Biology subjects

Arnold, A. C.

Publications and source records attributed to Arnold, A. C..

4 recordsLinked to original sources

bioRxiv2022

Predictive link between systemic metabolism and immune signaling in the brain of APOE4 mice

The {varepsilon}4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimers disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying the APOE4 gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines, and these signatures are APOE genotype dependent. Ours is the first study to identify a quantitative and predictive link between systemic metabolism and specific pathological cytokine signatures in the brain. Our results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/480074v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@5865d5org.highwire.dtl.DTLVardef@185a0e0org.highwire.dtl.DTLVardef@4d2e7org.highwire.dtl.DTLVardef@b27318_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

The vagus nerve is critical for regulation of hypothalamic-pituitary-adrenal axis responses to acute stress

The hypothalamic pituitary adrenal (HPA) axis is a critical regulator of physiologic and psychological responses to acute and chronic stressors. HPA axis function is control by numerous feedback inhibitory mechanisms, disruptions of which can lead to various psychiatric conditions, such as depression, posttraumatic stress disorder, and schizophrenia. Vagus nerve stimulation has been shown to be efficacious in the treatment of in these various mental health issues potentially via modulation of HPA axis function, but the mechanisms by which the vagus nerve may regulate HPA function has not been fully elucidated. In the present studies, we sought to test the hypothesis that the vagus nerve is a critical regulator of HPA function. Neuroendocrine function and neurocircuit changes in corticotropin releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVN) were examined following acute stress after subdiaphragmatic left vagotomy (VX) in adult male Sprague-Dawley rats. We found that VX mimics HPA activation seen in sham surgery animals exposed to acute restraint stress, particularly increased plasma corticosterone levels, elevated PVN CRF mRNA, and increased action potential firing of putative CRF neurons in PVN brain slices. Furthermore, VX animals exposed to acute restraint stress showed increased elevations of plasma corticosterone and PVN CRF mRNA which may be due to lack of compensatory PVN GABAergic signaling in response to acute stress. Both Sham/Stress and VX/no stress conditions increased action potential firing in putative PVN CRF neurons, but this effect was not seen in the VX/stress condition, suggesting that not all forms of stress compensation are lost following VX. Overall, these findings suggest that the vagus nerve may play a critical role in regulating HPA axis function via modulation of local PVN neurocircuit activity.

neuroscience↗

bioRxiv2021

Disruption of the surfactant protein A receptor SP-R210L (CD245α/MYO18Aα) alters respiratory function and iron sequestration in alveolar macrophages of aged mice

Previous studies demonstrated that the host defense collectins, surfactant protein A and complement component 1q, modulate tissue-dependent macrophage activation, pathogen clearance, and regulatory macrophage functions through the receptor SP-R210, which consists of two isoforms SP-R210L and SP-R210S. These isoforms are encoded by alternatively spliced mRNAs of the Myo18a MYO18A gene in mice and humans. The present study in conditional transgenic mice revealed novel age-related functions of the SP-R210L isoform in modulating pulmonary mechanics, iron sequestration in alveolar macrophages (AMs), and life-long maintenance of the alveolar macrophage population. Our findings support the novel idea that SP-R210L-deficient AMs undergo bi-directional epigenetic adaptation that results in chronic dysregulation of broncho-alveolar function, immune homeostasis, and maintenance of oncotic balance at the airway-capillary interface. Disruption of SP-R210L increases the risk for development of severe interstitial lung disease during development and aging.

physiology↗

bioRxiv2018

Access schedules mediate the impact of high fat diet on ethanol intake in mice.

Alcoholism and high fat diet (HFD)-induced obesity individually promote insulin resistance and glucose intolerance in clinical populations, increasing risk for metabolic diseases. Conversely, animal studies, typically utilizing forced/continuous alcohol (EtOH) access, tend to show that EtOH intake mitigates HFD-induced effects on insulin and glucose function, while HFD decreases voluntary EtOH intake in continuous access models. However, the impact of HFD on intermittent EtOH intake and resultant changes to metabolic function are not well characterized. The present studies sought to determine if HFD alters EtOH intake in male C57Bl/6J mice given differing two-bottle choice EtOH access schedules, and to assess resultant impact on insulin sensitivity and glucose tolerance. In the first experiment, mice had Unlimited Access EtOH (UAE)+HFD (n=15; HFD=60% calories from fat, 10% EtOH v/v, ad libitum) or UAE+Chow (n=15; control diet=16% calories from fat, ad libitum) for 6 weeks. UAE+HFD mice had lower EtOH preference, consumed significantly less EtOH, and were insulin resistant and hyperglycemic compared with UAE+Chow mice. In the second experiment, mice had Limited Access EtOH (LAE, 4 hrs/d; 3 d/wk)+HFD (n=15) or LAE+Chow (n=15) with increasing EtOH concentrations (10%, 15%, 20%). LAE+HFD mice had no difference in total EtOH consumption compared to LAE+Chow mice, but exhibited hyperglycemia, insulin resistance, and glucose intolerance. In the third experiment, mice had intermittent HFD access (single 24 hr session/week) with limited access to EtOH (iHFD-E, 4hrs/d; 4 d/wk) (n=10). iHFD-E mice displayed binge eating behaviors and consumed significantly more EtOH than mice given ad libitum chow or HFD, suggesting transfer of binge eating to binge drinking behaviors. Although iHFD-E mice did not have significantly altered body composition, they developed insulin insensitivity and glucose intolerance. These results suggest that access schedules determine the impact of HFD on EtOH consumption and resultant metabolic dysfunction.

animal behavior and cognition↗