Biology subjects

Watters, J. J.

Publications and source records attributed to Watters, J. J..

3 recordsLinked to original sources

bioRxiv2024

Microglia regulate motor neuron plasticity via reciprocal fractalkine/adenosine signaling

Microglia are innate CNS immune cells that play key roles in supporting key CNS functions including brain plasticity. We now report a previously unknown role for microglia in regulating neuroplasticity within spinal phrenic motor neurons, the neurons driving diaphragm contractions and breathing. We demonstrate that microglia regulate phrenic long-term facilitation (pLTF), a form of respiratory memory lasting hours after repetitive exposures to brief periods of low oxygen (acute intermittent hypoxia; AIH) via neuronal/microglial fractalkine signaling. AIH-induced pLTF is regulated by the balance between competing intracellular signaling cascades initiated by serotonin vs adenosine, respectively. Although brainstem raphe neurons release the relevant serotonin, the cellular source of adenosine is unknown. We tested a model in which hypoxia initiates fractalkine signaling between phrenic motor neurons and nearby microglia that triggers extracellular adenosine accumulation. With moderate AIH, phrenic motor neuron adenosine 2A receptor activation undermines serotonin-dominant pLTF; in contrast, severe AIH drives pLTF by a unique, adenosine-dominant mechanism. Phrenic motor neuron fractalkine knockdown, cervical spinal fractalkine receptor inhibition on nearby microglia, and microglial depletion enhance serotonin-dominant pLTF with moderate AIH but suppress adenosine-dominant pLTF with severe AIH. Thus, microglia play novel functions in the healthy spinal cord, regulating hypoxia-induced neuroplasticity within the motor neurons responsible for breathing.

physiology↗

bioRxiv2023

Metabolic response of microglia to amyloid deposition during Alzheimer's disease progression in a mouse model

Alzheimers disease (AD) drives metabolic changes in the central nervous system (CNS). In AD microglia are activated and proliferate in response to amyloid {beta} plaques. To further characterize the metabolic changes in microglia associated with plaque deposition in situ, we examined cortical tissue from 2, 4, and 8-month-old wild type and 5XFAD mice, a mouse model of plaque deposition. 5XFAD mice exhibited progressive microgliosis and plaque deposition as well as changes in microglial morphology and neuronal dystrophy. Multiphoton-based fluorescent lifetime imaging microscopy (FLIM) metabolic measurements showed that older mice had an increased amount of free NAD(P)H, indicative of a shift towards glycolysis. Interestingly in 5XFAD mice, we also found an abundant previously undescribed third fluorescence component that suggests an alternate NAD(P)H binding partner associated with pathology. This work demonstrates that FLIM in combination with other quantitative imaging methods, is a promising label-free tool for understanding the mechanisms of AD pathology.

neuroscience↗

bioRxiv2022

Recurrent hypoxia in a rat model of sleep apnea during pregnancy leads to microglia-dependent respiratory deficits and persistent neuroinflammation in adult male offspring

Sleep apnea (SA) during pregnancy is detrimental to the health of the pregnancy and neonate, but little is known regarding long-lasting consequences of maternal SA during pregnancy on adult offspring. SA is characterized by repeated cessations in breathing during sleep, resulting in intermittent hypoxia (IH). We show that gestational IH (GIH) in rats reprograms the male fetal neuroimmune system toward enhanced inflammation in a region- and sex-specific manner, which persists into adulthood. Male GIH offspring also had deficits in the neural control of breathing, specifically in the ability to mount compensatory responses to central apnea, an effect that was rescued by a localized anti-inflammatory or microglial depletion. Female GIH offspring appeared unaffected. These results indicate that SA during pregnancy sex- and region-dependently skews offspring microglia toward a pro-inflammatory phenotype, which leads to long-lasting deficits in the capacity to elicit important forms of respiratory neuroplasticity in response to breathing instability. These studies contribute to the growing body of recent evidence indicating that SA during pregnancy may lead to sex-specific neurological deficits in offspring that persist into adulthood.

neuroscience↗