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Objective: This study aimed to determine a dopaminergic circuit required for diet‐induced obesity in mice. Methods: We created conditional deletion mutants for tyrosine hydroxylase (TH) using neurotensin receptor 1 (Ntsr1) Cre and other Cre drivers and measured feeding and body weight on standard and high‐fat diets. We then used an adeno‐associated virus to selectively restore TH to the ventral tegmental area (VTA) Ntsr1 neurons in conditional knockout (cKO) mice. Results: Mice with cKO of Th using Vglut2‐Cre, Cck‐Cre, Calb1‐Cre, and Bdnf‐Cre were susceptible to obesity on a high‐fat diet; however, Ntsr1‐CreTh cKO mice resisted weight gain on a high‐fat diet and did not experience an increase in day eating unlike their wild‐type littermate controls. Restoration of TH to the VTA Ntsr1 neurons of the Ntsr1‐CreTh cKO mice using an adeno‐associated virus resulted in an increase in weight gain and day eating on a high‐fat diet. Conclusions: Ntsr1‐CreTh cKO mice failed to increase day eating on a high‐fat diet, offering a possible explanation for their resistance to diet‐induced obesity. These results implicate VTA Ntsr1 dopamine neurons as promoting out‐of‐phase feeding behavior on a high‐fat diet that could be an important contributor to diet‐induced obesity in humans. [ABSTRACT FROM AUTHOR]

Author(s): Wooseong Kim [1]; Wenpeng Zhu [2]; Gabriel Lambert Hendricks [1]; Daria Van Tyne [3, 4]; Andrew D. Steele [5, 6]; Colleen E. Keohane [5, 6]; Nico Fricke [2]; Annie [...]

Neurodegenerative disorders (NDDs) such as Huntington's disease (HD) and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by progressive loss of selectively vulnerable populations of neurons. Although often associated with motor impairments, these NDDs share several commonalities in early symptoms and signs that extend beyond motor dysfunction. These include impairments in social cognition and psychiatric symptoms. Oxytocin (OXT) is a neuropeptide known to play a pivotal role in the regulation of social cognition as well as in emotional behaviors such as anxiety and depression. Here, we present an overview of key results implicating OXT in the pathology of HD, ALS and FTD and seek to identify commonalities across these NDDs. OXT is produced in the hypothalamus, a region in the brain that during the past decade has been shown to be affected in HD, ALS, and FTD. Several studies using human postmortem neuropathological analyses, measurements of cerebrospinal fluid, experimental treatments with OXT as well as genetic animal models have collectively implicated an important role of central OXT in the development of altered social cognition and psychiatric features across these diseases. Understanding central OXT signaling may unveil the underlying mechanisms of early signs of the social cognitive impairment and the psychiatric features in NDDs. It is therefore possible that OXT might have potential therapeutic value for early disease intervention and better symptomatic treatment in NDDs. [ABSTRACT FROM AUTHOR]

The misfolding of the prion protein (Pr[P.sup.c]) is a central event in prion diseases, yet the normal function of Pr[P.sup.c] remains unknown. Pr[P.sup.c] has putative roles in many cellular processes including signaling, survival, adhesion, and differentiation. Given the abundance of Pr[P.sup.c] in the developing and mature mammalian CNS, we investigated the role of Pr[P.sup.c] in neural development and in adult neurogenesis, which occurs constitutively in the dentate gyrus (DG) of the hippocampus and in the olfactory bulb from precursors in the subventricular zone (SVZ)/rostral migratory stream. In vivo, we find that Pr[P.sup.c] is expressed immediately adjacent to the proliferative region of the SVZ but not in mitotic cells. In vivo and in vitro studies further find that Pr[P.sup.c] is expressed in multipotent neural precursors and mature neurons but is not detectable in glia. Loss- and gain-of-function experiments demonstrate that Pr[P.sup.c] levels correlate with differentiation of multipotent neural precursors into mature neurons in vitro and that Pr[P.sup.c] levels positively influence neuronal differentiation in a dose-dependent manner. Pr[P.sup.c] also increases cellular proliferation in vivo; in the SVZ, Pr[P.sup.c] overexpresser (OE) mice have more proliferating cells compared with wild-type (WT) or knockout (KO) mice; in the DG, Pr[P.sup.c] OE and WT mice have more proliferating cells compared with KO mice. Our results demonstrate that Pr[P.sup.c] plays an important role in neurogenesis and differentiation. Because the final number of neurons produced in the DG is unchanged by Pr[P.sup.c] expression, other factors must control the ultimate fate of new neurons. neural development | neural precursor | subventricular zone dentate gyrus

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.05.041 Byline: Adriano Aguzzi (1), Andrew D. Steele (2) Abstract: Inactivation of mahogunin, an E3 ubiquitin ligase, causes a spongiform encephalopathy resembling prion disease. now report that prion proteins with aberrant topologies inactivate mahogunin, providing a plausible explanation for certain aspects of prion pathology. Author Affiliation: (1) Institute of Neuropathology, University Hospital Zurich, Zurich CH-8091, Switzerland (2) Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA

Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillinresistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membraneactive antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent. [ABSTRACT FROM AUTHOR]