Abstract
The dorsal raphe (DR) is a heterogeneous nucleus containing dopamine (DA), serotonin (5HT), γ-aminobutyric acid (GABA) and glutamate neurons. Consequently, investigations of DR circuitry require Cre-driver lines that restrict transgene expression to precisely defined cell populations. Here, we present a systematic evaluation of mouse lines targeting neuromodulatory cells in the DR. We find substantial differences in specificity between lines targeting DA neurons, and in penetrance between lines targeting 5HT neurons. Using these tools to map DR circuits, we show that populations of neurochemically distinct DR neurons are arranged in a stereotyped topographical pattern, send divergent projections to amygdala subnuclei, and differ in their presynaptic inputs. Importantly, targeting DR DA neurons using different mouse lines yielded both structural and functional differences in the neural circuits accessed. These results provide a refined model of DR organization and support a comparative, case-by-case evaluation of the suitability of transgenic tools for any experimental application.
Highlights
The dorsal raphe (DR) is a heterogeneous nucleus containing dopamine (DA), serotonin (5HT), γ-aminobutyric acid (GABA) and glutamate neurons
Colocalization between eYFP-positive and tryptophan hydroxylase 2 (TpH) −immunopositive (TpH+) neurons was high for both SERTCre and ePET-Cre mice (SERT-Cre: eYFP+/TpH+ 95.3%, n = 1619/1698 cells from n = 5 mice; ePET-Cre: eYFP+/TpH+ 92%, n = 834/907 cells from n = 5 mice), and there were no significant differences in cell-type specificity between the SERT-Cre and ePET-Cre lines in any DR subregion (Fig. 1c, d, f, g, q)
While both Cre lines were specific for DR 5HT neurons, we found that the SERT-Cre-line labeled significantly more TpH+ neurons per mouse, as assessed by the average number of virally-labeled TpH+ cells counted in our analysis, compared to the ePET-Cre line (SERT-Cre: 323.8 ± 43.3 eYFP+/TpH+ cells, n = 5 mice; ePET-Cre: 166.8 ± 29.9 eYFP+/TpH+ cells, n = 5 mice) (Fig. 1r)
Summary
The dorsal raphe (DR) is a heterogeneous nucleus containing dopamine (DA), serotonin (5HT), γ-aminobutyric acid (GABA) and glutamate neurons. The confluence of Cre-driver mouse lines with viral vector technologies has enabled labeling, manipulation, and recording of genetically defined neural circuits The application of these tools to study neuromodulatory systems has been useful because they provide a handle onto neurons that are interspersed among other cell-types in heterogeneous nuclei[1,2,3,4,5,6]. The DR is best known for its population of serotonin neurons, which can be targeted with mouse lines expressing Cre under the promoter of the serotonin transporter (SERT-Cre) or the enhancer of the transcription factor Pet[1] (ePET-Cre)[3,6,9,10] These neurons send broadly collateralizing axons to most regions of the forebrain[11,12] and have been shown to play a role in behaviors ranging from locomotion[12,13,14] to reward[15,16,17], anxiety[18], allodynia[19], and social interaction[20,21]. We find substantial differences in cell-type specificity between DA-
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