Extending Chirality in Group XIV Metallatranes.

The syntheses of the racemic amino alcohol rac-N(CH2CMe2OH)(CMe2CH2OH)(CH2CHMeOH) (L22'1*H3, 2) and its representative N(CH2CMe2OH)(CMe2CH2OH)(CH2C(R)HMeOH) (L22'1RH3, 3) with the stereogenic carbon center being R-configured are reported. Also reported are the stannatranes L22'1*SnOt-Bu (4) L22'1RSnOt-Bu (6) and germatranes L22'1*GeOEt (5) and L22'1RGeOEt (7) as well as the trinuclear tin oxocluster [(µ3-O)(µ3-O-t-Bu){SnL22'1R}3] (8). NMR and IR spectroscopy, electrospray ionization mass spectrometry (ESI MS), and single crystal X-ray diffraction analysis characterize these compounds. Computational studies accompany the experimental work and help understand the diastereoselectivity observed in the course of the metallatrane syntheses.

Chelating Phosphorus-An O, C, O-Coordinating Pincer-Type Ligand Coordinating PIII and PV Centres.

The sequence of reactions of the phosphorus-containing aryllithium compound 5-t-Bu-1,3-[(P(O)(O-i-Pr)2 ]2 C6 H2 Li (ArLi) with Ph2 PCl, KMnO4 , elemental sulfur and elemental selenium, respectively, gave the aryldiphenylphosphane chalcogenides 5-t-Bu-1,3-[(P(O)(O-i-Pr)2 ]2 C6 H2 P(E)Ph2 (1, E=O; 2, E=S; 3, E=Se). Compound 1 partially hydrolysed giving [5-t-Bu-1-{(P(O)(O-i-Pr)2 }-3-{(P(O)(OH)2 }C6 H2 ]P(O)Ph2 (4). The reaction of ArLi with PhPCl2 provided the benzoxaphosphaphosphole [1(P), 3(P)-P(O)(O-i-Pr)OPPh-6-t-Bu-4-P(O)(O-i-Pr)2 ]C6 H2 P (5i) as a mixture of the two diastereomers. The oxidation of 5i with elemental sulfur gave the benzoxaphosphaphosphole sulfide [1(P), 3(P)-P(O)(O-i-Pr)OP(S)Ph-6-t-Bu-4-P(O)(O-i-Pr)2 ]C6 H2 (5) as pair of enantiomers P1(R), P3(S)/P1(S), P3(R) of the diastereomer (RS/SR)-5 (5b). The aryldiphenylphosphane 5-t-Bu-1,3-[(P(O)(O-i-Pr)2 ]2 C6 H2 PPh2 (6) was obtained from the reaction of the corresponding aryldiphenylphosphane sulfide 2 with either sodium hydride, NaH, or disodium iron tetracarbonyl, Na2 Fe(CO)4 . The oxidation of the aryldiphenylphosphane 6 with elemental iodine and subsequent hydrolysis yielded the aryldiphenyldioxaphosphorane 9-t-Bu-2,6-(OH)-4,4-Ph2 -3,5-O2 -2,6-P2 -4λ5 -P-[5.3.1.0]-undeca-1(10),7(11),8-triene (7). Both of its diastereomers, (RR/SS)-7 (7a) and (RS/SR)-7 (7b), were separated as their chloroform and i-propanol solvates, 7a⋅2CHCl3 and 7b⋅i-PrOH, respectively. DFT calculations accompanied the experimental work.

MeSi(CH2 SnRO)3 (R=Ph, Me3 SiCH2 ): Building Blocks for Triangular-Shaped Diorganotin Oxide Macrocycles.

