Temporal relationships of blood pressure, heart rate, baroreflex function, and body temperature change over a hibernation bout in Syrian hamsters.

Hibernating mammals undergo torpor during which blood pressure (BP), heart rate (HR), metabolic rate, and core temperature (TC) dramatically decrease, conserving energy. While the cardiovascular system remains functional, temporal changes in BP, HR, and baroreceptor-HR reflex sensitivity (BRS) over complete hibernation bouts and their relation to TC are unknown. We implanted BP/temperature telemetry transmitters into Syrian hamsters to test three hypotheses: H-1) BP, HR, and BRS decrease concurrently during entry into hibernation and increase concurrently during arousal; H-2) these changes occur before changes in TC; and H-3) the pattern of changes is consistent over successive bouts. We found: 1) upon hibernation entry, BP and HR declined before TC and BRS, suggesting baroreflex control of HR continues to regulate BP as the BP set point decreases; 2) during the later phase of entry, BRS decreased rapidly whereas BP and TC fell gradually, suggesting the importance of TC in further BP declines; 3) during torpor, BP slowly increased (but remained relatively low) without changes in HR or BRS or increased TC, suggesting minimal baroreflex or temperature influence; 4) during arousal, increased TC and BRS significantly lagged increases in BP and HR, consistent with establishment of tissue perfusion before increased TC/metabolism; and 5) the temporal pattern of these changes was similar over successive bouts in all hamsters. These results negate H-1, support H-2 with respect to BP and HR, support H-3, and indicate that the baroreflex contributes to cardiovascular regulation over a hibernation bout, albeit operating in a fundamentally different manner during entry vs. arousal.

Longitudinal analysis of a dietary mouse model of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

Non-alcoholic fatty liver disease (NAFLD), and resultant non-alcoholic steatohepatitis (NASH), incidence and prevalence are rising globally due to increasing rates of obesity and diabetes. Currently, there are no approved pharmacological treatments for NAFLD, highlighting a need for additional mechanistic studies to develop prevention and/or therapeutic strategies. Diet-induced preclinical models of NAFLD can be used to examine the dynamic changes that occur during NAFLD development and progression throughout the lifespan. To date, most studies utilizing such models have focused exclusively on terminal time points and have likely missed critical early and late changes that are important for NAFLD progression (i.e, worsening). We performed a longitudinal analysis of histopathological, biochemical, transcriptomic, and microbiome changes that occurred in adult male mice fed either a control diet or a NASH-promoting diet (high in fat, fructose, and cholesterol) for up to 30 weeks. We observed progressive development of NAFLD in mice fed the NASH diet compared to the control diet. Differential expression of immune-related genes was observed at an early stage of diet-induced NAFLD development (10 weeks) and persisted into the later stages of the disease (20 and 30 weeks). Differential expression of xenobiotic metabolism related genes was observed at the late stage of diet-induced NAFLD development (30 weeks). Microbiome analysis revealed an increased abundance of Bacteroides at an early stage (10 weeks) that persisted into the later stages of the disease (20 and 30 weeks). These data provide insight into the progressive changes that occur during NAFLD/NASH development and progression in the context of a typical Western diet. Furthermore, these data are consistent with what has been reported in patients with NAFLD/NASH, supporting the preclinical use of this diet-induced model for development of strategies to prevent or treat the disease.

Pharmacokinetics of Sustained-release and Extended-release Buprenorphine in Mice after Surgical Catheterization.

The Guide for the Care and Use of Laboratory Animals strongly encourages the use of pharmaceutical-grade chemicals and analgesics. Sustained-release buprenorphine (SRB) is administered extralabel to rodents to mitigate moderate to severe pain. An FDA-indexed buprenorphine formulation-extended-release buprenorphine (XRB)-has recently become available and is currently the only pharmaceutical-grade slow-release buprenorphine formulation approved for use in mice and rats. However, no studies have directly compared the pharmacokinetic parameters of SRB and XRB in surgically catheterized mice. To this end, we compared the plasma buprenorphine concentrations and pharmacokinetic parameters of SRB and XRB in mice after surgical catheterization. We hypothesized that mice treated before surgery with SRB or XRB would have circulating buprenorphine concentrations that exceeded the therapeutic threshold for as long as 72 h after surgery. Male and female C57Bl/6J mice were anesthetized, treated with a single dose of either SRB (1 mg/kg SC) or XRB (3.25 mg/kg SC), and underwent surgical catheterization. Arterial blood samples were collected at 6, 24, 48, and 72 h after administration. Weight loss after surgery (mean ± SEM) was similar between groups (SRB: males, 12% ± 2%; females, 8% ± 2%; XRB: males, 12% ± 1%; females, 8% ± 1%). Both SRB and XRB maintained circulating buprenorphine concentrations above the therapeutic level of 1.0 ng/mL for 72 h after administration. Plasma buprenorphine concentrations at 6, 24, and 48 h were significantly greater (3- to 4-fold) with XRB than SRB, commensurate with XRB's higher dose. These results support the use of either SRB or XRB for the alleviation of postoperative pain in mice. The availability of FDA-indexed XRB increases options for safe and effective pharmaceutical-grade analgesia in rodents.

Down-regulation of fatty acid binding protein 7 (Fabp7) is a hallmark of the postpartum brain.

Fatty acid binding protein 7 (Fabp7) is a versatile protein that is linked to glial differentiation and proliferation, neurogenesis, and multiple mental health disorders. Recent microarray studies identified a robust decrease in Fabp7 expression in key brain regions of the postpartum rodents. Given its diverse functions, Fabp7 could play a critical role in sculpting the maternal brain and promoting the maternal phenotype. The present study aimed at investigating the expression profile of Fabp7 across the postpartum CNS. Quantitative real-time PCR (qPCR) analysis showed that Fabp7 mRNA was consistently down-regulated across the postpartum brain. Of the 9 maternal care-related regions tested, seven exhibited significant decreases in Fabp7 in postpartum (relative to virgin) females, including medial prefrontal cortex (mPFC), nucleus accumbens (NA), lateral septum (LS), bed nucleus of stria terminalis dorsal (BnSTd), paraventricular nucleus (PVN), lateral hypothalamus (LH), and basolateral and central amygdala (BLA/CeA). For both ventral tegmental area (VTA) and medial preoptic area (MPOA) levels of Fabp7 were lower in mothers, but levels of changes did not reach significance. Confocal microscopy revealed that protein expression of Fabp7 in the LS paralleled mRNA findings. Specifically, the caudal LS exhibited a significant reduction in Fabp7 immunoreactivity, while decreases in medial LS were just above significance. Double fluorescent immunolabeling confirmed the astrocytic phenotype of Fabp7-expressing cells. Collectively, this research demonstrates a broad and marked reduction in Fabp7 expression in the postpartum brain, suggesting that down-regulation of Fabp7 may serve as a hallmark of the postpartum brain and contribute to the maternal phenotype.