Subanesthetic ketamine treatment promotes abnormal interactions between neural subsystems and alters the properties of functional brain networks

Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine-treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia

Roles of Molecular Layer Interneurons in Sensory Information Processing in Mouse Cerebellar Cortex Crus II In Vivo

Cerebellar cortical molecular layer interneurons (MLIs) play essential roles in sensory information processing by the cerebellar cortex. However, recent experimental and modeling results are questioning traditional roles for molecular layer inhibition in the cerebellum. receptors uncovered larger EPSCs in PCs whose time to peak, half-width and 10–90% rising time were also significantly slower than in MLIs. Biocytin labeling indicated that the MLIs (but not PCs) are dye-coupled.These findings indicate that tactile face stimulation evokes rapid excitation in MLIs and inhibition occurring at later latencies in PCs in mouse cerebellar cortex Crus II. These results support previous suggestions that the lack of parallel fiber driven PC activity is due to the effect of MLI inhibition

Synaptic Responses Evoked by Tactile Stimuli in Purkinje Cells in Mouse Cerebellar Cortex Crus II In Vivo

Sensory stimuli evoke responses in cerebellar Purkinje cells (PCs) via the mossy fiber-granule cell pathway. However, the properties of synaptic responses evoked by tactile stimulation in cerebellar PCs are unknown. The present study investigated the synaptic responses of PCs in response to an air-puff stimulation on the ipsilateral whisker pad in urethane-anesthetized mice.Thirty-three PCs were recorded from 48 urethane-anesthetized adult (6-8-week-old) HA/ICR mice by somatic or dendritic patch-clamp recording and pharmacological methods. Tactile stimulation to the ipsilateral whisker pad was delivered by an air-puff through a 12-gauge stainless steel tube connected with a pressurized injection system. Under current-clamp conditions (I = 0), the air-puff stimulation evoked strong inhibitory postsynaptic potentials (IPSPs) in the somata of PCs. Application of SR95531, a specific GABA(A) receptor antagonist, blocked IPSPs and revealed stimulation-evoked simple spike firing. Under voltage-clamp conditions, tactile stimulation evoked a sequence of transient inward currents followed by strong outward currents in the somata and dendrites in PCs. Application of SR95531 blocked outward currents and revealed excitatory postsynaptic currents (EPSCs) in somata and a temporal summation of parallel fiber EPSCs in PC dendrites. We also demonstrated that PCs respond to both the onset and offset of the air-puff stimulation.These findings indicated that tactile stimulation induced asynchronous parallel fiber excitatory inputs onto the dendrites of PCs, and failed to evoke strong EPSCs and spike firing in PCs, but induced the rapid activation of strong GABA(A) receptor-mediated inhibitory postsynaptic currents in the somata and dendrites of PCs in the cerebellar cortex Crus II in urethane-anesthetized mice

The X-Ray Crystal Structure of Escherichia coli Succinic Semialdehyde Dehydrogenase; Structural Insights into NADP+/Enzyme Interactions

In mammals succinic semialdehyde dehydrogenase (SSADH) plays an essential role in the metabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to succinic acid (SA). Deficiency of SSADH in humans results in elevated levels of GABA and gamma-Hydroxybutyric acid (GHB), which leads to psychomotor retardation, muscular hypotonia, non-progressive ataxia and seizures. In Escherichia coli, two genetically distinct forms of SSADHs had been described that are essential for preventing accumulation of toxic levels of succinic semialdehyde (SSA) in cells.Here we structurally characterise SSADH encoded by the E coli gabD gene by X-ray crystallographic studies and compare these data with the structure of human SSADH. In the E. coli SSADH structure, electron density for the complete NADP+ cofactor in the binding sites is clearly evident; these data in particular revealing how the nicotinamide ring of the cofactor is positioned in each active site.Our structural data suggest that a deletion of three amino acids in E. coli SSADH permits this enzyme to use NADP+, whereas in contrast the human enzyme utilises NAD+. Furthermore, the structure of E. coli SSADH gives additional insight into human mutations that result in disease

Geometry and field theory in multi-fractional spacetime

We construct a theory of fields living on continuous geometries with fractional Hausdorff and spectral dimensions, focussing on a flat background analogous to Minkowski spacetime. After reviewing the properties of fractional spaces with fixed dimension, presented in a companion paper, we generalize to a multi-fractional scenario inspired by multi-fractal geometry, where the dimension changes with the scale. This is related to the renormalization group properties of fractional field theories, illustrated by the example of a scalar field. Depending on the symmetries of the Lagrangian, one can define two models. In one of them, the effective dimension flows from 2 in the ultraviolet (UV) and geometry constrains the infrared limit to be four-dimensional. At the UV critical value, the model is rendered power-counting renormalizable. However, this is not the most fundamental regime. Compelling arguments of fractal geometry require an extension of the fractional action measure to complex order. In doing so, we obtain a hierarchy of scales characterizing different geometric regimes. At very small scales, discrete symmetries emerge and the notion of a continuous spacetime begins to blur, until one reaches a fundamental scale and an ultra-microscopic fractal structure. This fine hierarchy of geometries has implications for non-commutative theories and discrete quantum gravity. In the latter case, the present model can be viewed as a top-down realization of a quantum-discrete to classical-continuum transition.Comment: 1+82 pages, 1 figure, 2 tables. v2-3: discussions clarified and improved (especially section 4.5), typos corrected, references added; v4: further typos correcte

Theoretical Approaches to Quotation in Hip-Hop Recordings

Intertextuality is pervasive in multiple forms of popular music, but is arguably most overtly presented in hip-hop music and culture. While much academic work has focused on linking practices of quotation, reference, allusion and Signifyin(g) in hip-hop to earlier forms of African-American music, the main purpose of this article is to outline and illustrate the variety of ways that one can borrow from a source text or trope and ways that audiences identify and respond to them. Distinctions between allosonic and autosonic quotations (Lacasse), ‘intention’ versus sociohistorically situated interpretations (Nattiez), as well as ‘textually signalled’ and ‘textually unsignalled’ intertextuality (Dyer), help create a more detailed taxonomy within the genre. These and other distinctions, which transcend narrow discourses that only focus on ‘sampling’ (digital sampling), provide a toolkit that sets a context for more nuanced discussions of borrowing practices and offers broader implications for intertextuality within and outside of hip-hop culture. By drawing from a range of examples (e.g. The Pharcyde, Dr Dre, Xzibit), this article demonstrates that a thorough investigation of musical borrowing in hip-hop requires attention to the texts (hip-hop recordings), their reception and wider cultural contexts. Theoretical Approaches to Quotation in Hip-Hop Recordings - ResearchGate. Available from: http://www.researchgate.net/publication/267929949_Theoretical_Approaches_to_Quotation_in_Hip-Hop_Recordings [accessed Mar 26, 2015]