Publications by authors named "Garrett M Fogo"

5 Publications

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Rapid Treatment with Intramuscular Magnesium Sulfate During Cardiopulmonary Resuscitation Does Not Provide Neuroprotection Following Cardiac Arrest.

Mol Neurobiol 2022 Jan 14. Epub 2022 Jan 14.

Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

Brain injury is the most common cause of death for patients resuscitated from cardiac arrest. Magnesium is an attractive neuroprotective compound which protects neurons from ischemic injury by reducing neuronal calcium overload via NMDA receptor modulation and preventing calcium-induced mitochondrial permeability transition. Intramuscular (IM) delivery of MgSO during CPR has the potential to target these mechanisms within an early therapeutic window. We hypothesize that IM MgSO administrated during CPR could achieve therapeutic serum magnesium levels within 15 min after ROSC and improve neurologic outcomes in a rat model of asphyxial cardiac arrest. Male Long Evans rats were subjected to 8-min asphyxial cardiac arrest and block randomized to receive placebo, 107 mg/kg, 215 mg/kg, or 430 mg/kg MgSO IM at the onset of CPR. Serum magnesium concentrations increased rapidly with IM delivery during CPR, achieving twofold to fourfold increase by 15 min after ROSC in all magnesium dose groups. Rats subjected to cardiac arrest or sham surgery were block randomized to treatment groups for assessment of neurological outcomes. We found that IM MgSO during CPR had no effect on ROSC rate (p > 0.05). IM MgSO treatment had no statistically significant effect on 10-day survival with good neurologic function or hippocampal CA1 pyramidal neuron survival compared to placebo treatment. In conclusion, a single dose IM MgSO during CPR achieves up to fourfold baseline serum magnesium levels within 15 min after ROSC; however, this treatment strategy did not improve survival, recovery of neurologic function, or neuron survival. Future studies with repeated dosing or in combination with hypothermic targeted temperature management may be indicated.
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http://dx.doi.org/10.1007/s12035-021-02645-xDOI Listing
January 2022

Mitochondrial fission and mitophagy are independent mechanisms regulating ischemia/reperfusion injury in primary neurons.

Cell Death Dis 2021 05 12;12(5):475. Epub 2021 May 12.

Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

Mitochondrial dynamics and mitophagy are constitutive and complex systems that ensure a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Disruption of these systems can lead to mitochondrial dysfunction and has been established as a central mechanism of ischemia/reperfusion (I/R) injury. Emerging evidence suggests that mitochondrial dynamics and mitophagy are integrated systems; however, the role of this relationship in the context of I/R injury remains unclear. To investigate this concept, we utilized primary cortical neurons isolated from the novel dual-reporter mitochondrial quality control knockin mice (C57BL/6-Gt(ROSA)26Sortm1(CAG-mCherry/GFP)Ganl/J) with conditional knockout (KO) of Drp1 to investigate changes in mitochondrial dynamics and mitophagic flux during in vitro I/R injury. Mitochondrial dynamics was quantitatively measured in an unbiased manner using a machine learning mitochondrial morphology classification system, which consisted of four different classifications: network, unbranched, swollen, and punctate. Evaluation of mitochondrial morphology and mitophagic flux in primary neurons exposed to oxygen-glucose deprivation (OGD) and reoxygenation (OGD/R) revealed extensive mitochondrial fragmentation and swelling, together with a significant upregulation in mitophagic flux. Furthermore, the primary morphology of mitochondria undergoing mitophagy was classified as punctate. Colocalization using immunofluorescence as well as western blot analysis revealed that the PINK1/Parkin pathway of mitophagy was activated following OGD/R. Conditional KO of Drp1 prevented mitochondrial fragmentation and swelling following OGD/R but did not alter mitophagic flux. These data provide novel evidence that Drp1 plays a causal role in the progression of I/R injury, but mitophagy does not require Drp1-mediated mitochondrial fission.
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http://dx.doi.org/10.1038/s41419-021-03752-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115279PMC
May 2021

Machine learning-based classification of mitochondrial morphology in primary neurons and brain.

Sci Rep 2021 03 4;11(1):5133. Epub 2021 Mar 4.

Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.

