Biology subjects

Garcia-Ramirez, D. L.

Publications and source records attributed to Garcia-Ramirez, D. L..

3 recordsLinked to original sources

bioRxiv2024

Postnatal maturation of serotonergic modulation of spinal RORβ interneurons in the medial deep dorsal horn

Proprioceptive input is essential for coordinated locomotion and this input must be properly gated to ensure smooth and effective movement. Presynaptic inhibition mediated by GABAergic interneurons provides regulation of sensory afferent feedback. Serotonin not only promotes locomotion, but also modulates feedback from sensory afferents, both directly and indirectly, potentially by acting on the GABAergic interneurons that mediate presynaptic inhibition. Developmental disruptions in presynaptic inhibition can produce deficits in sensorimotor processing. Importantly, both presynaptic inhibition of proprioceptive afferents and serotonergic innervation of the spinal cord become mature and functional after the first postnatal week. However, little is known about the serotonergic receptors involved in the modulation of interneurons mediating presynaptic inhibition and when developmentally their actions mature. Here, we used whole-cell patch clamp recordings in lumbar spinal slices from neonatal and juvenile mice to assess the intrinsic properties and serotonergic modulation of deep dorsal horn GABAergic ROR{beta} interneurons previously shown to mediate presynaptic inhibition of proprioceptive afferents. ROR{beta} interneurons from juvenile cords displayed more mature membrane properties. Further, serotonin increased the excitability of ROR{beta} interneurons via actions at 5-HT2A, 5-HT2B/2C, and 5-HT7 receptors in juvenile but not early neonatal spinal cords. Our findings indicate that deep dorsal horn ROR{beta} interneurons undergo postnatal maturation in both their intrinsic excitability and ability to respond to serotonin, concurrent with the maturation of serotonergic innervation of the dorsal horn. This information can prompt future targeted studies testing relationships between impairments of serotonergic development, proprioceptive processing disorders, and presynaptic inhibition mediated by ROR{beta} interneurons.

neuroscience↗

bioRxiv2024

Covert actions of epidural stimulation on spinal locomotor circuits

Spinal circuitry produces the rhythm and patterning of locomotion. However, both descending and sensory inputs are required to initiate and adapt locomotion to the environment. Spinal cord injury (SCI) disrupts descending controls of the spinal cord, producing paralysis. Epidural stimulation (ES) is a promising clinical therapy for motor control recovery and is capable of reactivating the lumbar spinal locomotor networks, yet little is known about the effects of ES on locomotor neurons. Previously, we found that both sensory afferent pathways and serotonin exert mixed excitatory and inhibitory actions on lumbar interneurons involved in the generation of the locomotor rhythm, identified by the transcription factor Shox2. However, after chronic complete SCI, sensory afferent inputs to Shox2 interneurons become almost exclusively excitatory and Shox2 interneurons are supersensitive to serotonin. Here, we investigated the effects of ES on these SCI-induced changes. Inhibitory input from sensory pathways to Shox2 interneurons was maintained and serotonin supersensitivity was not observed in SCI mice that received daily sub-motor threshold ES. Interestingly, the effects of ES were maintained for at least three weeks after the ES was discontinued. In contrast, the effects of ES were not observed in Shox2 interneurons from mice that received ES after the establishment of the SCI-induced changes. Our results demonstrate mechanistic actions of ES at the level of identified spinal locomotor circuit neurons and the effectiveness of early treatment with ES on preservation of spinal locomotor circuitry after SCI, suggesting possible therapeutic benefits prior to the onset of motor rehabilitation.

neuroscience↗

bioRxiv2024

Activity of spinal RORβ neurons is related to functional improvements following combination treatment after complete SCI

Various strategies targeting spinal locomotor circuitry have been associated with functional improvements after spinal cord injury (SCI). However, the neuronal populations mediating beneficial effects remain largely unknown. In a mouse model of complete SCI, virally-delivered BDNF (AAV-BDNF) activates hindlimb stepping and causes hyperreflexia, whereas sub-motor threshold epidural stimulation (ES) reduced BDNF-induced hyperreflexia. Given their role in gating proprioceptive afferents and potential convergence point of BDNF and ES, we hypothesized that an enhanced excitability of inhibitory ROR{beta} neurons would be associated with locomotor improvements. Ex vivo spinal slice recordings revealed that the excitability of ROR{beta} neurons was decreased in mice with poor locomotor function after SCI, but was similar between the uninjured and best stepping SCI groups. Further, chemogenetic excitation of ROR{beta} neurons reduced BDNF-induced hyperreflexia and improved stepping, similar to ES. Our findings identify inhibitory ROR{beta} neurons as a target population to limit hyperreflexia and enhance locomotor function after SCI.

neuroscience↗