Convergent effects of mouse Pet-1 deletion and human PET-1 variation on amygdala fear and threat processing

Serotonin is critical for shaping the development of neural circuits regulating emotion. Pet-1 (FEV-1) is an ETS-domain transcription factor essential for differentiation and forebrain targeting of serotonin neurons. Constitutive Pet-1 knockout (KO) causes major loss of serotonin neurons and forebra...

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Bibliographic Details
Published in:Experimental neurology 2013-12, Vol.250, p.260-269
Main Authors: Wellman, Cara L., Camp, Marguerite, Jones, V. Morgan, MacPherson, Kathryn P., Ihne, Jessica, Fitzgerald, Paul, Maroun, Mouna, Drabant, Emily, Bogdan, Ryan, Hariri, Ahmad R., Holmes, Andrew
Format: Article
Language:English
Subjects:
Amygdala - physiology
Animals
Anxiety Disorders - genetics
Basolateral amygdala
Biological and medical sciences
Conditioning, Classical
Dendrites - ultrastructure
DNA-Binding Proteins - genetics
Emotions - physiology
Extinction, Psychological - physiology
Fear - physiology
Fear conditioning
Female
FEV
Genetic Predisposition to Disease - genetics
Genotype
Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy
Humans
Image Processing, Computer-Assisted
Magnetic Resonance Imaging
Male
Medial prefrontal cortex
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Nervous system (semeiology, syndromes)
Neurology
Nuclear Proteins - genetics
Polymorphism, Single Nucleotide
Serotonin
Transcription Factors - genetics
Young Adult
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Summary:Serotonin is critical for shaping the development of neural circuits regulating emotion. Pet-1 (FEV-1) is an ETS-domain transcription factor essential for differentiation and forebrain targeting of serotonin neurons. Constitutive Pet-1 knockout (KO) causes major loss of serotonin neurons and forebrain serotonin availability, and behavioral abnormalities. We phenotyped Pet-1 KO mice for fear conditioning and extinction, and on a battery of assays for anxiety- and depression-related behaviors. Morphology of Golgi-stained neurons in basolateral amygdala (BLA) and prelimbic cortex was examined. Using human imaging genetics, a common variant (rs860573) in the PET-1 (FEV) gene was tested for effects on threat-related amygdala reactivity and psychopathology in 88 Asian-ancestry subjects. Pet-1 KO mice exhibited increased acquisition and expression of fear, and elevated fear recovery following extinction, relative to wild-type (WT). BLA dendrites of Pet-1 KO mice were significantly longer than in WT. Human PET-1 variation associated with differences in amygdala threat processing and psychopathology. This novel evidence for the role of Pet-1 in fear processing and dendritic organization of amygdala neurons and in human amygdala threat processing extends a growing literature demonstrating the influence of genetic variation in the serotonin system on emotional regulation via effects on structure and function of underlying corticolimbic circuitry. •Pet-1 knockout (KO) causes loss of serotonin neurons and forebrain serotonin availability.•We examined fear conditioning and extinction and corticolimbic morphology in Pet-1 KO mice.•We tested a variant in the human PET-1 gene for effects on threat-related amygdala reactivity in Asian-ancestry subjects.•In mice, Pet-1 deletion produced amygdala dendritic hypertrophy and an augmented, extinction-resistant fear memory.•In humans, a PET-1 gene variant associated with threat-driven amygdala reactivity and risk for psychopathology.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2013.09.025