230 research outputs found
The role of Wnt signalling in hippocampal synapse formation and function
Wnt proteins are a large and diverse family of secreted signalling factors that play key
roles in the development of the nervous system, including control of neuronal proliferation and differentiation, axon guidance, dendritogenesis and synaptogenesis.
Despite recent advances in our understanding of Wnt function at synapses, key
questions remain unanswered. For example the role of Wnt signalling in central
postsynaptic development remains unclear, as does the specificity of Wnts for
regulating different sub-types of synapse. The aim of this thesis was to investigate the
role of Wnts in regulating the formation and function of central glutamatergic and
GABAergic synapses in the rodent hippocampus, using complementary cell biological
and electrophysiological approaches.
I find that Wnt7a specifically promotes the formation of excitatory glutamatergic
synapses in cultured hippocampal neurons, with no effect on inhibitory GABAergic
synapses. Furthermore, specific postsynaptic activation of Wnt signalling results in
increased dendritic spine size, increased clustering of the postsynaptic protein PSD-95
and increased presynaptic innervation of dendritic spines. In contrast, GABAergic
synapses are unaffected by Dishevelled-1 expression.
I also find that endogenous Wnt signalling regulates excitatory synaptic function. Acute
blockade of endogenous Wnt signalling using the Wnt antagonists sFRP1, 2 and 3
results in a decrease in mEPSC frequency and evoked release probability at
glutamatergic synapses, with no effect on GABAergic synapses. A similar decrease in
evoked release probability is observed at glutamatergic Schaffer collateral-CA1
synapses in hippocampal slices from Wnt7a-/-; Dvl1-/- double knockout mice. Finally,
I demonstrate that a prolonged reduction in glutamatergic release probability caused by
chronic Wnt signalling blockade elicits a homeostatic increase in glutamatergic synapse
number that acts to maintain normal levels of excitatory signalling.
In conclusion, the work presented in this thesis significantly advances our
understanding of the role of Wnts at central synapses. Wnt signalling regulates multiple
processes throughout the lifetime of an excitatory glutamatergic synapse. Wnt7a
promotes the formation of excitatory synapses through the co-ordinated clustering of
pre- and postsynaptic proteins. Postsynaptic Wnt signalling can directly regulate excitatory postsynaptic formation at central synapses, and can also signal back to the
presynaptic side. Endogenous Wnt signalling plays a role in maintaining normal levels
of glutamate release, and chronic perturbation of this signalling results in compensatory
changes in synapse density
Distinct forms of synaptic inhibition and neuromodulation regulate calretinin positive neuron excitability in the spinal cord dorsal horn
The dorsal horn (DH) of the spinal cord contains a heterogenous population of neurons that process incoming sensory signals before information ascends to the brain. We have recently characterized calretinin-expressing (CR+) neurons in the DH and shown that they can be divided into excitatory and inhibitory subpopulations. The excitatory population receives high-frequency excitatory synaptic input and expresses delayed firing action potential discharge, whereas the inhibitory population receives weak excitatory drive and exhibits tonic or initial bursting discharge. Here, we characterize inhibitory synaptic input and neuromodulation in the two CR+ populations, in order to determine how each is regulated. We show that excitatory CR+ neurons receive mixed inhibition from GABAergic and glycinergic sources, whereas inhibitory CR+ neurons receive inhibition, which is dominated by glycine. Noradrenaline and serotonin produced robust outward currents in excitatory CR+ neurons, predicting an inhibitory action on these neurons, but neither neuromodulator produced a response in CR+ inhibitory neurons. In contrast, enkephalin (along with selective mu and delta opioid receptor agonists) produced outward currents in inhibitory CR+ neurons, consistent with an inhibitory action but did not affect the excitatory CR+ population. Our findings show that the pharmacology of inhibitory inputs and neuromodulator actions on CR+ cells, along with their excitatory inputs can define these two subpopulations further, and this could be exploited to modulate discrete aspects of sensory processing selectively in the DH
Functional and molecular analysis of proprioceptive sensory neuron excitability in mice
