Biology subjects

Borges, G.

Publications and source records attributed to Borges, G..

3 recordsLinked to original sources

bioRxiv2023

Endogenous opioids gate the locus coeruleus pain generator

The locus coeruleus (LC) plays a paradoxical role in chronic pain. Although largely known as a potent source of endogenous analgesia, increasing evidence suggests injury can transform the LC into a chronic pain generator. We sought to clarify the role of this system in pain. Here, we show optogenetic inhibition of LC activity is acutely antinociceptive. Following long-term spared nerve injury, the same LC inhibition is analgesic - further supporting its pain generator function. To identify inhibitory substrates that may naturally serve this function, we turned to endogenous LC mu opioid receptors (LC-MOR). These receptors provide powerful LC inhibition and exogenous activation of LC-MOR is antinociceptive. We therefore hypothesized that endogenous LC-MOR-mediated inhibition is critical to how the LC modulates pain. Using cell type-selective conditional knockout and rescue of LC-MOR receptor signaling, we show these receptors bidirectionally regulate thermal and mechanical hyperalgesia - providing a functional gate on the LC pain generator.

neuroscience↗

bioRxiv2022

Neuropathic injury drives a generalized negative affective state in mice

Neuropathic pain causes both sensory and emotional maladaptation. Preclinical animal studies of neuropathic pain-induced negative affect could result in novel insights into the mechanisms of chronic pain. Modeling pain-induced negative affect, however, is variable across research groups and conditions. The same injury may or may not produce robust negative affective behavioral responses across different species, strains, and laboratories. Here we sought to identify negative affective consequences of the spared nerve injury model on C57BL/6J male and female mice. We found no significant effect of spared nerve injury across a variety of approach-avoidance, hedonic choice, and coping strategy assays. We hypothesized these inconsistencies may stem in part from the short test duration of these assays. To test this hypothesis, we used the homecage-based Feeding Experimentation Device version 3 to conduct 12-hour, overnight progressive ratio testing to determine whether mice with chronic spared nerve injury had decreased motivation to earn palatable food rewards. Our data demonstrate that despite equivalent task learning, spared nerve injury mice are less motivated to work for a sugar pellet than sham controls. Further, when we normalized behavioral responses across all the behavioral assays we tested, we found that a combined normalized behavioral score is predictive of injury-state and significantly correlates with mechanical thresholds. Together these results suggest that homecage-based operant behaviors provide a useful platform for modeling nerve injury-induced negative affect and that valuable pain-related information can arise from agglomerative data analyses across behavioral assays - even when individual inferential statistics do not demonstrate significant mean differences.

neuroscience↗

bioRxiv2022

Sustained spinal motor activity triggered by direct mechanosensory stimulation in adult Drosophila melanogaster

Most vertebrates and invertebrates such as Drosophila melanogaster are able to move in complex environments due to their ability to integrate sensory information along with motor commands. Mechanosensory structures exist along each leg to assist in motor coordination by transmitting external cues or proprioceptive information to motor centers in the central nervous system. Nevertheless, how different mechanosensory structures engage these locomotor centers and their underlying circuits remains poorly understood. Here, we tested the role of mechanosensory structures in movement initiation by optogenetically stimulating specific classes of leg sensory structures. We found that stimulation of leg Mechanosensory Bristles (MsB) and femoral Chordotonal Organ (ChO) is sufficient to initiate forward movement in immobile animals. While the stimulation of the ChO required brain centers to induce forward movement, unexpectedly, brief stimulation of leg MsB triggered sustained cyclic motor activity dependent only on circuits within the Ventral Nerve Cord (VNC). The duration of the MsB-induced movement was dependent on the number of excited cells and specific to leg afferents, since stimulation of MsB in other segments lead to different motor outcomes. MsB-mediated movement lacked inter and intra-leg coordination, but preserved antagonistic muscle activity within joints. Our data shows that sensory stimulation can act in combination with descending commands in order to elicit a faster response to mechanical stimulation. In addition, it sheds light on the ability of specific sensory circuits to modulate motor control, including initiation of movement, presenting a new system to better understand how different levels of coordination are controlled by VNC and central brain locomotor circuits. Significance StatementSensory feedback is critical to allow smooth and stable locomotion. Proprioceptors interact directly with pre-motor centers optimizing and sustaining coordinated movement. However, initiation of moment is considered to be triggered by higher-order centers in the brain. Here we took advantage of the genetic toolkit provided by the fruit fly Drosophila melanogaster to optogenetically activate different classes of leg sensory cells in immobile animals. We found that leg mechanosensory bristles can specifically trigger sustained leg activity independently of higher-order centers as headless flies could sustain prolonged leg movement upon mechanosensory stimulation. Moreover, while this sensory-evoked movement lacks intra- and inter-leg coordination, it still preserved basic antagonistic muscle activity. These findings suggest a parallel mechanism to trigger fast movement upon sensory stimulation. In addition, it provides a new model for movement initiation and a point-of-entry to define pre-motor circuits.

neuroscience↗