BACKGROUND Weight-loss diets often target dietary fat or carbohydrates, macronutrients that are sensed via distinct gut-brain pathways and differentially affect peripheral hormones and metabolism. However, the effects of such diet changes on the human brain are unclear. METHODS We investigated whether selective isocaloric reductions in dietary fat or carbohydrates altered dopamine D2/3 receptor binding potential (D2BP) and neural activity in brain-reward regions in response to visual food cues in 17 inpatient adults with obesity as compared with a eucaloric baseline diet using a randomized crossover design. RESULTS On the fifth day of dietary fat restriction, but not carbohydrate restriction, both D2BP and neural activity to food cues were decreased in brain-reward regions. After the reduced-fat diet, ad libitum intake shifted toward foods high in both fat and carbohydrates. CONCLUSION These results suggest that dietary fat restriction increases tonic dopamine in brain-reward regions and affects food choice in ways that may hamper diet adherence. TRIAL REGISTRATION ClinicalTrials.gov NCT00846040 FUNDING. NIDDK 1ZIADK013037.
Valerie L. Darcey, Juen Guo, Amber B. Courville, Isabelle Gallagher, Jason A. Avery, W. Kyle Simmons, John E. Ingeholm, Peter Herscovitch, Alex Martin, Kevin D. Hall
Changes in neuronal activity modulate the vulnerability of motoneurons (MNs) in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). So far, the molecular basis of neuronal activity’s impact in ALS is poorly understood. Herein we investigated the impact of deleting the neuronal activity stimulated transcription factor (TF) serum response factor (SRF) in MNs of SOD1G93A mice. SRF was present in vulnerable MMP9 positive MNs. Ablation of SRF in MNs induced an earlier disease onset starting around 7-8 weeks after birth revealed by enhanced weight loss and decreased motor ability. This earlier disease onset in SRF depleted MNs was accompanied by mild elevation of neuroinflammation and neuromuscular synapse degeneration whereas overall MN numbers and mortality were unaffected. In SRF deficient mice, MNs showed impaired induction of autophagy encoding genes suggesting a new SRF function in transcriptional regulation of autophagy. Complementary, constitutive-active SRF-VP16 enhanced autophagy encoding gene transcription and autophagy progression in cells. Furthermore, SRF-VP16 decreased ALS-associated aggregate induction. Chemogenetic modulation of neuronal activity uncovered SRF as important TF mediating activity-dependent effects which might be beneficial to reduce ALS disease burden. Thus, our data identify with SRF a new gene regulator connecting neuronal activity with the cellular autophagy program initiated in degenerating MNs.
Jialei Song, Natalie Yashoda Dikwella, Daniela Sinske, Francesco Roselli, Bernd Knöll
Fragile X syndrome is a neurodevelopmental disorder caused by the absence of the mRNA-binding protein fragile X messenger ribonucleoprotein (FMRP). Because FMRP is a highly pleiotropic protein controlling the expression of hundreds of genes, viral vector–mediated gene replacement therapy is viewed as a potential viable treatment to correct the fundamental underlying molecular pathology inherent in the disorder. Here, we studied the safety profile and therapeutic effects of a clinically relevant dose of a self-complementary adeno-associated viral (AAV) vector containing a major human brain isoform of FMRP after intrathecal injection into wild-type and fragile X–KO mice. Analysis of the cellular transduction in the brain indicated primarily neuronal transduction with relatively sparse glial expression, similar to endogenous FMRP expression in untreated wild-type mice. AAV vector–treated KO mice showed recovery from epileptic seizures, normalization of fear conditioning, reversal of slow-wave deficits as measured via electroencephalographic recordings, and restoration of abnormal circadian motor activity and sleep. Further assessment of vector efficacy by tracking and analyzing individual responses demonstrated correlations between the level and distribution of brain transduction and drug response. These preclinical findings further demonstrate the validity of AAV vector–mediated gene therapy for treating the most common genetic cause of cognitive impairment and autism in children.
