Sonic hedgehog signaling regulates amygdalar neurogenesis and extinction of fear memory.
It is now recognized that neurogenesis occurs throughout life predominantly in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle. In the present study, we investigated the relationship between neurogenesis in the amygdala and extinction of fear memory. Mice received 15 tone-footshock pairings. Twenty-four hours after training, the mice were given 15 tone-alone trials (extinction training) once per day for 7 days. Two hours before extinction training, the mice were injected intraperitoneally with 5-bromo-3-deoxyuridine (BrdU). BrdU-positive and NeuN-positive cells were analyzed 52 days after the training. A group of mice that received tone-footshock pairings but no extinction training served as controls (FC+No-Ext). The number of BrdU(+)/NeuN(+) cells was significantly higher in the extinction (FC+Ext) than in the FC+No-Ext mice. Proliferation inhibitor methylazoxymethanol acetate (MAM) or DNA synthesis inhibitor cytosine arabinoside (Ara-C) reduced neurogenesis and retarded extinction. Silencing Sonic hedgehog (Shh) gene with short hairpin interfering RNA (shRNA) by means of a retrovirus expression system to knockdown Shh specifically in the mitotic neurons reduced neurogenesis and retarded extinction. By contrast, over-expression of Shh increased neurogenesis and facilitated extinction. These results suggest that amygdala neurogenesis and Shh signaling are involved in the extinction of fear memory.
Institute of Basic Medical Sciences and Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan.
Hui-Chi
HC
Hung
Institute of Basic Medical Sciences and Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan.
Ya-Hsin
YH
Hsiao
Institute of Basic Medical Sciences and Department of Pharmacology, National Cheng-Kung University, Tainan 701, Taiwan. Electronic address: powu@mail.ncku.edu.tw.
Po-Wu
PW
Gean
D000679:Amygdala / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology; D001307:Auditory Perception / Q000187:drug effects / Q000502:physiology; D003561:Cytarabine / Q000494:pharmacology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008746:Methylazoxymethanol Acetate / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects
D050256:Antimitotic Agents; D053823:Hedgehog Proteins; D019384:Nucleic Acid Synthesis Inhibitors; C465570:Shh protein, mouse; D003561:Cytarabine; D008746:Methylazoxymethanol Acetate
Amygdala; Extinction; Fear conditioning; Neurogenesis; Sonic hedgehog