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The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD)-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER) stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment.

Following the suggestion of arXiv:1407.6319 to lift the knot polynomials for virtual knots and links from Jones to HOMFLY, we apply the evolution method to calculate them for an infinite series of twist-like virtual knots and antiparallel 2-strand links. Within this family one can check topological invariance and understand how differential hierarchy is modified in virtual case. This opens a way towards a definition of colored (not only cabled) knot polynomials, though problems still persist beyond the first symmetric representation., Comment: 28 pages

Virtual knots are associated with knot diagrams, which are not obligatory planar. The recently suggested generalization from N=2 to arbitrary N of the Kauffman-Khovanov calculus of cycles in resolved diagrams can be straightforwardly applied to non-planar case. In simple examples we demonstrate that this construction preserves topological invariance -- thus implying the existence of HOMFLY extension of cabled Jones polynomials for virtual knots and links., Comment: 12 pages

Every higher-order association cortex receives a variety of synaptic signals from different regions of the brain. How these cortical networks are capable of differentially responding to these various extrinsic synaptic inputs remains unclear. To address this issue, we studied how the basolateral amygdala (BLA) and the anterior piriform cortex (aPC) were functionally connected to the association olfactory cortex, the posterior piriform cortex (pPC). We infected the BLA and aPC with adeno-associated virus expressing channelrhodopsin-2-Venus fusion protein (ChR2-AAV) and recorded the excitatory postsynaptic currents (EPSC) resulting from photostimulation of either BLA or aPC axons in the major classes of excitatory and inhibitory neurons of the pPC. We found that BLA and aPC axons evoked monosynaptic EPSCs in every type of pPC neuron, but each fiber system preferentially targeted one excitatory and one inhibitory neuronal subtype. BLA fibers were most strongly connected to deep pyramidal cells (DP) and fast-spiking interneurons (FS), while aPC axons formed the strongest synaptic connections with DPs and irregular-spiking interneurons (IR). Overall, our findings show that the pPC differentially responds to amygdaloid versus cortical inputs by utilizing distinct local microcircuits, each defined by one predominant interneuronal subtype: FS for the BLA and IR for the aPC. It would thus seem that preferential excitation of a single neuronal class could be sufficient for the pPC to generate unique electrophysiological outputs in response to divergent synaptic input sources.

In temporal gauge A_{0}=0 the 3d Chern-Simons theory acquires quadratic action and an ultralocal propagator. This directly implies a 2d R-matrix representation for the correlators of Wilson lines (knot invariants), where only the crossing points of the contours projection on the xy plane contribute. Though the theory is quadratic, P-exponents remain non-trivial operators and R-factors are easier to guess then derive. We show that the topological invariants arise if additional flag structure (xy plane and an y line in it) is introduced, R is the universal quantum R-matrix and turning points contribute the "enhancement" factors q^{\rho}., Comment: 27 pages, 17 figures

We perform a systematic study of various versions of massive gravity with and without violation of Lorentz symmetry in arbitrary dimension. These theories are well known to possess very unusual properties, unfamiliar from studies of gauge and Lorentz invariant models. These peculiarities are caused by mixing of familiar transverse fields with revived longitudinal and pure gauge (Stueckelberg) fields and are all seen already in quadratic approximation. They are all associated with non-trivial dispersion laws, which easily allow superluminal propagation, ghosts, tachyons and essential irrationalities. Moreover, coefficients in front of emerging modes are small, what makes the theories essentially non-perturbative within a large Vainshtein radius. Attempts to get rid of unwanted degrees of freedom by giving them infinite masses lead to DVZ discontinuities in parameter (moduli) space, caused by un-permutability of different limits. Also, the condition m_{gh}=\infty can not be preserved already in non-trivial gravitational backgrounds and is unstable under any other perturbations of linearized gravity. At the same time an {\it a priori} healthy model of massive gravity in quadratic approximation definitely exists: provided by any mass level of Kaluza-Klein tower. It bypasses the problems because gravity field is mixed with other fields, and this explains why such mixing helps in other models. At the same time this can imply that the really healthy massive gravity can still require infinite number of extra fields beyond quadratic approximation., Comment: 46 pages

We analyze the pattern of normal modes in linearized Lorentz-violating massive gravity over the 5-dimensional moduli space of mass terms. Ghost-free theories arise at bifurcation points when the ghosts get out of the spectrum of propagating particles due to vanishing of the coefficient in front of \omega^2 in the propagator. Similarly, the van Dam-Veltman-Zakharov (DVZ) discontinuities in the Newton law arise at another type of bifurcations, when the coefficient vanishes in front of \vec k^2. When the Lorentz invariance is broken, these two kinds of bifurcations get independent and one can easily find a ghost-free model without the DVZ discontinuity in the moduli space, at least, in the quadratic (linearized) approximation., Comment: 29 pages

Expression of VP16-CREB, a constitutively active form of CREB, in hippocampal neurons of the CA1 region lowers the threshold for eliciting the late, persistent phase of long-term potentiation (L-LTP) in the Schaffer collateral pathway. This VP16-CREB-mediated L-LTP differs from the conventional late phase of LTP in not being dependent on new transcription. This finding suggests that in the transgenic mice the mRNA transcript(s) encoding the protein(s) necessary for this form of L-LTP might already be present in CA1 neurons in the basal condition. We used high-density oligonucleotide arrays to identify the mRNAs differentially expressed in the hippocampus of transgenic and wild-type mice. We then explored the contribution of the most prominent candidate genes revealed by our screening, namely prodynorphin, BDNF, and MHC class I molecules, to the facilitated LTP of VP16-CREB mice. We found that the overexpression of brain-derived neurotrophic factor accounts for an important component of this phenotype.