title: 5-HT1B autoreceptors differentially modulate the expression of conditioned fear in a circuit-specific manner.
abstract: Located in the nerve terminals of serotonergic neurons, 5-HT1B autoreceptors are poised to modulate synaptic 5-HT levels with precise temporal and spatial control, and play an important role in various emotional behaviors. This study characterized two novel, complementary viral vector strategies to investigate the contribution of 5-HT1B autoreceptors to fear expression, displayed as freezing, during contextual fear conditioning. Increased expression of 5-HT1B autoreceptors throughout the brain significantly decreased fear expression in both wild-type (WT) and 5-HT1B knockout (1BKO) mice when receptor levels were increased with a cell-type-specific herpes simplex virus (HSV) vector injected into the dorsal raphe nucleus (DRN). Additional studies used an intersectional viral vector strategy, in which an adeno-associated virus containing a double-floxed inverted sequence for the 5-HT1B receptor (AAV-DIO-1B) was combined with the retrogradely transported canine adenovirus-2 expressing Cre (CAV-Cre) in order to increase 5-HT1B autoreceptor expression only in neurons projecting from the DRN to the amygdala. Surprisingly, selective expression of 5-HT1B autoreceptors in just this circuit led to an increase in fear expression in WT, but not 1BKO, mice. These results suggest that activation of 5-HT1B autoreceptors throughout the brain may have an overall effect of attenuating fear expression, but activation of subsets of 5-HT1B autoreceptors in particular brain regions, reflecting distinct projections of serotonergic neurons from the DRN, may have disparate contributions to the ultimate response.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. Electronic address: ykliu@uw.edu.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. Electronic address: kellymi@uw.edu.
authors.forename: M A
authors.initials: MA
authors.lastname: Kelly
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. Electronic address: tsexton@uw.edu.
authors.forename: T J
authors.initials: TJ
authors.lastname: Sexton
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA. Electronic address: neumaier@uw.edu.
authors.forename: J F
authors.initials: JF
authors.lastname: Neumaier
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000033:anatomy & histology* / Q000378:metabolism*; D003213:Conditioning, Psychological / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics; D005239:Fear; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D044302:Receptor, Serotonin, 5-HT1B; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D049452:Green Fluorescent Proteins; D014365:Tryptophan Hydroxylase
keywords: adeno-associated virus; amygdala; canine adenovirus-2; dorsal raphe; serotonin; viral vector