Hayes Wong, Alexander W.M. Hooper, Hye Ri Kang, Shiron J. Lee, Jiayi Zhao, Chanchal Sadhu, Satinder Rawat, Steven J. Gray, David R. Hampson
Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify “off-target effects” shaping long-term outcomes. For this purpose, we studied a cohort of MG patients treated with either eculizumab (n = 10) or azathioprine (n = 10) as well as treatment-naïve (n = 10) patients using a combined proteomics and metabolomics approach. This strategy confirmed known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients including the oxidative stress response, mitogen-activated protein kinase signaling and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 (LTA4) in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct “off-target effects” induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.
Christopher Nelke, Christina B. Schroeter, Frauke Stascheit, Niklas Huntemann, Marc Pawlitzki, Alice G. Willison, Saskia Räuber, Nico Melzer, Ute Distler, Stefan Tenzer, Kai Stühler, Andreas Roos, Andreas Meisel, Sven G. Meuth, Tobias Ruck
Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a Gβ5-dependent regulatory pathway within mechanical nociceptors that restrains anti-nociceptive input from metabotropic GABA-B receptors. In mice with conditional knockout (cKO) of Gnb5 targeted to peripheral sensory neurons, we demonstrate the impairment of mechanical, thermal, and chemical nociception. We further report the specific loss of mechanical nociception in Rgs7-Cre+/-; Gnb5fl/fl mice but not in Rgs9-Cre+/-; Gnb5fl/fl mice, suggesting that Gβ5 might specifically regulate mechanical pain in Rgs7+ cells. Additionally, Gβ5-dependent and Rgs7-associated mechanical nociception is dependent upon GABA-B receptor signaling since both were abolished by treatment with a GABA-B receptor antagonist and since cKO of Gβ5 from sensory cells or from Rgs7+ cells potentiated the analgesic effects of GABA-B agonists. Following activation by the Mrgprd agonist β-alanine, enhanced sensitivity to inhibition by baclofen was observed in primary cultures of Rgs7+ sensory neurons harvested from Rgs7-Cre+/-; Gnb5fl/fl mice. Taken together, these results suggest that the targeted inhibition of Gβ5 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.
Mritunjay Pandey, Jian-Hua Zhang, Poorni R. Adikaram, Claire M. Kittock, Nicole Lue, Adam M. Awe, Katherine N. Degner, Nirmal Jacob, Jenna N. Staples, Rachel Thomas, Allison B. Kohnen, Sundar Ganesan, Juraj Kabat, Ching-Kang Chen, William F. Simonds
Elderly individuals frequently report cognitive decline, while various studies indicate hippocampal functional declines with advancing age. Hippocampal function is influenced by ghrelin through hippocampus-expressed growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous GHSR antagonist that attenuates ghrelin signaling. Here, we measured plasma ghrelin and LEAP2 levels in a cohort of cognitively normal individuals older than 60 and found that LEAP2 increased with age while ghrelin (also referred to in literature as “acyl-ghrelin”) marginally declined. In this cohort, plasma LEAP2/ghrelin molar ratios were inversely associated with Mini-Mental State Examination scores. Studies in mice showed an age-dependent inverse relationship between plasma LEAP2/ghrelin molar ratio and hippocampal lesions. In aged mice, restoration of the LEAP2/ghrelin balance to youth-associated levels with lentiviral shRNA Leap2 downregulation improved cognitive performance and mitigated various age-related hippocampal deficiencies such as CA1 region synaptic loss, declines in neurogenesis, and neuroinflammation. Our data collectively suggest that LEAP2/ghrelin molar ratio elevation may adversely affect hippocampal function and, consequently, cognitive performance; thus, it may serve as a biomarker of age-related cognitive decline. Moreover, targeting LEAP2 and ghrelin in a manner that lowers the plasma LEAP2/ghrelin molar ratio could benefit cognitive performance in elderly individuals for rejuvenation of memory.
Jing Tian, Lan Guo, Tienju Wang, Kun Jia, Russell H. Swerdlow, Jeffrey M. Zigman, Heng Du
Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics’ ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) — brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.
