BackgroundGamma motor neurons (γ-MNs) selectively innervate muscle spindle intrafusal fibers and regulate their sensitivity to stretch. They constitute a distinct subpopulation that differs in morphology, physiology and connectivity from α-MNs, which innervate extrafusal muscle fibers and exert force. The mechanisms that control the differentiation of functionally distinct fusimotor neurons are unknown. Progress on this question has been limited by the absence of molecular markers to specifically distinguish and manipulate γ-MNs. Recently, it was reported that early embryonic γ-MN precursors are dependent on GDNF. Using this knowledge we characterized genetic strategies to label developing γ-MNs based on GDNF receptor expression, showed their strict dependence for survival on muscle spindle-derived GDNF and generated an animal model in which γ-MNs are selectively lost.ResultsIn mice heterozygous for both the Hb9::GFP transgene and a tau-lacZ-labeled (TLZ) allele of the GDNF receptor Gfrα1, we demonstrated that small motor neurons with high Gfrα1-TLZ expression and lacking Hb9::GFP display structural and synaptic features of γ-MNs and are selectively lost in mutants lacking target muscle spindles. Loss of muscle spindles also results in the downregulation of Gfrα1 expression in some large diameter MNs, suggesting that spindle-derived factors may also influence populations of α-MNs with β-skeletofusimotor collaterals. These molecular markers can be used to identify γ-MNs from birth to the adult and to distinguish γ- from β-motor axons in the periphery. We also found that postnatal γ-MNs are also distinguished by low expression of the neuronal nuclear protein (NeuN). With these markers of γ-MN identity, we show after conditional elimination of GDNF from muscle spindles that the survival of γ-MNs is selectively dependent on spindle-derived GDNF during the first 2 weeks of postnatal development.ConclusionNeonatal γ-MNs display a unique molecular profile characterized by the differential expression of a series of markers - Gfrα1, Hb9::GFP and NeuN - and the selective dependence on muscle spindle-derived GDNF. Deletion of GDNF expression from muscle spindles results in the selective elimination of γ-MNs with preservation of the spindle and its sensory innervation. This provides a mouse model with which to explore the specific role of γ-fusimotor activity in motor behaviors.

SUMMARY The mammalian Protocadherin (Pcdh) alpha, beta, and gamma gene clusters encode a large family of cadherin-like transmembrane proteins that are differentially expressed in individual neurons. The 22 isoforms of the Pcdhg gene cluster are diversified into A-, B- and C-types, and the C-type isoforms differ from all other clustered Pcdhs in sequence and expression. Here we show that mice lacking the 3 C-type isoforms are phenotypically indistinguishable from the Pcdhg null mutants, displaying virtually identical cellular and synaptic alterations resulting from neuronal apoptosis. By contrast, mice lacking 3 A-type isoforms exhibit no detectable phenotypes. Remarkably, however, genetically blocking apoptosis rescues the neonatal lethality of the C-type isoform knockouts, but not that of the Pcdhg null mutants. We conclude that the role of the Pcdhg gene cluster in neuronal survival is primarily, if not specifically mediated by its C-type isoforms, whereas a separate role essential for postnatal development, likely in neuronal wiring, requires isoform diversity.

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The diversity of premotor interneurons in the mammalian spinal cord is generated from a few phylogenetically conserved embryonic classes of interneurons (V0, V1, V2, V3). Their mechanisms of diversification remain unresolved, although these are clearly important to understand motor circuit assembly in the spinal cord. Some Ia inhibitory interneurons (IaINs) and all Renshaw cells (RCs) derive from embryonic V1 interneurons; however, in adult they display distinct functional properties and synaptic inputs, for example proprioceptive inputs preferentially target IaINs, while motor axons target RCs. Previously, we found that both inputs converge on RCs in neonates, raising the possibility that proprioceptive (VGLUT1-positive) and motor axon synapses (VAChT-positive) initially target several different V1 interneurons populations and then become selected or deselected postnatally. Alternatively, specific inputs might precisely connect only with predefined groups of V1 interneurons. To test these hypotheses we analyzed synaptic development on V1-derived IaINs and compared them to RCs of the same age and spinal cord levels. V1-interneurons were labeled using genetically encoded lineage markers in mice. The results show that although neonatal V1-derived IaINs and RCs are competent to receive proprioceptive synapses, these synapses preferentially target the proximal somato-dendritic regions of IaINs and postnatally proliferate on IaINs, but not on RCs. In contrast, cholinergic synapses on RCs are specifically derived from motor axons, while on IaINs they originate from Pitx2 V0c interneurons. Thus, motor, proprioceptive, and even some interneuron inputs are biased toward specific subtypes of V1-interneurons. Postnatal strengthening of these inputs is later superimposed on this initial preferential targeting.

This work bridges a gap in the cross‐coupling of aliphatic redox‐active esters with aryl zinc reagents. Previously limited to primary, secondary, and specialized tertiary centers, a new protocol has been devised to enable the coupling of general tertiary systems using nickel catalysis. The scope of this operationally simple method is broad, and it can be used to simplify the synthesis of medicinally relevant motifs bearing quaternary centers.

This article looks at how the new atheist phenomenon has been interpreted and appropriated by those involved in atheist and secular humanist organizations. We see a connection between new atheism as a broad social phenomenon and the publicly emerging needs and desires of secularists; they are both cause and effect of the transformation of experience with the expansion of electronic communication technologies. While even some secularists claim the new atheists are doing more harm than good, we argue that such critiques ultimately miss the function of the books. Taken collectively they provide a highly diverse population of secularists with a common and general set of issues and ideas in which to imagine a sense of community. form the "canon" of the new atheism, but media in the form of magazines, Web sites, blogs, online forums, and other books have also played an important role in driving this social phenomenon. This is especially the case with new media; they have created new forms of interaction and communication among secularists who may feel isolated in their communities. In highlighting the role of media, we look at both the content and the medium. An analysis of articles on atheism in two secularist magazines, coupled with an Internet survey of self-identified atheists on the new atheism and their use of the media, allows us to see how secularists themselves are interpreting and evaluating the new atheism. Medium theory situates these interpretations and evaluations in a broader media context; conceiving of such as ongoing effects resulting from the process of mediation that secularists themselves go through in defining and understanding themselves as secularists. Examining the relation Correspondence should be addressed to Richard Cimino,

Objectives Few longitudinal studies have studied the influence of the care environment on the clinical progression of dementia. We examined whether caregiver coping strategies predict dementia progression in a population-based sample. Design Longitudinal, prospective cohort study Setting Cache County (Utah) Population Participants 226 persons with dementia, and their caregivers, assessed semi-annually for up to 6 years. Measurements Ways of Coping Checklist-Revised, Mini-Mental State Exam (MMSE), Clinical Dementia Rating (CDR). Results Mean (SD) age of dementia onset was 82.11 (5.84) and mean caregiver age was 67.41 (13.95). Mean (SD) follow-up was 1.65 (1.63) years from baseline. In univariate linear mixed effects models, increasing use of problem-focused and counting blessings by caregivers was associated with slower patient worsening on the MMSE. Problem-focused coping, seeking social support, and wishful thinking were associated with slower CDR-SB worsening. Considering covariates, increasing use of problem-focused coping was associated with 0.70 points per year less worsening on the MMSE and 0.55 point per year less worsening on the CDR-sb. Compared to no use, “regular” use of this strategy was associated with a 2-point per year slower worsening on the MMSE and 1.65-point per year slower worsening on the CDR-sb. Conclusions Caregiver coping strategies are associated with slower dementia progression. Developing interventions that target these strategies may benefit dementia patients.