Integrative Physiology

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    Association of low-frequency oscillations in arterial pressure and cerebral blood flow on cerebral oxygenation during stimulated hemorrhage
    (2017-03-14) Rickards, Caroline; Colby, Hannah; Sprick, Justin; Kay, Victoria; Petree, Tyler
    Background: Sustaining adequate cerebral perfusion and oxygenation are essential for maintaining consciousness. It has been shown that healthy individuals subjected to central hypovolemia show a continuum of tolerance to this stress, including simulated hemorrhage induced via application of lower body negative pressure (LBNP). Differences in tolerance to central hypovolemia have been associated with elevated release of vasoactive hormones, increased compensatory tachycardia and vasoconstriction, and higher endogenous low frequency (LF; ~0.1 Hz) arterial pressure and cerebral blood flow oscillations. We hypothesize that an increase in oscillations in middle cerebral artery velocity (MCAv) during maximal LBNP will result in an attenuated decrease in cerebral oxygenation, subsequently resulting in higher tolerance to this stress. Methods: 25 healthy human subjects were subjected to pre-syncopal limited LBNP. Continuous waveform data was obtained for mean arterial pressure (MAP), MCAv, and cerebral oxygen saturation (ScO2). Spectral analysis was performed on MAP and MCAv to assess oscillations in the low frequency range (LF; 0.04-0.15 Hz). Subjects were divided into “Oscillators” and “Non-oscillators” based upon the increase or decrease in LF oscillations in MAP. The % change in ScO2 was assessed between “Oscillators” and “Non-oscillators” to determine if the presence of oscillations caused attenuated decrease in ScO2. Coefficients of determination (R2) were calculated between % changes in ScO2 and LF oscillations, and % changes in ScO2 and LBNP tolerance across all subjects. Results: By design, MAP LF power was higher in the “Oscillators” vs. “Non-oscillators” (17.6 ± 3.6 vs. 6.5 vs. 1.3 mmHg2; P=0.01). This also resulted in higher MCAv LF power in the “Oscillators” (5.9 ± 1.2 vs. 2.9 ± 0.6 cm/s2; P=0.03). Contrary to our hypothesis, however, the “Oscillators” exhibited a greater reduction in ScO2 vs. the “Non-oscillators” (-7.1 ± 0.7 vs. -4.1 ± 1.6%; P=0.04), but there was no difference is LBNP tolerance time between groups (Oscillators: 1558 ± 81 s vs. Non-oscillators: 1661 ± 162 s; P=0.27). There were also poor associations between % changes in ScO2 vs. MAP LF power (R2=0.06), and % change in ScO2 vs. LBNP tolerance (R2=0.001). Conclusions: These results suggest that increased oscillations in arterial pressure and cerebral blood flow do not result in an attenuated decrease in cerebral oxygen saturation.
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    Differential effects of curcumin on renal and systemic inflammation in a mouse model of systemic lupus erythematosus
    (2017-03-14) Mathis, Keisa W.; Pham, Grace
    Purpose: The afferent vagus nerve, through its connection to the hypothalamic pituitary adrenal (HPA) axis, may help regulate inflammation by relaying inflammatory stimuli to prompt release of the anti-inflammatory hormone cortisol. Afferent vagal sensitivity may be diminished in chronic inflammatory diseases, such as systemic lupus erythematosus (SLE). SLE primarily affects reproductive age women, who commonly present with inflammatory kidney disease, diminished vagal tone, dysregulated HPA function, and inadequate basal cortisol. There is evidence that curcumin, the active compound of the spice turmeric, activates vagal afferent neurons, which may lead to increased HPA axis function and heightened cortisol release. We hypothesized that chronic curcumin administration (50mg/kg in sesame oil as vehicle; 4 weeks, daily; i.p.) would protect against chronic inflammation in the NZBWF1 mouse model of SLE by ameliorating HPA axis dysfunction. Methods: At 30 weeks of age, female mice were designated into four groups (n = 4-5/group): SLE-CURC, SLE-VEH, CTL-CURC, and CTL-VEH. We measured splenic cytokines as endogenously released cortisol from the HPA aixis modulates activity of this immune organ. Results: Splenic TNF-α and IL-1β expression (normalized to total protein) were increased in SLE mice compared to controls (2.57 