The syntheses of the novel silicon-bridged tris(tetraorganotin) compounds MeSi(CH2 SnPh2 R)3 (2, R=Ph; 5, R=Me3 SiCH2 ) and their halogen-substituted derivatives MeSi(CH2 SnPh(3-n) In )3 (3, n=1; 4, n=2) and MeSi(CH2 SnI2 R)3 (6, R=Me3 SiCH2 ) are reported. The reaction of compound 4 with di-t-butyltin oxide (t-Bu2 SnO)3 gives the oktokaideka-nuclear (18-nuclear) molecular diorganotin oxide [MeSi(CH2 SnPhO)3 ]6 (7) while the reaction of 6 with sodium hydroxide, NaOH, provides the trikonta-nuclear (30-nuclear) molecular diorganotin oxide [MeSi(CH2 SnRO)3 ]10 (8, R=Me3 SiCH2 ). Both 7 and 8 show belt-like ladder-type macrocyclic structures and are by far the biggest molecular diorganotin oxides reported to date. The compounds have been characterized by elemental analyses, electrospray mass spectrometry (ESI-MS), NMR spectroscopy, 1 H DOSY NMR spectroscopy (7), IR spectroscopy (7, 8), and single-crystal X-ray diffraction analysis (2, 7, 8).

Control of Λ- and Δ-Isomerization of the Atrane Cages in Group XIV Metallatranes by Chiral Axial Substituents.

The syntheses of the novel stannatranes N(CH2CMe2O)3Sn-(1 S)-(-)-OC(O)C(OMe)(CF3)(C6H5), 1( S, Δ), and N(CH2CMe2O)3Sn-(1 R)-(+)-OC(O)C(OMe)(CF3)(C6H5), 2( R, Λ), and germatranes N(CH2CMe2O)3Ge-(1 S)-(-)-OC(O)C(OMe)(CF3)(C6H5), 3( S, Δ), and N(CH2CMe2O)3Ge-(1 R)-(+)-OC(O)C(OMe)(CF3)(C6H5), 4( R, Λ) (with 1, S, Δ-configured/2, R, Λ-configured and 3, S, Δ-configured/4, R, Λ-configured being pairs of enantiomers) are reported. The compounds were characterized by NMR and IR spectroscopy, electrospray ionization mass spectrometry, and single crystal X-ray diffraction analysis. The epimerization via Λ â‡Œ Δ ring flip of the enantiomeric stannatrane pair 1( S, Δ)/2( R, Λ) was investigated by NMR experiments at variable temperatures and density functional theory (DFT) calculations.

Cis versus Trans: The Coordination Environment about the Tin(IV) Atom in Spirocyclic Amino Alcohol Derivatives.

The syntheses of amino alcohols MeN(CH2 CH2 CMe2 OH)2 (1), MeN(CMe2 CH2 OH)(CH2 CMe2 OH) (2), MeN(CH2 CH2 CH2 OH)(CH2 CMe2 OH) (3), MeN(CH2 CH2 CMe2 OH)(CH2 CMe2 OH) (4), MeN(CH2 CH2 CMe2 OH)(CH2 CH2 OH) (5), and MeN(CH2 CH2 OH) (CH2 CH2 CH2 OH) (6) as well as spirocyclic tin(IV) alkoxides spiro-[nBuN(CH2 CMe2 O)2 ]2 Sn (7), spiro-[MeN(CH2 CH2 CMe2 O)2 ]2 Sn (8), spiro-[para-FC6 H4 N (CH2 CMe2 O)2 ]2 Sn (9), spiro-[MeN(CMe2 CH2 O)(CH2 CMe2 O)]2 Sn (10), spiro-[MeN(CH2 CH2 CH2 O)(CH2 CMe2 O)]2 Sn (11), spiro-[MeN(CH2 CH2 CMe2 O)(CH2 CMe2 O)]2 Sn (12), spiro-[MeN(CH2 CH2 CMe2 O)(CH2 CH2 O)]2 Sn (13) and spiro-[MeN(CH2 CH2 O)(CH2 CH2 CH2 O)]2 Sn (14) are reported. The compounds were characterized by 1 H, 13 C (1-14) and 119 Sn (7-14) NMR and IR spectroscopy, EIMS and single-crystal XRD (2, 7-10 and 13, 14). Graph-set analyses were performed for compounds [(MeNH(CMe2 CH2 OH)(CH2 CMe2 OH)][HC(O)O] (2 a) and 2. The coordination environment about the tin(IV) centre of the spirocyclic compounds and their possible stereoisomers were analysed by DFT calculations (spiro-[MeN(CH2 CMe2 O)2 ]2 Sn, 8-10 and 13).

