriched Brain Regions in EPOCH, a Phase 3 which the expression of Cre recombinase allows for the Trial in Mild-To-Moderate Alzheimer’s Disease Patients conditional deletion of endogenous Top2b. To understand whether DSBs formed in vivo are also a result of Top2B activity, Abstract not included. conditional Top2bf/f mice were crossed with CaMKIIα-Cre mice, which causes for the deletion of Top2b from excitatory forebrain neurons in adult mice. The resultant Top2bCKO mice were subject M3 to CFC at 8 weeks of age, following which hippocampal lysates were prepared and γH2AX levels were assessed by western blotting. To understand whether the formation of activity-induced Prenatal Stress Exposure Modulates Resting State Functional DSBs affects learning behaviors, two month-old male Top2bCKO Connectivity by Sex in Midlife mice (12 animal per group) were subjected to various behavioral paradigms, including open-field and light-dark tests, object Kyoko Konishi*, Justine Cohen, Emily Jacobs, Anne Remington, recognition and object location tasks, and contextual and cued Harlyn Aizley, Susan Whitfield-Gabrieli, Jill Goldstein fear conditioning tests. Finally, molecular mechanisms that regulate the formation of Top2B-mediated DSBs were investigated Harvard Medical School, Massachusetts General Hospital, Boston, through a combination of targeted mass spectrometry, Massachusetts, United States © American College of Neuropsychopharmacology 2019 ACNP 58th Annual Meeting: Poster Session I 79 these results suggest that menopause may present a critical Background: Over the lifespan, many factors contribute to risk period of accelerated brain aging in women and that prenatal and resilience in healthy brain aging, even beginning in fetal stress exposure may increase vulnerability to these changes. development. There is growing evidence that brain development Uniquely, at a human population-level, findings demonstrated beginning in utero has implications for brain aging, potentially that prenatal stress exposure is significantly associated with sex through the disruption of stress-immune pathways, known as differences, that implicate reproductive aging, in the intrinsic prenatal stress models of brain aging. The default mode network functional connectivity in the brain. (DMN) in the brain, which primarily includes medial prefrontal Keywords: Prenatal Stress, Sex Differences, Menopause, Default cortex (mPFC), posterior cingulate cortex (PCC), lateral parietal Mode Network (DMN), Resting-state fMRI cortex (LP), and hippocampus (HIPP), some areas which are shared Disclosure: Nothing to disclose. with stress circuitry regions, has been found to be important for cognitive aging and vulnerable to early Alzheimer’s disease pathology. In aging, intrinsic functional connectivity within the M4 DMN breaks down, with decreased connectivity between anterior and posterior regions as well as within posterior regions of the network. In addition to chronological aging, women undergo Optogenetic Inactivation of Prefrontal Cortex During reproductive aging, during which they experience a depletion of Intertemporal Choice Reveals Unique Roles for This Structure sex steroid hormones such as estradiol, which we previously in Young and Aged Rat Decision Making demonstrated is directly related to decreased memory perfor- mance and reorganization of functional memory circuitries. Here, Caesar Hernandez*, Chase Labiste, Alexa-Rae Wheeler, Tyler we aim to integrate previous work on brain aging through a Ten Eyck, Noelle Wright, Sara Betzhold, Barry Setlow, Jennifer combined investigation of prenatal stress exposures, reproductive Bizon aging in women, and the DMN. We tested the impact of preeclampsia (PE) or fetal growth restriction (FGR) on sex University of Florida, Gainesville, Florida, United States differences in the intrinsic functional connectivity of the DMN in early midlife as women transition through menopause. Background: The medial prefrontal cortex (mPFC) is the rodent Methods: Two hundred and twelve middle-aged adults (age homologue of human dorsolateral prefrontal cortex and is critical range 45–55; 106 women and 106 men) recruited from the New for mediating executive functions such as working memory and England Family Study (NEFS) cohort underwent clinical assess- cognitive flexibility. These executive functions are important for ment, blood collection, and fMRI scanning. NEFS is a unique supporting cost-benefit decision making such as whether to population-based prenatal cohort born between the years 1959 choose an option that yields a small reward delivered immediately and 1966. Their mothers were followed through pregnancy and versus an option that yields a larger reward delivered at some the cohort have been followed since birth for > 50 years, point in the future (intertemporal choice). Previous work in both contributing to an extensive dataset comprised of prenatal and rats and humans indicates that older subjects exhibit greater developmental information. Subjects were siblings discordant for preference than young for large, delayed over small, immediate prenatal stress exposure (PE or FGR), such that one sibling was rewards. These preferences correlate with age-associated impair- exposed and the other was not. STRAW-10 criteria and serology ments on a PFC-dependent task of cognitive flexibility, suggesting were used to determine pre-, peri and post-menopausal staging. PFC dysfunction in aging contributes to altered intertemporal Subjects underwent a resting state fMRI scan and data were decision making. The current study used an optogenetic approach analyzed using ROI-to-ROI-based functional connectivity
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