x 107 ± 4.41 x 106 vs. 1.56 x 107 ± 1.99 x 106; p = 0.006 and 2.76 x 105 ± 9.86 x 104 vs. 3.35 x 104 ± 2.49 x 104; p = 0.020). Curcumin accentuated splenic TNF (4.85 x 107 ± 7.06 x 106; p = 0.016), while reducing splenic IL-1β in SLE mice (1.36 x 105 ± 1.74 x 104; p = 0.092). Preliminary in vitro splenocyte data support curcumin as being pro-inflammatory in SLE. Splenocytes isolated from curcumin- and vehicle-treated SLE mice released increased TNF-α when stimulated with LPS (100 ng) or norepinephrine (50 nM), (2.76 x 105 vs. 6.88 x 104 and 4.69 x 105 vs. 1.42 x 105, respectively; n = 1/group). In order to determine curcumin’s effects on kidney inflammation, we measured renal cytokine expression. SLE mice had elevated renal cortical IL-6 and TGF-β1 compared to control mice (1.27 x 105 ± 6.16 x 104 vs. 7.49 x 104 ± 1.50 x 104; p = 0.130 and 1.90 x 105 ± 7.17 x 104 vs. 7.67 x 103 ± 2.58 x 103; p = 0.006). Curcumin increased renal cortical expression of both IL-6 and TGF-β1 in SLE mice (3.37 x 105 ± 1.44 x 104 vs. 1.28 x 105 ± 6.16 x 104; p = 0.128 and 3.536 x 105 ± 1.16 x 105 vs. 1.90 x 105 ± 7.17 x 104; p = 0.152). Conclusions: Taken together these data indicate that curcumin mostly yields pro-inflammatory effects in the setting of SLE, although its anti-inflammatory suppression of splenic IL-1β suggests a more complex interaction with the immune system. Additional studies are needed to investigate renal and cardiovascular outcomes. Further inquiry into vagal control of inflammation and the use of naturally derived compounds as an adjunct treatment of chronic inflammatory processes is warranted.
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    DREADD-Induced cFos Expression in the Basal Forebrain of Male Rats
    (2017-03-14) Cunningham, J. Thomas; Marciante, Alexandria B.
    Purpose: Designer Receptors Exclusively Activated by Designer Drugs, or DREADDs, are genetically modified G-protein coupled receptors (GPCR) that are sensitive to an exogenous pharmacological agent, clozapine-N-oxide (CNO). DREADDs can be packaged in viral vectors with specific promoters or combined with CRE dependent platforms to express these receptors in specific neuronal phenotypes. This chemogenetic approach can be used to activate (Gq), inhibit (Gi), or stimulate cAMP (Gs) in neurons expressing DREADD receptors. In the present study, we tested the effects of a CRE independent Gq DREADD, using a CaM Kinase (CaMKIIa) promoter, and a mCherry reporter (rAAV5-CaMKIIa-hM3D(Gq)-mCherry) on Fos staining in the basal forebrain. Methods: Adult male Sprague-Dawely rats (250-300 g bw, Charles River) were anesthetized with isoflurane and stereotaxically injected with an AAV containing the hM3D(Gq) or a control virus (rAAV5-CaMKIIa-mCherry) in either the diagonal band of bregma (DBB) or the median preoptic nucleus (MnPO). Animals were monitored for recovery for two weeks and then administered CNO or vehicle. CNO was dissolved into dimethylsulfoxide (DMSO) and saline (ratio 20% to 80%) and given via intraperitoneal injection (IP) at a concentration of 10mg/kg. Rats were food and water deprived for 90 minutes following administration of CNO or vehicle and then perfused transcardially using 4% paraformaldehyde. Brains were harvested and placed into 30% sucrose until proper dehydration of the brain. Forebrains were then sliced into 40 micron segments using cryostat. Immunohistological techniques were performed as previously described using peroxidase staining for Fos to determine activation of the DREADD virus and fluorescent staining for mCherry to verify cells transfected with either the DREADD or control virus. Results: Overall, rats transfected with the Gq DREADD virus and treated with CNO showed significantly elevated Fos staining in the DBB or MnPO than groups transfected with either Gq DREADD and treated with vehicle or the control virus and treated with CNO or vehicle. Those transfected with the Gq DREADD virus in the DBB and treated with CNO, showed significantly more Fos staining than those transfected with either Gq DREADD and treated with vehicle (P Conclusions: These results indicate that Gq DREADD can be used to differentially activate neurons in either the DBB or the MnPO to influence activity in downstream regions that control autonomic and neuroendocrine function.