title: Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling.
abstract: Fear memory-encoding thalamic input synapses to the lateral amygdala (T-LA) exhibit dynamic efficacy changes that are tightly correlated with fear memory strength. Previous studies have shown that auditory fear conditioning involves strengthening of synaptic strength, and conversely, fear extinction training leads to T-LA synaptic weakening and occlusion of long-term depression (LTD) induction. These findings suggest that the mechanisms governing LTD at T-LA synapses may determine the behavioral outcomes of extinction training. Here, we explored this hypothesis by implementing food deprivation (FD) stress in mice to determine its effects on fear extinction and LTD induction at T-LA synapses. We found that FD increased plasma acylated ghrelin levels and enhanced fear extinction and its retention. Augmentation of fear extinction by FD was blocked by pretreatment with growth hormone secretagogue receptor type-1a antagonist D-Lys(3)-GHRP-6, suggesting an involvement of ghrelin signaling. Confirming previous findings, two distinct forms of LTD coexist at thalamic inputs to LA pyramidal neurons that can be induced by low-frequency stimulation (LFS) or paired-pulse LFS (PP-LFS) paired with postsynaptic depolarization, respectively. Unexpectedly, we found that FD impaired the induction of PP-LFS- and group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD, but not LFS-induced LTD. Ghrelin mimicked the effects of FD to impair the induction of PP-LFS- and DHPG-induced LTD at T-LA synapses, which were blocked by co-application of D-Lys(3)-GHRP-6. The sensitivity of synaptic transmission to 1-naphthyl acetyl spermine was not altered by either FD or ghrelin treatment. These results highlight distinct features of fear extinction and LTD at T-LA synapses.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Chiung-Chun
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Dylan
authors.initials: D
authors.lastname: Chou
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Yeh
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Electronic address: richard@mail.ncku.edu.tw.
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000523:psychology*; D005508:Food Deprivation / Q000502:physiology*; D054439:Ghrelin / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D001565:Benzoates; D018691:Excitatory Amino Acid Antagonists; D054439:Ghrelin; C079694:alpha-methyl-4-carboxyphenylglycine; D008734:Methoxyhydroxyphenylglycol; D005998:Glycine; C010117:3,4-dihydroxyphenylglycol; D003345:Corticosterone
keywords: Fear extinction; Food deprivation; Ghrelin; Lateral amygdala; Long-term depression