Reactivity of Elemental Tin and Zinc toward Organophosphonic Acid Dialkyl Esters: A New One-Pot Recipe for the Synthesis of Coordination Assemblies Derived from O-Alkylorganophosphonate Ligands.

A new recipe for the synthesis of diorganotin bis(O-alkylorganophosphonate)s, R12Sn{O(P)(O)(OR1)R}2 [R = R1 = methyl (1); R1 = ethyl and R = methyl (2), allyl (3), 2-thienyl (4), benzyl (5)], has been developed from the direct reaction of elemental tin (powder) with organophosphonic acid dialkyl esters, RP(O)(OR1)2, in the presence of a catalytic amount of potassium iodide under ambient conditions (130 °C, 18-20 h). The key steps in the proposed catalytic cycle involve the monodealkylation of phosphonate diester and in situ generation of a R1SnI or R12SnI2 intermediate via the oxidative addition of alkyl iodide on tin. Evidence in support of the formation of organotin species comes from the isolation of Me2Sn{O(P)(O)(OiPr)Me}2 (6) from the direct reaction of tin metal with MeP(O)(OiPr)2 in the presence of methyl iodide. The method has also been extended to isolate Zn{OP(O)(OMe)Me}2 (7) using metallic zinc as the precursor. All of the compounds have been characterized by IR and NMR studies as well as X-ray crystallography for 2, 4, 6, and 7.

Introducing Stereogenic Centers to Group XIV Metallatranes.

The syntheses of the novel amino alcohols NH(CH2CMe2OH)2(CMe2CH2OH) (1) and N(CH2CMe2OH)(CMe2CH2OH)(CH2CH2OH) (2) as well as the stannatranes N(CH2CMe2O)(CMe2CH2O)(CH2CH2O)SnX (3, X = Ot-Bu), N(CH2CMe2O)3SnOC(O)C9H13O2, 4, and germatranes N(CH2CMe2O)(CMe2CH2O)(CH2CH2O)GeX (5, X = OEt; 6, X = Br) are reported. The compounds were characterized by 1H, 13C (1-6), 119Sn (3, 4), and 15N (2, 3, 5) NMR and IR spectroscopy, electrospray ionization mass spectrometry, and single crystal X-ray diffraction analysis. Graphset analyses were performed for compounds 1 and 2. Detailed NMR spectroscopic studies including variable temperature 1H (3, 5, 6) and 119Sn (3, 4) DOSY experiments reveal the stannatrane 3 being involved in a monomer-dimer equilibrium. Both the stannatranes 3 and 4 as well as the germatranes 5 and 6 show Λ â‡Œ Δ isomerization of the atrane cages in solution.

Silicon- and Tin-Containing Open-Chain and Eight-Membered-Ring Compounds as Bicentric Lewis Acids toward Anions.

Herein, we report the syntheses of silicon- and tin-containing open-chain and eight-membered-ring compounds Me2 Si(CH2 SnMe2 X)2 (2, X=Me; 3, X=Cl; 4, X=F), CH2 (SnMe2 CH2 I)2 (7), CH2 (SnMe2 CH2 Cl)2 (8), cyclo-Me2 Sn(CH2 SnMe2 CH2 )2 SiMe2 (6), cyclo-(Me2 SnCH2 )4 (9), cyclo-Me(2-n) Xn Sn(CH2 SiMe2 CH2 )2 SnXn Me(2-n) (5, n=0; 10, n=1, X=Cl; 11, n=1, X=F; 12, n=2, X=Cl), and the chloride and fluoride complexes NEt4 [cyclo- Me(Cl)Sn(CH2 SiMe2 CH2 )2 Sn(Cl)Me⋅F] (13), PPh4 [cyclo-Me(Cl)Sn(CH2 SiMe2 CH2 )2 Sn(Cl)Me⋅Cl] (14), NEt4 [cyclo-Me(F)Sn(CH2 SiMe2 CH2 )2 Sn(F)Me⋅F] (15), [NEt4 ]2 [cyclo-Cl2 Sn(CH2 SiMe2 CH2 )2 SnCl2 ⋅2 Cl] (16), M[Me2 Si(CH2 Sn(Cl)Me2 )2 ⋅Cl] (17 a, M=PPh4 ; 17 b, M=NEt4 ), NEt4 [Me2 Si(CH2 Sn(Cl)Me2 )2 ⋅F] (18), NEt4 [Me2 Si(CH2 Sn(F)Me2 )2 ⋅F] (19), and PPh4 [Me2 Si(CH2 Sn(Cl)Me2 )2 ⋅Br] (20). The compounds were characterised by electrospray mass-spectrometric, IR and (1) H, (13) C, (19) F, (29) Si, and (119) Sn NMR spectroscopic analysis, and, except for 15 and 18, single-crystal X-ray diffraction studies.

