Transcript of My Father’s Heroics

This story is an excerpt from a longer interview that was collected as part of the Launching through the Surf: The Dory Fleet of Pacific City project. In this story, Sid Fisher recounts how his father, Walt Fisher, saved him from rolling his dory

Scoping exercise on fallers’ clinics : report to the National Co-ordinating Centre for NHS Service Delivery and Organisation R & D (NCCSDO)

The National Service Framework for Older People has stated the need for fall-prevention programmes. An appraisal of fallers’ clinics launched by the National Institute for Health and Clinical Excellence (NICE) was suspended because of a lack of information regarding existing services and typology. This project aimed to determine the feasibility of conducting economic modelling to appraise fallers’ clinics. To achieve this a national survey of services and reviews of the evidence of effectiveness of various models of fallers’ clinics and screening tools were undertaken

Foxp2 Mutations Impair Auditory-Motor Association Learning

Heterozygous mutations of the human FOXP2 transcription factor gene cause the best-described examples of monogenic speech and language disorders. Acquisition of proficient spoken language involves auditory-guided vocal learning, a specialized form of sensory-motor association learning. The impact of etiological Foxp2 mutations on learning of auditory-motor associations in mammals has not been determined yet. Here, we directly assess this type of learning using a newly developed conditioned avoidance paradigm in a shuttle-box for mice. We show striking deficits in mice heterozygous for either of two different Foxp2 mutations previously implicated in human speech disorders. Both mutations cause delays in acquiring new motor skills. The magnitude of impairments in association learning, however, depends on the nature of the mutation. Mice with a missense mutation in the DNA-binding domain are able to learn, but at a much slower rate than wild type animals, while mice carrying an early nonsense mutation learn very little. These results are consistent with expression of Foxp2 in distributed circuits of the cortex, striatum and cerebellum that are known to play key roles in acquisition of motor skills and sensory-motor association learning, and suggest differing in vivo effects for distinct variants of the Foxp2 protein. Given the importance of such networks for the acquisition of human spoken language, and the fact that similar mutations in human FOXP2 cause problems with speech development, this work opens up a new perspective on the use of mouse models for understanding pathways underlying speech and language disorders

What drives change? A framework to observe and understand broad-­‐ scale change in river basins

Development in river basins is strongly influenced by a range of non-­‐random factors, called global drivers. These can present a bewildering array of effects that confound concerted action. This report summarizes these effects with the CPWF’s six basins and presents a method of visualizing them together within a process of scenario visualization

Recent advances in the genetics of language impairment

Specific language impairment (SLI) is defined as an unexpected and persistent impairment in language ability despite adequate opportunity and intelligence and in the absence of any explanatory medical conditions. This condition is highly heritable and affects between 5% and 8% of pre-school children. Over the past few years, investigations have begun to uncover genetic factors that may contribute to susceptibility to language impairment. So far, variants in four specific genes have been associated with spoken language disorders - forkhead box P2 (FOXP2) and contactin-associated protein-like 2 (CNTNAP2) on chromosome7 and calcium-transporting ATPase 2C2 (ATP2C2) and c-MAF inducing protein (CMIP) on chromosome 16. Here, we describe the different ways in which these genes were identified as candidates for language impairment. We discuss how characterization of these genes, and the pathways in which they are involved, may enhance our understanding of language disorders and improve our understanding of the biological foundations of language acquisition

Effects of Cortical FoxP1 Knockdowns on Learned Song Preference in Female Zebra Finches

The search for molecular underpinnings of human vocal communication has focused on genes encoding forkhead-box transcription factors, as rare disruptions of FOXP1, FOXP2, and FOXP4 have been linked to disorders involving speech and language deficits. In male songbirds, an animal model for vocal learning, experimentally altered expression levels of these transcription factors impair song production learning. The relative contributions of auditory processing, motor function or auditory-motor integration to the deficits observed after different FoxP manipulations in songbirds are unknown. To examine the potential effects on auditory learning and development, we focused on female zebra finches (Taeniopygia guttata) that do not sing but develop song memories, which can be assayed in operant preference tests. We tested whether the relatively high levels of FoxP1 expression in forebrain areas implicated in female song preference learning are crucial for the development and/or maintenance of this behavior. Juvenile and adult female zebra finches received FoxP1 knockdowns targeted to HVC (proper name) or to the caudomedial mesopallium (CMM). Irrespective of target site and whether the knockdown took place before (juveniles) or after (adults) the sensitive phase for song memorization, all groups preferred their tutor’s song. However, adult females with FoxP1 knockdowns targeted at HVC showed weaker motivation to hear song and weaker song preferences than sham-treated controls, while no such differences were observed after knockdowns in CMM or in juveniles. In summary, FoxP1 knockdowns in the cortical song nucleus HVC were not associated with impaired tutor song memory but reduced motivation to actively request tutor songs

Foxp2 loss of function increases striatal direct pathway inhibition via increased GABA release

JRvR is supported by an RUMC Junior Round grant from the Donders institute Ph.D. program, awarded to NNK and SCV. SCV is supported by a Marie Curie Career Integration Grant (PCIG12-GA-2012-333978) and by a Max Planck Research Group Award. SEF is supported by the Max Planck Society.Heterozygous mutations of the Forkhead-box protein 2 (FOXP2) gene in humans cause childhood apraxia of speech. Loss of Foxp2 in mice is known to affect striatal development and impair motor skills. However, it is unknown if striatal excitatory/inhibitory balance is affected during development and if the imbalance persists into adulthood. We investigated the effect of reduced Foxp2 expression, via a loss-of-function mutation, on striatal medium spiny neurons (MSNs). Our data show that heterozygous loss of Foxp2 decreases excitatory (AMPA receptor-mediated) and increases inhibitory (GABA receptor-mediated) currents in D1 dopamine receptor positive MSNs of juvenile and adult mice. Furthermore, reduced Foxp2 expression increases GAD67 expression, leading to both increased presynaptic content and release of GABA. Finally, pharmacological blockade of inhibitory activity in vivo partially rescues motor skill learning deficits in heterozygous Foxp2 mice. Our results suggest a novel role for Foxp2 in the regulation of striatal direct pathway activity through managing inhibitory drive.Publisher PDFPeer reviewe

Cerebellar developmental deficits underlie neurodegenerative disorder spinocerebellar ataxia type 23

Contains fulltext : 231334.pdf (Publisher’s version ) (Open Access

Generation of mice with a conditional Foxp2 null allele

Disruptions of the human FOXP2 gene cause problems with articulation of complex speech sounds, accompanied by impairment in many aspects of language ability. The FOXP2/Foxp2 transcription factor is highly similar in humans and mice, and shows a complex conserved expression pattern, with high levels in neuronal subpopulations of the cortex, striatum, thalamus, and cerebellum. In the present study we generated mice in which loxP sites flank exons 12–14 of Foxp2; these exons encode the DNA-binding motif, a key functional domain. We demonstrate that early global Cre-mediated recombination yields a null allele, as shown by loss of the loxP-flanked exons at the RNA level and an absence of Foxp2 protein. Homozygous null mice display severe motor impairment, cerebellar abnormalities and early postnatal lethality, consistent with other Foxp2 mutants. When crossed to transgenic lines expressing Cre protein in a spatially and/or temporally controlled manner, these conditional mice will provide new insights into the contributions of Foxp2 to distinct neural circuits, and allow dissection of roles during development and in the mature brain. genesis 45:440–446, 2007. Published 2007 Wiley-Liss, Inc