Abstract
Spinally-projecting serotonergic neurons play a key role in controlling pain sensitivity and can either increase or decrease nociception depending on physiological context. It is currently unknown how serotonergic neurons mediate these opposing effects. Utilizing virus-based strategies, we identified two anatomically separated populations of serotonergic hindbrain neurons located in the lateral paragigantocellularis (LPGi) and the medial hindbrain, which respectively innervate the superficial and deep spinal dorsal horn and have contrasting effects on sensory perception. Our tracing experiments revealed that serotonergic neurons of the LPGi were much more susceptible to transduction with spinally injected AAV2retro vectors than medial hindbrain serotonergic neurons. Taking advantage of this difference, we employed intersectional chemogenetic approaches to demonstrate that activation of the LPGi serotonergic projections decreases thermal sensitivity, whereas activation of medial serotonergic neurons increases sensitivity to mechanical von Frey stimulation. Together these results suggest that there are functionally distinct classes of serotonergic hindbrain neurons that differ in their anatomical location in the hindbrain, their postsynaptic targets in the spinal cord, and their impact on nociceptive sensitivity. The LPGi neurons that give rise to rather global and bilateral projections throughout the rostrocaudal extent of the spinal cord appear to be ideally posed to contribute to widespread systemic pain control.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest: none
- Sex differences are now studied in behavioural experiments (figure 5 figure supplement 3 and figure 6 figure supplement 2 - Injection sites are indicated for data used in the final figure to highlight spread of the viral expression (figure 6 figure supplement 1) - Additional quantifications of the brain injection sites for behaviour experiments are included (figure 5 figure supplement 5 and figure 6 figure supplement 3). - More precise description of the spinal cord regions innervated by serotonergic projection neurons in terms of laminar location (figure 3 figure supplement 1)