Novel Stannatrane N(CH2CMe2O)2(CMe2CH2O)SnO-t-Bu and Related Oligonuclear Tin(IV) Oxoclusters. Two Isomers in One Crystal.

The syntheses of the alkanolamine N(CH2CMe2OH)2(CMe2CH2OH) (1), of the stannatrane N(CH2CMe2O)2(CMe2CH2O)SnO-t-Bu (2), and of the trinuclear tin oxocluster 3 consisting of the two isomers [(µ3-O)(O-t-Bu){Sn(OCH2CMe2)(OCMe2CH2)2N}3] (3a) and [(µ3-O)(µ3-O-t-Bu){Sn(OCH2CMe2)(OCMe2CH2)2N}3] (3b) as well as the isolation of a few crystals of the hexanuclear tin oxocluster [LSnOSn(OH)3LSnOH]2 [L = N(CH2CMe2O)2(CMe2CH2O)] (4) are reported. The compounds were characterized by 1H, 13C, 15N, and 119Sn (1-3) nuclear magnetic resonance and infrared spectroscopy, electrospray ionization mass spectrometry, and single-crystal X-ray diffraction analysis (1-4). A graph set analysis was performed for compound 1. The relative energies of 3a and 3b were estimated by density functional theory calculations that show that the energy differences are small.

Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice.

Compulsive behavior is a debilitating clinical feature of many forms of neuropsychiatric disease, including Tourette syndrome, obsessive-compulsive spectrum disorders, eating disorders, and autism. Although several studies link striatal dysfunction to compulsivity, the pathophysiology remains poorly understood. Here, we show that both constitutive and induced genetic deletion of the gene encoding the melanocortin 4 receptor (MC4R), as well as pharmacologic inhibition of MC4R signaling, normalize compulsive grooming and striatal electrophysiologic impairments in synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3)-null mice, a model of human obsessive-compulsive disorder. Unexpectedly, genetic deletion of SAPAP3 restores normal weight and metabolic features of MC4R-null mice, a model of human obesity. Our findings offer insights into the pathophysiology and treatment of both compulsive behavior and eating disorders.

Different Complexation Behavior of P-Functionalized Ferrocene Derivatives Towards SnCl2 , SnCl4 and SnPh2 Cl2 : Auto-ionization and Redox-Type Reactions.

The novel phosphonyl-substituted ferrocene derivatives [Fe(η(5) -Cp)(η(5) -C5 H3 {P(O)(O-iPr)2 }2 -1,2)] (Fc(1,2) ) and [Fe{η(5) -C5 H4 P(O)(O-iPr)2 }2 ] (Fc(1,1') ) react with SnCl2 , SnCl4 , and SnPh2 Cl2 , giving the corresponding complexes [(Fc(1,2) )2 SnCl][SnCl3 ] (1), [{(Fc(1,1') )SnCl2 }n ] (2), [(Fc(1,1') )SnCl4 ] (3), [{(Fc(1,1') )SnPh2 Cl2 }n ] (4), and [(Fc(1,2) )SnCl4 ] (5), respectively. The compounds are characterized by elemental analyses, (1) H, (13) C, (31) P, (119) Sn NMR and IR spectroscopy, (31) P and (119) Sn CP-MAS NMR spectroscopy, cyclovoltammetry, electrospray ionization mass spectrometry, and single-crystal as well as powder X-ray diffraction analyses. The experimental work is accompanied by DFT calculations, which help to shed light on the origin for the different reaction behavior of Fc(1,1') and Fc(1,2) towards tin(II) chloride.