Neurons located in dorsal root ganglia (DRG) are crucial for transmitting peripheral sensations such as proprioception, touch, temperature, and nociception to the spinal cord before propagating these signals to higher brain structures. To date, difficulty in identifying modality-specific DRG neurons has limited our ability to study specific populations in detail. As the calcium-binding protein parvalbumin (PV) is a neurochemical marker for proprioceptive DRG cells we used a transgenic mouse line expressing green fluorescent protein (GFP) in PV positive DRGs, to study the functional and molecular properties of putative proprioceptive neurons. Immunolabeled DRGs showed a 100% overlap between GFP positive (GFP+) and PV positive cells, confirming the PVeGFP mouse accurately labeled PV neurons. Targeted patch-clamp recording from isolated GFP+ and GFP negative (GFP−) neurons showed the passive membrane properties of the two groups were similar, however, their active properties differed markedly. All GFP+ neurons fired a single spike in response to sustained current injection and their action potentials (APs) had faster rise times, lower thresholds and shorter half widths. A hyperpolarization-activated current (Ih) was observed in all GFP+ neurons but was infrequently noted in the GFP− population (100% vs. 11%). For GFP+ neurons, Ih activation rates varied markedly, suggesting differences in the underlying hyperpolarization-activated cyclic nucleotide-gated channel (HCN) subunit expression responsible for the current kinetics. Furthermore, quantitative polymerase chain reaction (qPCR) showed the HCN subunits 2, 1, and 4 mRNA (in that order) was more abundant in GFP+ neurons, while HCN 3 was more highly expressed in GFP− neurons. Likewise, immunolabeling confirmed HCN 1, 2, and 4 protein expression in GFP+ neurons. In summary, certain functional properties of GFP+ and GFP− cells differ markedly, providing evidence for modality-specific signaling between the two groups. However, the GFP+ DRG population demonstrates considerable internal heterogeneity when hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel) properties and subunit expression are considered. We propose this heterogeneity reflects the existence of different peripheral receptors such as tendon organs, muscle spindles or mechanoreceptors in the putative proprioceptive neuron population
Cystic Fibrosis Foundation and European Cystic Fibrosis Society Survey of cystic fibrosis mental health care delivery
Background: Psychological morbidity in individuals with cystic fibrosis (CF) and their caregivers is common. The Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) Guidelines Committee on Mental Health sought the views of CF health care professionals concerning mental health care delivery.
Methods: An online survey which focused on the current provision and barriers to mental health care was distributed to CF health care professionals.
Results: Of the 1454 respondents, many did not have a colleague trained in mental health issues and 20% had no one on their team whose primary role was focused on assessing or treating these issues. Insufficient resources and a lack of competency were reported in relation to mental health referrals. Seventy-three percent of respondents had no experience with mental health screening. Of those who did, they utilized 48 different, validated scales.
Conclusions: These data have informed the decision-making, dissemination and implementation strategies of the Mental Health Guidelines Committee sponsored by the CFF and ECFS
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Measurement of Bottom versus Charm as a Function of Transverse Momentum with Electron-Hadron Correlations in p+p Collisions at sqrt(s)=200 GeV
The momentum distribution of electrons from semi-leptonic decays of charm and
bottom for mid-rapidity |y|<0.35 in p+p collisions at sqrt(s)=200 GeV is
measured by the PHENIX experiment at the Relativistic Heavy Ion Collider (RHIC)
over the transverse momentum range 2 < p_T < 7 GeV/c. The ratio of the yield of
electrons from bottom to that from charm is presented. The ratio is determined
using partial D/D^bar --> e^{+/-} K^{-/+} X (K unidentified) reconstruction. It
is found that the yield of electrons from bottom becomes significant above 4
GeV/c in p_T. A fixed-order-plus-next-to-leading-log (FONLL) perturbative
quantum chromodynamics (pQCD) calculation agrees with the data within the
theoretical and experimental uncertainties. The extracted total bottom
production cross section at this energy is \sigma_{b\b^bar}= 3.2
^{+1.2}_{-1.1}(stat) ^{+1.4}_{-1.3}(syst) micro b.Comment: 432 authors, 6 pages text, 3 figures. Submitted to Phys. Rev. Lett.
