Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior.

Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects

Pathotype variation of barley powdery mildew in Western Australia

Barley powdery mildew caused by the fungus Blumeria graminis f. sp. hordei (Bgh) has emerged as the most damaging disease of barley in Western Australia (WA). Many of the available cultivars display high levels of disease in the field when climatic conditions are conducive. As a result, fungicides have become the main method of disease control in the last 10 years. Different types and sources of genetic disease resistance are available but to optimise their deployment it is necessary to evaluate the spectrum of pathotypes present in the pathogen population. Sixty isolates of Bgh were collected in the 2009 season from 9 locations, single spored and characterised by infection on reference barley lines and cultivars. Eighteen unique pathotypes were resolved. Virulence against many of the R-genes in the reference lines was present in at least one pathotype. Isolates were virulent against 16 out of a total of 23 resistance gene combinations. Undefeated resistance genes included the major R-genes Mla-6, Mla-9, Ml-ra and the combinations of Mla-1 plus Mla-A12 and Mla-6 plus Mla-14 and Mla-13 plus Ml-Ru3 together with the recessive resistance gene mlo-5. There was significant pathotype spatial differentiation suggesting limited gene flow between different regions with WA or localised selection pressures and proliferation. On the basis of the results we recommend a number of strategies to manage powdery mildew disease levels within WA

A ten-dimensional action for non-geometric fluxes

The NSNS Lagrangian of ten-dimensional supergravity is rewritten via a change of field variables inspired by Generalized Complex Geometry. We obtain a new metric and dilaton, together with an antisymmetric bivector field which leads to a ten-dimensional version of the non-geometric Q-flux. Given the involved global aspects of non-geometric situations, we prescribe to use this new Lagrangian, whose associated action is well-defined in some examples investigated here. This allows us to perform a standard dimensional reduction and to recover the usual contribution of the Q-flux to the four-dimensional scalar potential. An extension of this work to include the R-flux is discussed. The paper also contains a brief review on non-geometry.Comment: 47 pages; v2: minor modifications, references added, version to be published in JHE

Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior.

Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects

Cross-hemispheric gamma synchrony between prefrontal parvalbumin interneurons supports behavioral adaptation during rule shift learning.

Organisms must learn new strategies to adapt to changing environments. Activity in different neurons often exhibits synchronization that can dynamically enhance their communication and might create flexible brain states that facilitate changes in behavior. We studied the role of gamma-frequency (~40 Hz) synchrony between prefrontal parvalbumin (PV) interneurons in mice learning multiple new cue-reward associations. Voltage indicators revealed cell-type-specific increases of cross-hemispheric gamma synchrony between PV interneurons when mice received feedback that previously learned associations were no longer valid. Disrupting this synchronization by delivering out-of-phase optogenetic stimulation caused mice to perseverate on outdated associations, an effect not reproduced by in-phase stimulation or out-of-phase stimulation at other frequencies. Gamma synchrony was specifically required when new associations used familiar cues that were previously irrelevant to behavioral outcomes, not when associations involved new cues or for reversing previously learned associations. Thus, gamma synchrony is indispensable for reappraising the behavioral salience of external cues