The Gaudet lab aims to reveal links between molecular, cellular, and behavioral changes elicited during neuropathology. We have several research interests:
Spatial dynamics of spinal cord injury-elicited glial cell activation. For more, please see our 2018 review in Neurotherapeutics.
1. Neuroinflammation. Spinal cord injury (SCI) causes massive neuroinflammation, which can worsen pathology ("secondary damage"). We seek to better understand the post-SCI cascades that drive inflammation, and to shift the inflammatory response to better preserve/repair tissue and improve behavioral outcomes. Several strategies are used to modulate neuroinflammation; we are targeting circadian rhythms and clock-related proteins; phagocytosis and its pathways; and intracellular signaling pathways that could shift immune cell reactivity.
We revealed recently that spinal cord injury disrupts the circadian system. Please see our studies published in eNeuro and in J. Neurotrauma.
2. Biological clocks. Our work has shown that SCI can broadly disrupt function across peripheral organs. SCI disrupts molecular rhythms (e.g., in spinal cord, liver, and blood) that occur in parallel with altered diurnal rhythms in behavior. Ongoing work seeks to understand related mechanisms and potential treatments that boost rhythm recovery.
Successful axon regeneration requires growth-promoting responses by the injured neuron and by its local environment. Please see our J. Neuroinflammation review on axon degeneration and regeneration.
3. Axon plasticity and regeneration. After SCI, central nervous system axons fail to regenerate. This is due to a poor neuron-intrinsic growth response, and ineffective neuroinflammatory and glial dynamics. Improving post-SCI plasticity of these axons could enhance recovery of function.
One NIH-funded project involves manipulating a circadian-related transcription factor called REV-ERB. REV-ERB is a transcriptional repressor that controls the circadian clock - but also regulates other crucial body processes, including neuroinflammation (see our chapter on circadian-neuroimmune interactions after neurotrauma). We hypothesize that activating REV-ERB could dampen neuroinflammation to improve neuroprotection and functional recovery. We assess cellular, molecular, anatomical, and behavioral outcomes after spinal cord injury. Behavioral outcomes include locomotor recovery, neuropathic pain and chronic pain, and mood-related behaviors. Ongoing studies are using transgenic and pharmacologic approaches to reveal REV-ERB’s role in repair after spinal cord injury.
Another project in the lab involves enhancing phagocytosis after spinal cord injury. In a project funded by Mission Connect, a program of the TIRR Foundation, we are testing the prediction that boosting phagocytic capacity will remove apoptotic cells, thereby limiting secondary damage. We will explore the role of phagocytosis using cell-specific deletion and activation of phagocytic receptors after spinal cord injury.
In addition to studying spinal cord injury, we have also performed behavioral neuroscience research related to mood and metabolic disorders. For instance, we have published recent papers revealing that females (vs. males) and spinal cord injury (vs. uninjured mice) predispose mice to anxiety-like behaviors using a novel “TIDAL” conflict test. We also established that miR-155 knockout mice display worsened recovery after spinal cord injury, increased baseline anxiety- and depressive-like behavior, and increased susceptibility to obesity.
Our ongoing research also integrates the expertise of collaborators, who help us include additional innovative approaches to study spinal cord injury and mood disorders.