Plain text data tables for the points plotted in figures for this and
previous PHENIX publications are (or will be) publicly available at
http://www.phenix.bnl.gov/papers.htm
HCN4 subunit expression in fast-spiking interneurons of the rat spinal cord and hippocampus
Hyperpolarisation-activated (Ih) currents are considered
important for dendritic integration, synaptic transmission,
setting membrane potential and rhythmic action potential (AP) discharge in neurons of the central nervous system. Hyperpolarisation-activated cyclic nucleotide-gated
(HCN) channels underlie these currents and are composed
of homo- and hetero-tetramers of HCN channel subunits
(HCN1–4), which confer distinct biophysical properties on
the channel. Despite understanding the structure–function
relationships of HCN channels with different subunit stoichiometry, our knowledge of their expression in defined neuronal populations remains limited. Recently, we have shownthat HCN subunit expression is a feature of a specific population of dorsal horn interneurons that exhibit high-frequency AP discharge. Here we expand on this observation
and use neuroanatomical markers to first identify well-characterised neuronal populations in the lumbar spinal cord
and hippocampus and subsequently determine whether
HCN4 expression correlates with high-frequency AP discharge
in these populations. In the spinal cord, HCN4 is
expressed in several putative inhibitory interneuron populations including parvalbumin (PV)-expressing islet cells (84.1%; SD: ±2.87), in addition to all putative Renshaw cells and Ia inhibitory interneurons. Similarly, virtually all PVexpressing cells in the hippocampal CA1 subfield (93.5%;±3.40) and the dentate gyrus (90.9%; ±6.38) also express HCN4. This HCN4 expression profile in inhibitory interneurons mirrors both the prevalence of Ih sub-threshold currents and high-frequency AP discharge. Our findings indicate that HCN4 subunits are expressed in several populations of spinal and hippocampal interneurons, which are known to express both Ih sub-threshold currents and exhibit high-frequency AP discharge. As HCN channel function plays a critical role in pain perception, learning and memory,and sleep as well as the pathogenesis of several neurologicaldiseases, these findings provide important insights into the identity and neurochemical status of cells that could underlie such conditions
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Energetic particle influence on the Earth's atmosphere
This manuscript gives an up-to-date and comprehensive overview of the effects of energetic particle precipitation (EPP) onto the whole atmosphere, from the lower thermosphere/mesosphere through the stratosphere and troposphere, to the surface. The paper summarizes the different sources and energies of particles, principally
galactic cosmic rays (GCRs), solar energetic particles (SEPs) and energetic electron precipitation (EEP). All the proposed mechanisms by which EPP can affect the atmosphere
are discussed, including chemical changes in the upper atmosphere and lower thermosphere, chemistry-dynamics feedbacks, the global electric circuit and cloud formation. The role of energetic particles in Earth’s atmosphere is a multi-disciplinary problem that requires expertise from a range of scientific backgrounds. To assist with this synergy, summary tables are provided, which are intended to evaluate the level of current knowledge of the effects of energetic particles on processes in the entire atmosphere
Saturation of azimuthal anisotropy in Au + Au collisions at sqrt(s_NN) = 62 - 200 GeV
New measurements are presented for charged hadron azimuthal correlations at
mid-rapidity in Au+Au collisions at sqrt(s_NN) = 62.4 and 200 GeV. They are
compared to earlier measurements obtained at sqrt(s_NN) = 130 GeV and in Pb+Pb
collisions at sqrt(s_NN) = 17.2 GeV. Sizeable anisotropies are observed with
centrality and transverse momentum (p_T) dependence characteristic of elliptic
flow (v_2). For a broad range of centralities, the observed magnitudes and
trends of the differential anisotropy, v_2(p_T), change very little over the
collision energy range sqrt(s_NN) = 62-200 GeV, indicating saturation of the
excitation function for v_2 at these energies. Such a saturation may be
indicative of the dominance of a very soft equation of state for sqrt(s_NN) =
62-200 GeV.Comment: 432 authors, 7 pages text, 4 figures, REVTeX4. To be submitted to
Physical Review Letters. Plain text data tables for the points plotted in
figures for this and previous PHENIX publications are (or will be) publicly
available at http://www.phenix.bnl.gov/papers.htm
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