Targeting ASIC1a reduces innate fear and alters neuronal activity in the fear circuit.
BACKGROUND
The molecular mechanisms underlying innate fear are poorly understood. Previous studies indicated that the acid sensing ion channel ASIC1a influences fear behavior in conditioning paradigms. However, these differences may have resulted from an ASIC1a effect on learning, memory, or the expression of fear.


METHODS
To test the hypothesis that ASIC1a influences the expression of fear or anxiety independent of classical conditioning, we examined the effects of disrupting the mouse ASIC1a gene on unconditioned fear in the open field test, unconditioned acoustic startle, and fear evoked by the predator odor trimethylthiazoline (TMT). In addition, we tested the effects of acutely inhibiting ASIC1a with PcTx, an ASIC1a antagonist in tarantula venom. Our immunohistochemistry suggested ASIC1a is expressed in the bed nucleus of the stria terminalis, medial amygdala, and periaqueductal gray, which are thought to play important roles in the generation and expression of innate fear. Therefore, we also tested whether ASIC1a disruption altered c-fos expression in these structures following TMT exposure.


RESULTS
We found that the loss of ASIC1a reduced fear in the open field test, reduced acoustic startle, and inhibited the fear response to TMT. Similarly, intracerebroventricular administration of PcTx reduced TMT-evoked freezing in ASIC1a(+/+) mice but not ASIC1a(-/-) mice. In addition, loss of ASIC1a altered TMT-evoked c-fos expression in the medial amydala and dorsal periaqueductal gray.


CONCLUSIONS
These findings suggest that ASIC1a modulates activity in the circuits underlying innate fear. Furthermore, the data indicate that targeting the ASIC1a gene or acutely inhibiting ASIC1a suppresses fear and anxiety independent of conditioning.
Neuroscience Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City 52242, USA.
Matthew W
MW
Coryell
Adam E
AE
Ziemann
Patricia J
PJ
Westmoreland
Jill M
JM
Haenfler
Zlatan
Z
Kurjakovic
Xiang-ming
XM
Zha
Margaret
M
Price
Mikael K
MK
Schnizler
John A
JA
Wemmie
D062565:Acid Sensing Ion Channels; D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000502:physiology; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D009434:Neural Pathways / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009812:Odorants; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013216:Reflex, Startle / Q000235:genetics / Q000502:physiology; D015222:Sodium Channels / Q000172:deficiency*; D013844:Thiazoles / Q000494:pharmacology
D062565:Acid Sensing Ion Channels; D000697:Central Nervous System Stimulants; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010852:Picrotoxin; D016760:Proto-Oncogene Proteins c-fos; D015222:Sodium Channels; D013844:Thiazoles; C451263:2,4,5 trimethylthiazoline; C568267:ASIC1 protein, mouse