Alice Adriaenssens, Johannes Broichhagen, Anne de Bray, Julia Ast, Annie Hasib, Ben Jones, Alejandra Tomas, Natalie Figueredo Burgos, Orla Woodward, Jo Lewis, Elisabeth O’Flaherty, Kimberley El, Canqi Cui, Norio Harada, Nobuya Inagaki, Jonathan Campbell, Daniel Brierley, David J. Hodson, Ricardo Samms, Fiona Gribble, Frank Reimann
Inflammatory bowel disease (IBD) is a relapsing-remitting disorder characterized by chronic inflammation of the gastrointestinal (GI) tract. Anxiety symptoms are commonly observed in IBD patients, but the mechanistic link between IBD and anxiety remains elusive. Here, we sought to characterize gut-to-brain signaling and brain circuitry responsible for the pathological expression of anxiety-like behaviors in male dextran sulfate sodium (DSS)-induced experimental colitis mice. We found that DSS-treated mice displayed increased anxiety-like behaviors, which were prevented by bilateral GI vagal afferent ablation. The locus coeruleus (LC) is a relay center connecting the nucleus tractus solitarius to the basolateral amygdala (BLA) in controlling anxiety-like behaviors. Chemogenetic silencing of noradrenergic LC projections to the BLA reduced anxiety-like behaviors in DSS-treated mice. This work expands our understanding of the neural mechanisms by which IBD leads to comorbid anxiety and emphasizes a critical role of gastric vagal afferent signaling in gut-to-brain regulation of emotional states.
Chin-Hao Chen, Tsung-Chih Tsai, Yi-Jen Wu, Kuei-Sen Hsu
Growing evidence indicates that the glucagon-like-peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Semaglutide is a long-acting GLP-1 analogue with compelling characteristics for clinical translation. The goal of this study was to examine the effects of semaglutide on biobehavioral correlates of alcohol use in rodents, using psychopharmacology and electrophysiology experiments. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on both binge-like and dependence-induced alcohol drinking in male and female rats. Finally, the acute effects of semaglutide on GABA neurotransmission were examined by recording spontaneous inhibitory postsynaptic currents (sIPSCs) from central nucleus of the amygdala (CeA) and infralimbic cortex (ILC) neurons. Results showed that semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/non-caloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. In alcohol-naïve rats, an acute application of semaglutide increased sIPSC frequency in CeA and ILC neurons, suggesting enhanced GABA release, while in alcohol-dependent rats, semaglutide did not significantly alter overall CeA and ILC GABA transmission. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission in rodents, providing support for clinical testing of semaglutide as a potential novel pharmacotherapy for AUD.
Vicky Chuong, Mehdi Farokhnia, Sophia Khom, Claire L. Pince, Sophie K. Elvig, Roman Vlkolinsky, Renata C.N. Marchette, George F. Koob, Marisa Roberto, Leandro F. Vendruscolo, Lorenzo Leggio
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in SACS gene encoding sacsin, a huge protein highly expressed in cerebellar Purkinje cells (PCs). ARSACS patients, as well as mouse models, display early degeneration of PCs, but the underlying mechanisms remain unexplored, with no available treatments. In this work, we demonstrated aberrant calcium (Ca2+) homeostasis and its impact on PC degeneration in ARSACS. Mechanistically, we found pathological elevation in Ca2+-evoked responses in Sacs-/- PCs, as the result of defective mitochondria and ER trafficking to distal dendrites and strong downregulation of key Ca2+ buffer-proteins. Alteration of cytoskeletal linkers, that we identified as specific sacsin interactors, likely account for faulty organellar trafficking in Sacs-/- cerebellum. Based on this pathogenetic cascade, we treated Sacs-/- mice with Ceftriaxone, a repurposed drug which exerts neuroprotection by limiting neuronal glutamatergic stimulation, and thus Ca2+ fluxes into PCs. Ceftriaxone treatment significantly improved motor performances of Sacs-/- mice, at both pre- and post-symptomatic stages. We correlated this effect to restored Ca2+ homeostasis, which arrests PC degeneration and attenuates secondary neuroinflammation. These findings disclose new key steps in ARSACS pathogenesis and support further optimization of Ceftriaxone in pre-clinical and clinical settings for the treatment of ARSACS patients.
Andrea Del Bondio, Fabiana Longo, Daniele De Ritis, Erica Spirito, Paola Podini, Bernard Brais, Angela Bachi, Angelo Quattrini, Francesca Maltecca
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