title: Presynaptic Excitation via GABAB Receptors in Habenula Cholinergic Neurons Regulates Fear Memory Expression.
abstract: Fear behaviors are regulated by adaptive mechanisms that dampen their expression in the absence of danger. By studying circuits and the molecular mechanisms underlying this adaptive response, we show that cholinergic neurons of the medial habenula reduce fear memory expression through GABAB presynaptic excitation. Ablating these neurons or inactivating their GABAB receptors impairs fear extinction in mice, whereas activating the neurons or their axonal GABAB receptors reduces conditioned fear. Although considered exclusively inhibitory, here, GABAB mediates excitation by amplifying presynaptic Ca(2+) entry through Cav2.3 channels and potentiating co-release of glutamate, acetylcholine, and neurokinin B to excite interpeduncular neurons. Activating the receptors for these neurotransmitters or enhancing neurotransmission with a phosphodiesterase inhibitor reduces fear responses of both wild-type and GABAB mutant mice. We identify the role of an extra-amygdalar circuit and presynaptic GABAB receptors in fear control, suggesting that boosting neurotransmission in this pathway might ameliorate some fear disorders.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Juen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Lubin
authors.initials: L
authors.lastname: Tan
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China; PTN Graduate Program, Peking University School of Life Sciences, Beijing 100081, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Ren
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liang
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China; PTN Graduate Program, Peking University School of Life Sciences, Beijing 100081, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Lin
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Qiru
authors.initials: Q
authors.lastname: Feng
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China; PTN Graduate Program, Peking University School of Life Sciences, Beijing 100081, China.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Hu
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ren
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wei
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: National Institute of Biological Sciences, Beijing 102206, China.
authors.forename: Fengchao
authors.initials: F
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China. Electronic address: luominmin@nibs.ac.cn.
authors.forename: Minmin
authors.initials: M
authors.lastname: Luo
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism*; D005239:Fear / Q000502:physiology*; D005260:Female; D019262:Habenula / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways; D018377:Neurotransmitter Agents / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D015220:Calcium Channels; D018377:Neurotransmitter Agents; D018080:Receptors, GABA-B; D002118:Calcium