N-Coordinated Tin(II) Trifluoromethanesulfonates and Their Reactions with Transition Metal Carbonyls.

The syntheses of the compounds [L(1)SnCl][M(CO)5(SnCl3)] (3, M = W; 4, M = Cr), [L(1)SnCl]OTf (5), [L(1)SnCl][W(CO)5(SnCl2OTf)] (6), [L(1)SnOTf][OTf] (7), and [L(2)Sn(OTf)2] (8) with L(1) = {2,6-[(CH3)C═N(C6H3-2,6-(i)Pr2)2]C5H3N} (DIMPY) and L(2) = {2-[(CH3)C═N(C6H3-2,6-(i)Pr2)]-6-(CH3O)}C5H3N) is reported. The compounds were characterized by elemental analyses, (1)H, (13)C, (19)F, and (119)Sn NMR spectroscopy, electrospray ionization mass spectrometry, and single-crystal X-ray diffraction analyses (3·1.5C7H8, 5·CH2Cl2, 7·C7H8, 8). For compounds 7 and 8, the experimental work is accompanied by density functional theory calculations.

Differential effects of chronic social stress and fluoxetine on meal patterns in mice.

Both chronic stress and antidepressant medications have been associated with changes in body weight. In the current study, we investigate mechanisms by which stress and antidepressants interact to affect meal patterns. A group of mice was subjected to the chronic social defeat stress model of major depression followed by fluoxetine treatment and was subsequently analyzed for food intake using metabolic cages. We report that chronic social defeat stress increases food intake by specifically increasing meal size, an effect that is reversed by fluoxetine treatment. In an attempt to gain mechanistic insight into changes in meal patterning induced by stress and fluoxetine, fasting serum samples were collected every 4h over a 24-h period, and acyl-ghrelin, leptin, and corticosterone levels were measured. Chronic stress induces a peak in acyl-ghrelin levels just prior to the onset of the dark phase, which is shifted in mice treated with fluoxetine. Taken together, these results indicate that stress increases food intake by decreasing satiation, and that fluoxetine can reverse stress-induced changes in meal patterns.

Continuous-Time Fitted Value Iteration for Robust Policies.

Solving the Hamilton-Jacobi-Bellman equation is important in many domains including control, robotics and economics. Especially for continuous control, solving this differential equation and its extension the Hamilton-Jacobi-Isaacs equation, is important as it yields the optimal policy that achieves the maximum reward on a give task. In the case of the Hamilton-Jacobi-Isaacs equation, which includes an adversary controlling the environment and minimizing the reward, the obtained policy is also robust to perturbations of the dynamics. In this paper we propose continuous fitted value iteration (cFVI) and robust fitted value iteration (rFVI). These algorithms leverage the non-linear control-affine dynamics and separable state and action reward of many continuous control problems to derive the optimal policy and optimal adversary in closed form. This analytic expression simplifies the differential equations and enables us to solve for the optimal value function using value iteration for continuous actions and states as well as the adversarial case. Notably, the resulting algorithms do not require discretization of states or actions. We apply the resulting algorithms to the Furuta pendulum and cartpole. We show that both algorithms obtain the optimal policy. The robustness Sim2Real experiments on the physical systems show that the policies successfully achieve the task in the real-world. When changing the masses of the pendulum, we observe that robust value iteration is more robust compared to deep reinforcement learning algorithm and the non-robust version of the algorithm. Videos of the experiments are shown at https://sites.google.com/view/rfvi.

The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress.

