Hoxb8 intersection defines a role for Lmx1b in excitatory dorsal horn neuron development, spinofugal connectivity, and nociception

Abstract

Spinal cord neurons respond to peripheral noxious stimuli and relay this information to higher brain centers, but the molecules controlling the assembly of such pathways are poorly known. In this study, we use the intersection of Lmx1b and Hoxb8::Cre expression in the spinal cord to genetically define nociceptive circuits. Specifically, we show that Lmx1b, previously shown to be expressed in glutamatergic dorsal horn neurons and critical for dorsal horn development, is expressed in nociceptive dorsal horn neurons and that its deletion results in the specific loss of excitatory dorsal horn neurons by apoptosis, without any effect on inhibitory neuron numbers. To assess the behavioral consequences of Lmx1b deletion in the spinal cord, we used the brain-sparing driver Hoxb8::Cre. We show that such a deletion of Lmxb1 leads to a robust reduction in sensitivity to mechanical and thermal noxious stimulation. Furthermore, such conditional mutant mice show a loss of a subpopulation of glutamatergic dorsal horn neurons, abnormal sensory afferent innervations, and reduced spinofugal innervation of the parabrachial nucleus and the periaqueductal gray, important nociceptive structures. Together, our results demonstrate an important role for the intersection of Lmx1b and Hoxb8::cre expression in the development of nociceptive dorsal horn circuits critical for mechanical and thermal pain processing.

Keywords: Hoxb8:: Cre; Lmx1b; dorsal horn; mouse; nociception; projection neurons.