title: Experience-Dependent Induction of Hippocampal ΔFosB Controls Learning.
abstract: The hippocampus (HPC) is known to play an important role in learning, a process dependent on synaptic plasticity; however, the molecular mechanisms underlying this are poorly understood. ΔFosB is a transcription factor that is induced throughout the brain by chronic exposure to drugs, stress, and variety of other stimuli and regulates synaptic plasticity and behavior in other brain regions, including the nucleus accumbens. We show here that ΔFosB is also induced in HPC CA1 and DG subfields by spatial learning and novel environmental exposure. The goal of the current study was to examine the role of ΔFosB in hippocampal-dependent learning and memory and the structural plasticity of HPC synapses. Using viral-mediated gene transfer to silence ΔFosB transcriptional activity by expressing ΔJunD (a negative modulator of ΔFosB transcriptional function) or to overexpress ΔFosB, we demonstrate that HPC ΔFosB regulates learning and memory. Specifically, ΔJunD expression in HPC impaired learning and memory on a battery of hippocampal-dependent tasks in mice. Similarly, general ΔFosB overexpression also impaired learning. ΔJunD expression in HPC did not affect anxiety or natural reward, but ΔFosB overexpression induced anxiogenic behaviors, suggesting that ΔFosB may mediate attentional gating in addition to learning. Finally, we found that overexpression of ΔFosB increases immature dendritic spines on CA1 pyramidal cells, whereas ΔJunD reduced the number of immature and mature spine types, indicating that ΔFosB may exert its behavioral effects through modulation of HPC synaptic function. Together, these results suggest collectively that ΔFosB plays a significant role in HPC cellular morphology and HPC-dependent learning and memory.
  
  
  CONCLUSIONS
  Consolidation of our explicit memories occurs within the hippocampus, and it is in this brain region that the molecular and cellular processes of learning have been most closely studied. We know that connections between hippocampal neurons are formed, eliminated, enhanced, and weakened during learning, and we know that some stages of this process involve alterations in the transcription of specific genes. However, the specific transcription factors involved in this process are not fully understood. Here, we demonstrate that the transcription factor ΔFosB is induced in the hippocampus by learning, regulates the shape of hippocampal synapses, and is required for memory formation, opening up a host of new possibilities for hippocampal transcriptional regulation.
authors.affiliation: Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Andrew L
authors.identifier: http://orcid.org/0000-0002-7879-5996
authors.initials: AL
authors.lastname: Eagle
authors.affiliation: Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Gajewski
authors.affiliation: Department of Anatomy, School of Medicine, Wonkwang University, Iksan, Jeonbuk, 570-749, South Korea, and.
authors.forename: Miyoung
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Megan E
authors.identifier: http://orcid.org/0000-0002-0216-758X
authors.initials: ME
authors.lastname: Kechner
authors.affiliation: Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Basma S
authors.initials: BS
authors.lastname: Al Masraf
authors.affiliation: Department of Psychology, University of California Los Angeles, Los Angeles, California 90095.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kennedy
authors.affiliation: Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Michelle S
authors.identifier: http://orcid.org/0000-0002-2372-1420
authors.initials: MS
authors.lastname: Mazei-Robison
authors.affiliation: Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, Michigan 48824, robiso45@msu.edu.
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Robison
mesh_terms: D000818:Animals; D001362:Avoidance Learning; D003213:Conditioning, Psychological / Q000502:physiology; D049229:Dendritic Spines / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004777:Environment; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D007858:Learning / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D013037:Spatial Behavior
chemical_list: C483819:Fosb protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; C528955:junD protein, mouse; D049452:Green Fluorescent Proteins
keywords: dendritic spines; hippocampus; learning; transcription; ΔFosB