We found that increasing ghrelin levels, through subcutaneous injections or calorie restriction, produced anxiolytic- and antidepressant-like responses in the elevated plus maze and forced swim test. Moreover, chronic social defeat stress, a rodent model of depression, persistently increased ghrelin levels, whereas growth hormone secretagogue receptor (Ghsr) null mice showed increased deleterious effects of chronic defeat. Together, these findings demonstrate a previously unknown function for ghrelin in defending against depressive-like symptoms of chronic stress.

Estimating the Prevalence and Genetic Risk Mechanisms of ARFID in a Large Autism Cohort.

This study is the first genetically-informed investigation of avoidant/restrictive food intake disorder (ARFID), an eating disorder that profoundly impacts quality of life for those affected. ARFID is highly comorbid with autism, and we provide the first estimate of its prevalence in a large and phenotypically diverse autism cohort (a subsample of the SPARK study, N = 5,157 probands). This estimate, 21% (at a balanced accuracy 80%), is at the upper end of previous estimates from studies based on clinical samples, suggesting under-diagnosis and potentially lack of awareness among caretakers and clinicians. Although some studies suggest a decrease of disordered eating symptoms by age 6, our estimates indicate that up to 17% (at a balanced accuracy 87%) of parents of autistic children are also at heightened risk for ARFID, suggesting a lifelong risk for disordered eating. We were also able to provide the first estimates of narrow-sense heritability (h2) for ARFID risk, at 0.45. Genome-wide association revealed a single hit near ZSWIM6, a gene previously implicated in neurodevelopmental conditions. While, the current sample was not well-powered for GWAS, effect size and heritability estimates allowed us to project the sample sizes necessary to more robustly discover ARFID-linked loci via common variants. Further genetic analysis using polygenic risk scores (PRS) affirmed genetic links to autism as well as neuroticism and metabolic syndrome.

The legacy of hope summit: a consensus-based initiative and report on eating disorders in the U.S. and recommendations for the path forward.

BACKGROUND: Several unsuccessful attempts have been made to reach a cross-disciplinary consensus on issues fundamental to the field of eating disorders in the United States (U.S.). In January 2020, 25 prominent clinicians, academicians, researchers, persons with lived experience, and thought leaders in the U.S. eating disorders community gathered at the Legacy of Hope Summit to try again. This paper articulates the points on which they reached a consensus. It also: (1) outlines strategies for implementing those recommendations; (2) identifies likely obstacles to their implementation; and (3) charts a course for successfully navigating and overcoming those challenges. METHODS: Iterative and consensual processes were employed throughout the Summit and the development of this manuscript. RESULTS: The conclusion of the Summit culminated in several consensus points, including: (1) Eating disorder outcomes and prevention efforts can be improved by implementing creative health education initiatives that focus on societal perceptions, early detection, and timely, effective intervention; (2) Such initiatives should be geared toward parents/guardians, families, other caretakers, and frontline healthcare providers in order to maximize impact; (3) Those afflicted with eating disorders, their loved ones, and the eating disorders community as a whole would benefit from greater accessibility to affordable, quality care, as well as greater transparency and accountability on the part of in-hospital, residential, and outpatient health care providers with respect to their qualifications, methodologies, and standardized outcomes; (4) Those with lived experience with eating disorders, their loved ones, health care providers, and the eating disorders community as a whole, also would benefit from the establishment and maintenance of treatment program accreditation, professional credentialing, and treatment type and levels of care guidelines; and (5) The establishment and implementation of effective, empirically/evidence-based standards of care requires research across a diverse range of populations, adequate private and government funding, and the free exchange of ideas and information among all who share a commitment to understanding, treating, and, ultimately, markedly diminishing the negative impact of eating disorders. CONCLUSIONS: Widespread uptake and implementation of these recommendations has the potential to unify and advance the eating disorders field and ultimately improve the lives of those affected. A cross-disciplinary group of eating disorder professionals, thought leaders, and persons with lived experience have come together and reached a consensus on issues that are fundamental to the battle against the life-threatening and life-altering illnesses that are eating spectrum disorders. Those issues include: (1) the need for early detection, intervention, prevention, and evidenced-based standards of care; (2) the critical need to make specialized care more accessible and affordable to all those in need; (3) the importance of developing uniform, evidenced-based standards of care; (4) the need for funding and conducting eating spectrum disorder research; and (5) the indispensability of advocacy, education, and legislation where these illnesses are concerned. During the consensus process, the authors also arrived at strategies for implementing their recommendations, identified likely obstacles to their implementation, and charted a course for successfully navigating and overcoming those challenges. Above all else, the authors demonstrated that consensus in the field of eating spectrum disorders is possible and achievable and, in doing so, lit a torch of hope that is certain to light the path forward for years to come.

