The Journal of neuroscience : the official journal of the Society for Neuroscience
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C fibers display activity-dependent slowing (ADS), whereby repetitive stimulation (≥1 Hz) results in a progressive slowing of action potential conduction velocity, which manifests as a progressive increase in response latency. However, the impact of ADS on spinal pain processing has not been explored, nor whether ADS is altered in inflammatory pain conditions. To investigate, compound action potentials were made, from dorsal roots isolated from rats with or without complete Freund's adjuvant (CFA) hindpaw inflammation, in response to electrical stimulus trains. ⋯ We also demonstrate a progressive delay of C fiber monosynaptic transmission to the spinal cord that is similarly sex and inflammation dependent. Experimentally manipulating ADS strongly influences spinal summation consistent with sex differences in behavioral pain thresholds. This suggests that ADS provides a peripheral mechanism that can regulate spinal nociceptive processing and pain sensation.
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Long-term treatment with ceftriaxone attenuates the reinstatement of cocaine seeking while increasing the function of the glutamate transporter 1 (GLT-1) and system xC- (Sxc) in the nucleus accumbens core (NAc). Sxc contributes the majority of nonsynaptic extracellular glutamate in the NAc, while GLT-1 is responsible for the majority of glutamate uptake. Here we used antisense to decrease the expression of GLT-1 and xCT (a catalytic subunit of Sxc) to determine the relative importance of both proteins in mediating the ability of ceftriaxone to prevent cue-induced reinstatement of cocaine seeking and normalize glutamatergic proteins in the NAc of rats. ⋯ Here we used an antisense strategy to knock down GLT-1 or xCT in the nucleus accumbens core and examined the behavioral and molecular consequences. While upregulation of both xCT and GLT-1 are essential to the ability of ceftriaxone to attenuate cue-induced reinstatement of cocaine seeking, each protein uniquely affects the expression of other glutamate receptor and transporter proteins. We also report that reducing basal glutamate levels through the manipulation of xCT expression increases the surface expression of AMPA receptor subunits, providing insight to the mechanism by which cocaine alters AMPA surface expression.
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FGF signaling, an important component of intercellular communication, is required in many tissues throughout development to promote diverse cellular processes. Whether FGF receptors (FGFRs) accomplish such varied tasks in part by activating different intracellular transducers in different contexts remains unclear. Here, we used the developing mouse telencephalon as an example to study the role of the FRS adapters FRS2 and FRS3 in mediating the functions of FGFRs. ⋯ SIGNIFICANCE STATEMENT FGFs promote a range of developmental processes in many developing tissues and at multiple developmental stages. The mechanisms underlying this multifunctionality remain poorly defined in vivo Using telencephalon development as an example, we show here that FRS adapters exhibit some selectivity in their requirement for mediating FGF receptor (FGFR) signaling and activating downstream mediators that depend on the developmental process, with a requirement in neuronal differentiation but not cell survival. Differential engagement of FRS and non-FRS intracellular adapters downstream of FGFRs could therefore in principle explain how FGFs play several distinct roles in other developing tissues and developmental stages.
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The complement system, typically associated with innate immunity, is emerging as a key controller of nonimmune systems including in development, with recent studies linking complement mutations with neurodevelopmental disease. A key effector of the complement response is the activation fragment C5a, which, through its receptor C5aR1, is a potent driver of inflammation. Surprisingly, C5aR1 is also expressed during early mammalian embryogenesis; however, no clearly defined function is ascribed to C5aR1 in development. ⋯ This study has explored complement regulation of neurogenesis, identifying a novel relationship between the complement activation peptide C5a and the neural progenitor proliferation underpinning formation of the mammalian brain. C5a was identified as a regulator of cell polarity, with inhibition of C5a receptors during embryogenesis leading to abnormal brain development and behavioral deficits. This work demonstrates mechanisms through which dysregulation of complement causes developmental disease and highlights the potential risk of complement inhibition for therapeutic purposes in pregnancy.
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In multisensory integration, processing in one sensory modality is enhanced by complementary information from other modalities. Intersensory timing is crucial in this process because only inputs reaching the brain within a restricted temporal window are perceptually bound. Previous research in the audiovisual field has investigated various features of the temporal binding window, revealing asymmetries in its size and plasticity depending on the leading input: auditory-visual (AV) or visual-auditory (VA). ⋯ Our research demonstrates that evaluating synchrony of auditory-leading (AV) versus visual-leading (VA) audiovisual stimulus pairs is characterized by two distinct patterns of brain activity. This suggests that audiovisual integration is not a unitary process and that different binding mechanisms are recruited in the brain based on the leading sense. These mechanisms may be relevant for supporting different classes of multisensory operations, for example, auditory enhancement of visual attention (AV) and visual enhancement of auditory speech (VA).