title: Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation.
abstract: Posttraumatic stress disorder is characterized by hyperarousal, sensory processing impairments, sleep disturbances and altered fear regulation; phenotypes associated with changes in brain oscillatory activity. Molecules associated with activity-dependent plasticity, including brain-derived neurotrophic factor (BDNF), may regulate neural oscillations by controlling synaptic activity. BDNF synthesis includes production of multiple Bdnf transcripts, which contain distinct 5' noncoding exons. We assessed arousal, sensory processing, fear regulation and sleep in animals where BDNF expression from activity-dependent promoter IV is disrupted (Bdnf-e4 mice). Bdnf-e4 mice display sensory hyper-reactivity and impaired electrophysiological correlates of sensory information processing as measured by event-related potentials (ERP). Utilizing electroencephalogram, we identified a decrease in slow-wave activity during non-rapid eye movement sleep, suggesting impaired sleep homeostasis. Fear extinction is controlled by hippocampal-prefrontal cortical BDNF signaling, and neurophysiological communication patterns between the hippocampus (HPC) and medial prefrontal cortex (mPFC) correlate with behavioral performance during extinction. Impaired fear extinction in Bdnf-e4 mice is accompanied by increased HPC activation and decreased HPC-mPFC theta phase synchrony during early extinction, as well as increased mPFC activation during extinction recall. These results suggest that activity-dependent BDNF signaling is critical for regulating oscillatory activity, which may contribute to altered behavior.
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Hill
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: N F
authors.initials: NF
authors.lastname: Hardy
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: D V
authors.initials: DV
authors.lastname: Jimenez
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Maynard
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Kardian
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Pollock
authors.affiliation: Sheppard Pratt-Lieber Research Institute, Inc., Baltimore, MD, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Schloesser
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Martinowich
mesh_terms: D000818:Animals; D001143:Arousal / Q000235:genetics* / Q000502:physiology; D058256:Brain Waves / Q000235:genetics* / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D004569:Electroencephalography; D005071:Evoked Potentials / Q000235:genetics* / Q000502:physiology; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000503:physiopathology; D051379:Mice; D017397:Prefrontal Cortex / Q000503:physiopathology; D065808:Prepulse Inhibition; D011401:Promoter Regions, Genetic; D013216:Reflex, Startle; D012890:Sleep / Q000235:genetics* / Q000502:physiology; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics* / Q000503:physiopathology; D013826:Theta Rhythm / Q000235:genetics / Q000502:physiology
chemical_list: D019208:Brain-Derived Neurotrophic Factor