Enhancing Inhibition-Induced Plasticity in Tinnitus – Spectral Energy Contrasts in Tailor-Made Notched Music Matter

Chronic tinnitus seems to be caused by reduced inhibition among frequency selective neurons in the auditory cortex. One possibility to reduce tinnitus perception is to induce inhibition onto over-activated neurons representing the tinnitus frequency via tailor-made notched music (TMNM). Since lateral inhibition is modifiable by spectral energy contrasts, the question arises if the effects of inhibition-induced plasticity can be enhanced by introducing increased spectral energy contrasts (ISEC) in TMNM. Eighteen participants suffering from chronic tonal tinnitus, pseudo randomly assigned to either a classical TMNM or an ISEC-TMNM group, listened to notched music for three hours on three consecutive days. The music was filtered for both groups by introducing a notch filter centered at the individual tinnitus frequency. For the ISEC-TMNM group a frequency bandwidth of 3/8 octaves on each side of the notch was amplified, additionally, by about 20 dB. Before and after each music exposure, participants rated their subjectively perceived tinnitus loudness on a visual analog scale. During the magnetoencephalographic recordings, participants were stimulated with either a reference tone of 500 Hz or a test tone with a carrier frequency representing the individual tinnitus pitch. Perceived tinnitus loudness was significantly reduced after TMNM exposure, though TMNM type did not influence the loudness ratings. Tinnitus related neural activity in the N1m time window and in the so called tinnitus network comprising temporal, parietal and frontal regions was reduced after TMNM exposure. The ISEC-TMNM group revealed even enhanced inhibition-induced plasticity in a temporal and a frontal cortical area. Overall, inhibition of tinnitus related neural activity could be strengthened in people affected with tinnitus by increasing spectral energy contrast in TMNM, confirming the concepts of inhibition-induced plasticity via TMNM and spectral energy contrasts

Impacts of land use change to short rotation forestry for bioenergy on soil greenhouse gas emissions and soil carbon

Short Rotation Forestry (SRF) for bioenergy could be used to meet biomass requirements and contribute to achieving renewable energy targets. As an important source of biomass it is important to gain an understanding of the implications of large-scale application of SRF on the soil-atmosphere greenhouse gas (GHG) exchange. This study examined the effects of land use change (LUC) from grassland to SRF on soil fluxes of methane (CH4), nitrous oxide (N2O) and carbon dioxide (CO2), and the important drivers in action. Examining soils from a range of sites across the UK, CO2 emission potentials were reduced under SRF with differences between coniferous and broadleaved transitions; these changes were found to be related to changes in soil pH and microbial biomass. However, there were limited effects of SRF tree species type on CH4 and N2O fluxes. A detailed study at an experimental SRF site over 16 months demonstrated a reduction in CH4 and net CO2 emissions from soils under SRF and revealed intriguing temporal dynamics of N2O under Sitka spruce and common alder. A significant proportion of the variation in soil N2O fluxes was attributed to differences between tree species, water table depth, spatial effects, and their interactions. The effects of microtopography (ridges, troughs, flats), and its interactions with water table depth on soil GHG fluxes under different tree species was tested using mesocosm cores collected in the field. Microtopography did not significantly affect soil GHG fluxes but trends suggested that considering this spatial factor in sampling regimes could be important. N2O fluxes from Sitka spruce soils did not respond to water table depth manipulation in the laboratory suggesting that they may also be determined by tree-driven nitrogen (N) availability, with other research showing N deposition to be higher in coniferous plantations. An N addition experiment lead to increased N2O emissions with greatest relative response in the Sitka spruce soils. Overall, LUC from rough grassland to SRF resulted in a reduction in soil CH4 emissions, increased N2O emissions and a reduction or no change in net CO2 emissions. These changes in emissions were influenced both directly and indirectly by tree species type with Sitka spruce having the greatest effect on N2O in particular, thus highlighting the importance of considering soil N2O emissions in any life cycle analysis or GHG budgets of LUC to SRF for bioenergy. This research can help inform decisions around SRF tree species selection in future large-scale bioenergy planting

Hepatic leptin receptor expression can partially compensate for IL-6R alpha deficiency in DEN-induced hepatocellular carcinoma

Objective: The current obesity pandemic represents a major health burden, given that it predisposes to the development of numerous obesity-associated disorders. The obesity-derived adipokines not only impair systemic insulin action but also increase the incidence of hepatocellular carcinoma (HCC), a highly prevalent cancer with poor prognosis. Thus, worldwide incidences of HCC are expected to further increase, and defining the molecular as well as cellular mechanisms will allow for establishing new potential treatment options. The adipose tissue of obese individuals increases circulating leptin and interleukin-6 (IL-6) levels, which both share similar signaling capacities such as Signal Transducer and Activator of Transcription 3 (STAT3) and Phosphoinositide 3-kinase (PI3K)/Akt activation. While mouse models with deficient IL-6 signaling show an ameliorated but not absent Diethylnitrosamine (DEN)-induced HCC development, the morbid obesity in mice with mutant leptin signaling complicates the dissection of hepatic leptin receptor (LEPR) and IL-6 signaling in HCC development. Here we have investigated the function of compensating hepatic LEPR expression in HCC development of IL-6R alpha-deficient mice. Methods: We generated and characterized a mouse model of hepatic LEPR deficiency that was intercrossed with IL-6R alpha-deficient mice. Cohorts of single and double knockout mice were subjected to the DEN-HCC model to ascertain liver cancer development and characterize metabolic alterations. Results: We demonstrate that both high-fat diet (HFD)-induced obesity and IL-6R alpha deficiency induce hepatic Lepr expression. Consistently, double knockout mice show a further reduction in tumor burden in DEN-induced HCC when compared to control and single LepR(L-KO)/IL-6R alpha knock out mice, whereas metabolism remained largely unaltered between the genotypes. Conclusions: Our findings reveal a compensatory role for hepatic LEPR in HCC development of IL-6Ra-deficient mice and suggest hepatocyte-specific leptin signaling as promoter of HCC under obese conditions. (C) 2018 The Authors. Published by Elsevier GmbH

Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity

Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity leads to debilitating neuroendocrine or metabolic disorders such as Cushing's syndrome (CS). Glucocorticoids control HPA axis activity through negative feedback to the pituitary gland and the central nervous system (CNS). However, the cellular mechanisms involved are poorly understood, particularly in the CNS. Here we show that, in mice, selective loss of TrkB signalling in cholecystokinin (CCK)-GABAergic neurons induces glucocorticoid resistance, resulting in increased corticotrophin-releasing hormone expression, chronic hypercortisolism, adrenocortical hyperplasia, glucose intolerance and mature-onset obesity, reminiscent of the human CS phenotype. Interestingly, obesity is not due to hyperphagia or decreased energy expenditure, but is associated with increased de novo lipogenesis in the liver. Our study therefore identifies CCK neurons as a novel and critical cellular component of the HPA axis, and demonstrates the requirement of TrkB for the transmission of glucocorticoid signalling

Alteration of JNK-1 Signaling in Skeletal Muscle Fails to Affect Glucose Homeostasis and Obesity-Associated Insulin Resistance in Mice

<div><p>Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNK^C). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNK^C mice were crossed to Mck-Cre mice yielding JNK^SM-C mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNK^SM-C mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance.</p> </div

Unaltered glucose metabolism and insulin sensitivity in JNK^SM-C mice.

<p>(A) Glucose tolerance tests of control (white bar) and JNK^SM-C (grey bar) mice when feeding a NCD were performed at 11 weeks of age (n = 10–13). (B) Insulin tolerance tests of control (white bar) and JNK^SM-C (grey bar) mice upon NCD feeding were performed at 12 weeks of age (n = 13–15). (C) Insulin levels from sera isolated at week 17 from mice with the indicated genotypes upon NCD feeding determined by ELISA (n = 8–10). (D) Representative insulin-induced AKT phosphorylation of muscle and liver lysates isolated from control and JNK^SM-C mice when feeding NCD using Western Blot analysis with the indicated antibodies. Values are means ± SEM.</p

Unaltered body composition and energy homeostasis in JNK-1^SM-KO mice under normal and obese conditions.

<p>(A) The average bodyweight of control NCD fed (open circles) and HFD fed (open squares) mice was compared with JNK-1^SM-KO mice fed a NCD (black circles) or a HFD (black squares) from 3 to 17 weeks of age (n = 15–45). (B) Body length of control (white bar) and JNK-1^SM-KO (black bar) mice upon NCD and HFD feeding. (C) Body composition of control (white bar) and JNK-1^SM-KO (black bar) mice when exposed to NCD or HFD were determined by using a Brucker minispec in week 17 (n = 11–24). (D) Weight of epigonadal fat pads from NCD and HFD fed control (white bar) and JNK-1^SM-KO (black bar) mice in week 17 (n = 13–40). (E) Serum leptin levels of control (white bar) and JNK-1^SM-KO (black bar) mice upon NCD and HFD feeding at the age of 17 weeks (n = 8–18). (F) Daily food intake of control (white bar) and JNK-1^SM-KO (black bar) mice upon HFD feeding at the age of 14 weeks (n = 5–27). (G) Energy expenditure revealed by the daily and nightly volume of O₂ consumption and CO₂ release of control (white bar) and JNK-1^SM-KO (black bar) mice upon HFD feeding (n = 8). (H) Respiratory exchange rate (RER) of control (white bar) and JNK-1^SM-KO (black bar) mice upon HFD feeding (n = 8). Values are means ± SEM. **, p≤0.01; ***, p≤0.001.</p

Unaltered glucose metabolism and insulin sensitivity in JNK-1^SM-KO under normal and obese conditions.

<p>(A) Glucose tolerance tests of control NCD fed (open circles) and HFD fed (open squares) mice and JNK-1^SM-KO mice fed a NCD (black circles) or a HFD (black squares) were performed at 11 weeks of age (n = 9–49). (B) Insulin tolerance tests of control NCD fed (open circles) and HFD fed (open squares) mice and JNK-1^SM-KO fed a NCD (black circles) or a HFD (black squares) were performed at 12 weeks of age (n = 5–30). (C) Insulin levels from sera isolated at week 17 from mice with the indicated genotypes upon NCD or HFD feeding determined by ELISA (n = 5–9). (D) Representative insulin-induced AKT phosphorylation of muscle and liver lysates isolated from control and JNK-1^SM-KO mice when feeding NCD and HFD using Western Blot analysis with the indicated antibodies. Values are means ± SEM. **, p≤0.01; ***, p≤0.001.</p