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Animal Models of Down Syndrome and Other Genetic Diseases Associated with Mental Retardation
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Angela J. Villar, Charles J. Epstein
The mouse genome contains two Sim genes, Sim1 and Sim2. They are presumed to be important for central nervous system (CNS) development because they are orthologous to the Drosophila single-minded (Sim) gene, mutations of which cause a complete loss of CNS midline cells (117). Mice overexpressing mouse Sim2 under the control of the beta-actin promoter have normal skeletal brain and heart structures, but they exhibit a moderate defect in context-dependent fear conditioning and a mild defect in the Morris water maze test. Mice with an extra copy of human SIM2 display reduced exploratory behavior and sensitivity to pain (118). Taken together, overexpression of the Sim2 gene results in abnormalities involving spatial exploration, social interactions, and reduced nociception and may be important for the pathogenesis of DS, especially mental retardation (119).
Untangling Appetite Circuits with Optogenetics and Chemogenetics
Published in Ruth B.S. Harris, Appetite and Food Intake, 2017
To pinpoint the relevant downstream ARCAgRP circuits mediating feeding behavior, a variety of optogenetic and chemogenetic strategies were employed. The majority of studies focused on the PVH, based on (a) pharmacology, (b) lesion, (c) microscopy, and (d) mapping data, strongly implicating this structure as a putative downstream target of ARCAgRP neurons (Aravich and Sclafani 1983, Atasoy et al. 2014, Broberger et al. 1998, Gold, Jones, and Sawchenko 1977). The majority of PVH neurons are marked by the transcription factor Single-minded 1 (SIM1), which is required for proper development (Michaud et al. 1998). Both knock out of Sim1 or ablation of PVHSIM1 neurons trigger obesity (Tolson et al. 2010, Xi et al. 2012). To demonstrate sufficiency of these PVHSIM1 neurons as well as their direct influence on the ARCAgRP neural circuit, ChR2 was used to costimulate the ARCAgRP → PVH projections and PVHSIM1 neurons, which completely suppressed the ARCAgRP neuron-induced eating (Atasoy et al. 2012). Concordantly, deletion of the GABA-A receptor γ2 subunit in PVHSIM1 neurons impaired GABAergic input and reduced feeding (Wu et al. 2015).
Dopaminergic and other genes related to reward induced overeating, Bulimia, Anorexia Nervosa, and Binge eating
Published in Expert Review of Precision Medicine and Drug Development, 2022
Kenneth Blum, Panayotis K. Thanos, Gene -Jack Wang, Abdalla Bowirrat, Luis Llanos Gomez, David Baron, Rehan Jalali, Marjorie C Gondré-Lewis, Mark S Gold
It is now generally accepted that genetic predisposition may contribute as high as 70% to the overall disease of obesity, whereas the environmental contribution is 30% [89]. Like other reward deficit disorders, despite genetic antecedents, the development of obesity as a disease per se is complex involving epigenetic insults. One study investigating the role of mutations in the leptin-melanocortin pathway genes and monogenic obesity revealed that of all genes tested (MC4R, POMC, PCSK1, SIM1, or PTEN), the polymorphisms of the MC4R alone achieved the best outcomes in terms of weight loss after primary Roux-en-Y gastric bypass compared with sleeve gastrectomy after two years post-surgery [90]. It is noteworthy that López-Rodríguez et al. found children of European ancestry had a higher frequency of risk variants in the FTO and MC4R genes compared with Amerindian ancestral children [91]. Moreover, many researchers have confirmed the FTO risk polymorphism’s role in severe obesity [92–97].
Current understanding and controversies on the clinical implications of fibroblast growth factor 21
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
A recent study suggested that FGF21 also mediates water consumption following alcohol and KD consumption [102]. Plasma FGF21 levels were found to be increased by either alcohol or KD consumption in mice [102]. FGF21 administration increased water drinking behavior in mice, while FGF21 knockout mice failed to increase water intake in response to either alcohol or KD consumption. This study also indicated the involvement of single-minded homolog 1 (SIM1)-positive neurons in the hypothalamus [102]. Another recent study showed that FGF21 analogue administration in rats resulted in increased water intake and urinary output, associated with an elevated heart rate and blood pressure for 5–10 days after initial injection. The underlying mechanism was proposed to be sympathetic activation, leading to acute hypertension in FGF21 treated rats [103].
From leptin to lasers: the past and present of mouse models of obesity
Published in Expert Opinion on Drug Discovery, 2021
Joshua R. Barton, Adam E. Snook, Scott A. Waldman
Other methods of neuromodulation eliminate the need for light-producing hardware altogether. ‘Chemogenetics’ uses designer compounds to activate engineered G protein-coupled receptors (GPCRs) that modulate neuronal excitability and transmission [137]. These GPCRs, also known as designer receptors exclusively activated by designer drug (DREADDs), can be genetically encoded and expressed in particular tissues and cell types through viral or transgenic methods. Clozapine-N-oxide (CNO) is the designer drug used to activate DREADDs, as it is an inert, bioavailable compound that interacts solely with DREADDs [137]. Expression of an inhibitory DREADD (hM4D), in ARCAGRP+ neurons using the AGRP-Cre mouse, reduces feeding by 40% after injection of CNO [138]. These appetite-inducing ARCAGRP+ neurons were known to act on paraventricular hypothalamus SIM1+ neurons (PVHSIM1+), but the rest of the circuit was not known. Expression of the same inhibitory DREADD in PVHSIM1+ neurons revealed a new appetitive circuit from the PVH to the DRN in the brainstem. Injection of CNO into mice expressing hM4D in PVHSIM1+ neurons decreased synaptic transmission to the DRN and recapitulated the 40% feeding reduction produced by inhibiting ARCAGRP+ neurons [138].