The mitochondrial network continually undergoes events of fission and fusion. Under physiologic conditions, the network is in equilibrium and is characterized by the presence of both elongated and punctate mitochondria. However, this balanced, homeostatic mitochondrial profile can change morphologic distribution in response to various stressors. Therefore, it is imperative to develop a method that robustly measures mitochondrial morphology with high accuracy. Here, we developed a semi-automated image analysis pipeline for the quantitation of mitochondrial morphology for both in vitro and in vivo applications. The image analysis pipeline was generated and validated utilizing images of primary cortical neurons from transgenic mice, allowing genetic ablation of key components of mitochondrial dynamics. This analysis pipeline was further extended to evaluate mitochondrial morphology in vivo through immunolabeling of brain sections as well as serial block-face scanning electron microscopy. These data demonstrate a highly specific and sensitive method that accurately classifies distinct physiological and pathological mitochondrial morphologies. Furthermore, this workflow employs the use of readily available, free open-source software designed for high throughput image processing, segmentation, and analysis that is customizable to various biological models.
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http://dx.doi.org/10.1038/s41598-021-84528-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933342PMC
March 2021

Melanopsin-Containing ipRGCs Are Resistant to Excitotoxic Injury and Maintain Functional Non-Image Forming Behaviors After Insult in a Diurnal Rodent Model.

Neuroscience 2019 08 7;412:105-115. Epub 2019 Jun 7.

Department of Psychology and Neuroscience Program, Hope College, Holland, MI, USA. Electronic address:

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for the light signaling properties of non-image forming vision. Melanopsin-expressing ipRGCs project to retinorecipient brain regions involved in modulating circadian rhythms. Melanopsin has been shown to play an important role in how animals respond to light, including photoentrainment, masking (i.e., acute behavioral responses to light), and the pupillary light reflex (PLR). Importantly, ipRGCs are resistant to various forms of damage, including ocular hypertension, optic nerve crush, and excitotoxicity via N-methyl-D-aspartic acid (NMDA) administration. Although these cells are resistant to various forms of injury, the question still remains whether or not these cells remain functional following injury. Here we tested the hypothesis that ipRGCs would be resistant to excitotoxic damage in a diurnal rodent model, the Nile grass rat (Arvicanthis niloticus). In addition, we hypothesized that following insult, grass rats would maintain normal circadian entrainment and masking to light. In order to test these hypotheses, we injected NMDA intraocularly and examined its effect on the survivability of ipRGCs and RGCs, along with testing behavioral and functional consequences. Similar to findings in nocturnal rodents, ipRGCs were spared from significant damage but RGCs were not. Importantly, whereas image-forming vision was significantly impaired, non-image forming vision (i.e, photoentrainment, masking, and PLR) remained functional. The present study aims to characterize the resistance of ipRGCs to excitotoxicity in a diurnal rodent model.
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http://dx.doi.org/10.1016/j.neuroscience.2019.05.058DOI Listing
August 2019

The effects of ambient temperature and lighting intensity on wheel-running behavior in a diurnal rodent, the Nile grass rat (Arvicanthis niloticus).

J Comp Psychol 2019 05 5;133(2):215-222. Epub 2018 Nov 5.

Department of Psychology and Neuroscience Program, Hope College.

Environmental conditions, such as the light-dark cycle and temperature, affect the display of circadian rhythmicity and locomotor activity patterns in mammals. Here, we tested the hypothesis that manipulating these environmental conditions would affect wheel-running activity patterns in a diurnal rodent, the Nile grass rat (Arvicanthis niloticus). Grass rats are diurnal in the field, however, a subset switch from a day-active pattern to a night-active pattern of activity after the introduction of a running wheel. The mechanism of this chronotype switch remains largely unknown. In the present study, grass rats were presented with running wheels in 12:12 light-dark conditions. First, subjects were exposed to 25 °C during the day and 21 °C at night, which resulted in 100% of grass rats expressing diurnal behavior. Subjects were then exposed to manipulations of elevated ambient temperature, which resulted in a significant reduction in wheel-running activity. Reducing ambient temperature below 21 °C, however, did not disrupt the expression of diurnality or overall activity. Next, lighting intensity was reduced, which resulted in a switch from a diurnal to a nocturnal chronotype in a subset of animals and reduced overall wheel-running activity. Upon return to baseline lighting intensity, patterns of diurnal activity were restored. Altogether, increases in ambient temperature and decreases in lighting intensity significantly reduced overall wheel-running activity. Importantly, dim light resulted in a temporal niche switch in a subset of grass rats, suggesting a critical role for lighting intensity on the expression of wheel-running activity patterns. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/com0000154DOI Listing
May 2019
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