Biology subjects

Morrison, H. W.

Publications and source records attributed to Morrison, H. W..

3 recordsLinked to original sources

bioRxiv2021

Post-stroke administration of the p75 neurotrophin receptor modulator, LM11A-31, attenuates chronic changes in brain metabolism, increases neurotransmitter levels, and improves recovery

The aim of this study was to test whether post-stroke oral administration of a small molecule p75 neurotrophin receptor (p75NTR) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle treated mice by principal component analysis and had higher levels of serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks following stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31 treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31 treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nest construction test, and less impulsivity in an open field test. These data support small molecule modulation of the p75 neurotrophin receptor for preserving neuronal health and function during stroke recovery. SIGNIFICANCE STATEMENTThe findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimers disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.

neuroscience↗

bioRxiv2020

Can quantifying morphology and TMEM119 expression distinguish between microglia and infiltrating macrophages after ischemic stroke and reperfusion in male and female mice?

BackgroundIschemic stroke is an acquired brain injury with gender dependent outcomes. A persistent obstacle in understanding the sex-specific neuroinflammatory contributions to ischemic brain injury is distinguishing between resident microglia versus infiltrating macrophages--both phagocytes--and determining cell population specific contributions to injury evolution and recovery processes. Our purpose was to identify microglial and macrophage populations regulated by ischemic stroke using morphology analysis and the presence of microglia transmembrane protein 119 (TMEM119). Second, we examined sex and menopause differences in microglia/macrophage cell populations after an ischemic stroke. MethodsMale and female, premenopausal and postmenopausal, mice underwent either 60-min of middle cerebral artery occlusion and 24-h of reperfusion or sham surgery. The accelerated ovarian failure model was used to model post-menopause. Brain tissue was collected to quantify infarct area and for immunohistochemistry and western blot methods. Ionized calcium-binding adapter molecule, TMEM119, and confocal microscopy were used to analyze microglia morphology and TMEM119 area in ipsilateral brain regions. Western blot was used to quantify protein quantity. ResultsPost-stroke injury is increased in male and female post-menopause mice versus pre-menopause female mice (p<0.05) with differences primarily occurring in caudal sections. After stroke, microglia underwent a region, but not sex group, dependent transformation into less ramified cells (p<0.0001). However, the number of phagocytic microglia were increased in distal ipsilateral regions of postmenopausal mice versus the other sex groups (p<0.05). The number of TMEM119 positive cells was decreased in proximity to the infarct (p<0.0001) but without a sex group effect. Two key findings prevented distinguishing microglia from systemic macrophages. First, morphological data were not congruent with TMEM119 immunofluorescence data. Cells with severely decreased TMEM119 immunofluorescence were ramified, a distinguishing microglia characteristic. Second, whereas TMEM119 immunofluorescence area decreased in proximity to the infarcted area, TMEM119 protein quantity was unchanged in ipsilateral hemisphere regions using western blot methods. ConclusionsOur findings suggest that TMEM119 is not a stable microglia marker in male and female mice in the context of ischemic stroke. Until TMEM119 function in the brain is elucidated, its use to distinguish between cell populations following brain injury with cell infiltration is cautioned.

physiology↗

bioRxiv2019

Diffuse TBI-induced expression of anxiety-like behavior coincides with altered glutamatergic function, TrkB protein levels and region-dependent pathophysiology in amygdala circuitry

Up to 50% of traumatic brain injury (TBI) survivors demonstrate persisting affective symptoms indicative of limbic system dysregulation, yet the pathophysiology underlying the symptoms is unclear. We hypothesize that TBI-induced pathophysiologic changes within distinct amygdala nuclei contribute to the expression of late-onset anxiety-like behavior. Adult, male Sprague-Dawley rats underwent midline fluid percussion injury or sham surgery. Anxiety-like behavior was assessed at 7 and 28 days post-injury (DPI) followed by assessment of real-time glutamate neurotransmission in the basolateral amygdala (BLA) and central nucleus of the amygdala (CeA) using glutamate-selective microelectrode arrays. In separate animal cohorts, the presence of neuropathology, astrocytosis, and microglial activation were assessed at 1, 7, and 28DPI. Protein levels of glutamatergic transporters (Glt-1, GLAST) and presynaptic modulators of glutamate release (mGluR2, TrkB, BDNF, and glucocorticoid receptors) were quantified using automated capillary western techniques at 28DPI. The expression of anxiety-like behavior at 28DPI coincided with decreased glutamate release and slower glutamate clearance in the CeA, not BLA. Changes in glutamate neurotransmission were independent of protein levels of glutamate transporters and mGluR2 receptors, neuropathology, and astrocytosis. At 1DPI, microglia in the CeA demonstrated a neuroinflammatory response. BDNF and TrkB were decreased at 28DPI in the amygdala. These data indicate that diffuse axonal injury instigates sequences of molecular, structural and functional changes in the amygdala that contribute to circuit dysregulation relevant to the expression of affective disorders. Translationally, diffuse axonal injury can influence severity and incidence of affective symptoms and should be addressed in the history of patients with affective disorders.

neuroscience↗