Characterization of transgenic mouse models targeting neuromodulatory systems reveals organizational principles of the dorsal raphe

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.

Three-Week Treadmill Exercise Enhances Persistent Inward Currents, Facilitates Dendritic Plasticity, and Upregulates the Excitability of Dorsal Raphe Serotonin Neurons in ePet-EYFP Mice

“…TPH2-labeled EYFP-positive neurons within the rectangle area of 1 × 0.3 mm below the cerebral aqueduct in the DRN were counted manually from the merged pictures in Figure 1B (showed as dotted box). Statistical results showed that approximately 95% (309/324, mice: n = 3) of EYFP+ neurons expressed TPH2 ( Figure 1B, right), which was similar to the previous study (Pinto et al, 2019). Thus, the mouse model at this age was reliable for studying 5-HT neurons in the DRN.…”

Serotonergic Modulation of Locomotor Activity From Basal Vertebrates to Mammals

“…Context-dependent modulation of locomotor output by the same 5-HT nucleus suggests that different 5-HT cell subtypes in the dorsal raphe nucleus are recruited in a behavior-dependent manner (Correia et al, 2017;Seo et al, 2019). Such different cell subtypes likely exist in this nucleus, as recently uncovered by single-cell transcriptomics, anatomical and electrophysiological properties (Ren et al, 2018;Cardozo Pinto et al, 2019;Huang et al, 2019;Okaty et al, 2020). These likely project to different brain regions involved in modulating the locomotor circuitry.…”

“…that selectively innervates the basal ganglia in mice (Ren et al, 2018;Cardozo Pinto et al, 2019;Huang et al, 2019;Okaty et al, 2020).…”

“…In recent years, the use of genetic tools has allowed researchers to refine the characterization of 5-HT nuclei. In the dorsal raphe nucleus (the largest 5-HT nucleus), subtypes of 5-HT neurons with distinct molecular, electrophysiological, and anatomical signatures have been identified, with e.g., one cell type that selectively innervates the basal ganglia in mice (Ren et al, 2018 ; Cardozo Pinto et al, 2019 ; Huang et al, 2019 ; Okaty et al, 2020 ).…”

Serotonergic Axons as Fractional Brownian Motion Paths: Insights into the Self-organization of Regional Densities

“…Serotonergic neurons can release other major neurotransmitters, such as glutamate (Okaty et al, 2019) and perhaps GABA (Stamp and Semba, 1995;Okaty et al, 2019). In the raphe nuclei, serotonergic neurons coexist with many other neurons (Cardozo Pinto et al, 2019;Schneeberger et al, 2019), some of which may participate in stereotyped synaptic arrangements (Soiza-Reilly et al, 2013).…”