5-HT1B autoreceptors differentially modulate the expression of conditioned fear in a circuit-specific manner. (9th July 2015)

• Record Type: Journal Article
• Authors: Liu, Y.; Kelly, M.A.; Sexton, T.J.; Neumaier, J.F.
• Is Part Of: Neuroscience. Volume 298(2015)
• Page Start: 436
• Page End: 447
• Publication Date: 2015-07-09
• Subjects: 1BKO 5-HT1B receptor constitutive knockout mouse -- AAV adeno-associated virus -- CAV canine adenovirus -- DIO double-floxed inverted open reading frame -- DRN dorsal raphe nucleus -- HA hemagglutinin -- HSV herpes simplex virus -- NGS normal goat serum -- ORF open reading frame -- SERT serotonin transporter -- Tph tryptophan hydroxylase -- WT wild type; serotonin -- dorsal raphe -- amygdala -- viral vector -- adeno-associated virus -- canine adenovirus-2; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.04.032
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: Two novel viral vectors express 5-HT1B receptors in a cell-type-specific manner. The effect of 5-HT1B autoreceptors on fear depends on the circuitry involved. Increased levels of 5-HT1B autoreceptors in the brain decrease fear expression. Increased 5-HT1B receptors in raphe neurons projecting to the amygdala increase fear. 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.