Chronic social defeat stress disrupts regulation of lipid synthesis.

Several psychiatric disorders increase the risk of cardiovascular disease, including posttraumatic stress disorder and major depression. While the precise mechanism for this association has not yet been established, it has been shown that certain disorders promote an unfavorable lipid profile. To study the interaction of stress and lipid dysregulation, we utilized chronic social defeat stress (CSDS), a mouse model of chronic stress with features of posttraumatic stress disorder and major depression. Following exposure to CSDS, mice were given access to either regular chow or a Western-style diet high in fat and cholesterol (HFD). The combination of social stress and HFD resulted in significant perturbations in lipid regulation, including two key features of the metabolic syndrome: increased plasma levels of non-HDL cholesterol and intrahepatic accumulation of triglycerides. These effects were accompanied by a number of changes in the expression of hepatic genes involved in lipid regulation. Transcriptional activity of LXR, SREBP1c, and ChREBP were significantly affected by exposure to HFD and CSDS. We present CSDS as a model of social stress induced lipid dysregulation and propose that social stress alters lipid metabolism by increasing transcriptional activity of genes involved in lipid synthesis.

Behavioral Alterations in Mice Carrying Homozygous HDAC4 A778T Missense Mutation Associated With Eating Disorder.

Eating disorders (EDs) are serious mental illnesses thought to arise from the complex gene-environment interactions. DNA methylation patterns in histone deacetylase 4 (HDAC4) locus have been associated with EDs and we have previously identified a missense mutation in the HDAC4 gene (HDAC4 A786T ) that increases the risk of developing an ED. In order to evaluate the biological consequences of this variant and establish a useful mouse model of EDs, here we performed behavioral characterization of mice homozygous for Hdac4 A778T (corresponding to human HDAC4 A786T ) that were further backcrossed onto C57BL/6 background. When fed high-fat diet, male, but not female, homozygous mice showed a trend toward decreased weight gain compared to their wild-type littermates. Behaviorally, male, but not female, homozygous mice spent less time in eating and exhibited reduced motivation to work for palatable food and light phase-specific decrease in locomotor activity. Additionally, homozygous Hdac4 A778T female, but not male, mice display social subordination when subjected to a tube dominance test. Collectively, these results reveal a complex sex- and circadian-dependent role of ED-associated Hdac4 A778T mutation in affecting mouse behaviors. Homozygous Hdac4 A778T mice could therefore be a useful animal model to gain insight into the neurobiological basis of EDs.

Orexin signaling mediates the antidepressant-like effect of calorie restriction.

During periods of reduced food availability, animals must respond with behavioral adaptations that promote survival. Despite the fact that many psychiatric syndromes include disordered eating patterns as a component of the illness, little is known about the neurobiology underlying behavioral changes induced by short-term calorie restriction. Presently, we demonstrate that 10 d of calorie restriction, corresponding to a 20-25% weight loss, causes a marked antidepressant-like response in two rodent models of depression and that this response is dependent on the hypothalamic neuropeptide orexin (hypocretin). Wild-type mice, but not mice lacking orexin, show longer latency to immobility and less total immobility in the forced swim test after calorie restriction. In the social defeat model of chronic stress, calorie restriction reverses the behavioral deficits seen in wild-type mice but not in orexin knock-out mice. Additionally, chronic social defeat stress induces a prolonged reduction in the expression of prepro-orexin mRNA via epigenetic modification of the orexin gene promoter, whereas calorie restriction enhances the activation of orexin cells after social defeat. Together, these data indicate that orexin plays an essential role in mediating reduced depression-like symptoms induced by calorie restriction.