In vitro characterisation of cell-level neurophysiological diversity in the rostral nucleus reuniens of adult mice

PublishedThis is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The nucleus reuniens (Re) is the largest of the midline thalamic nuclei. We have performed a detailed neurophysiological characterization of neurons in the rostral Re of brain slices prepared from adult male mice. At resting potential (−63.7 ± 0.6 mV), circa 90% of Re neurons fired action potentials, typically continuously at ∼8 Hz. Although Re neurons experience a significant spontaneous barrage of fast, amino-acid-mediate synaptic transmission, this was not predominantly responsible for spontaneous spiking as firing persisted in the presence of glutamate and GABA receptor antagonists. With resting potential preset to −80 mV −20 pA current injections revealed a mean input resistance of 615 MΩ and mean time constant of 38 ms. Following cessation of this stimulus a significant rebound potential was seen that was sometimes large enough to trigger a short burst of very high frequency (100–300 Hz) firing. In most cells short (2 ms), strong (2 nA) current injections elicited a single spike followed by a large afterdepolarizing potential (ADP) which, when suprathreshold, generated high frequency spiking. Similarly, in the majority of cells preset at −80 mV, 500 ms depolarizing current injections to cells led to a brief initial burst of very high frequency firing, although this was lost when cells were preset at −72 mV. Biophysical and pharmacological experiments indicate a prominent role for T-type Ca2+ channels in the high-frequency bursting of Re neurons. Finally, we describe a novel form of activity-dependent intrinsic plasticity that persistently eliminates the burst firing potential of Re neurons

Conditions during adulthood affect cohort-specific reproductive success in an Arctic-nesting goose population

This is the final version of the article. Available from the publisher via the DOI in this record.Variation in fitness between individuals in populations may be attributed to differing environmental conditions experienced among birth (or hatch) years (i.e., between cohorts). In this study, we tested whether cohort fitness could also be explained by environmental conditions experienced in years post-hatch, using 736 lifelong resighting histories of Greenland white-fronted geese (Anser albifrons flavirostris) marked in their first winter. Specifically, we tested whether variation in age at first successful reproduction, the size of the first successful brood and the proportion of successful breeders by cohort was explained by environmental conditions experienced on breeding areas in west Greenland during hatch year, those in adulthood prior to successful reproduction and those in the year of successful reproduction, using North Atlantic Oscillation indices as proxies for environmental conditions during these periods. Fifty-nine (8%) of all marked birds reproduced successfully (i.e., were observed on wintering areas with young) only once in their lifetime and 15 (2%) reproduced successfully twice or thrice. Variation in age at first successful reproduction was explained by the environmental conditions experienced during adulthood in the years prior to successful reproduction. Birds bred earliest (mean age 4) when environmental conditions were 'good' prior to the year of successful reproduction. Conversely, birds successfully reproduced at older ages (mean age 7) if they experienced adverse conditions prior to the year of successful reproduction. Hatch year conditions and an interaction between those experienced prior to and during the year of successful reproduction explained less (marginally significant) variation in age at first successful reproduction. Environmental conditions did not explain variation in the size of the first successful brood or the proportion of successful breeders. These findings show that conditions during adulthood prior to the year of successful reproduction are most important in determining the age at first successful reproduction in Greenland white-fronted geese. Very few birds bred successfully at all (most only once), which suggests that May environmental conditions on breeding areas have cohort effects that influence lifetime (and not just annual) reproductive success.This research was funded through a joint PhD studentship from the Wildfowl & Wetlands Trust and the University of Exeter, and undertaken by MD Weegman. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Integrated population modelling reveals a perceived source to be a cryptic sink

This is the final version of the article. Available from the publisher via the DOI in this record.Demographic links among fragmented populations are commonly studied as source-sink dynamics, whereby source populations exhibit net recruitment and net emigration, while sinks suffer net mortality but enjoy net immigration. It is commonly assumed that large, persistent aggregations of individuals must be sources, but this ignores the possibility that they are sinks instead, buoyed demographically by immigration. We tested this assumption using Bayesian integrated population modelling of Greenland white-fronted geese (Anser albifrons flavirostris) at their largest wintering site (Wexford, Ireland), combining capture-mark-recapture, census and recruitment data collected from 1982 to 2010. Management for this subspecies occurs largely on wintering areas; thus, study of source-sink dynamics of discrete regular wintering units provides unprecedented insights into population regulation and enables identification of likely processes influencing population dynamics at Wexford and among 70 other Greenland white-fronted goose wintering subpopulations. Using results from integrated population modelling, we parameterized an age-structured population projection matrix to determine the contribution of movement rates (emigration and immigration), recruitment and mortality to the dynamics of the Wexford subpopulation. Survival estimates for juvenile and adult birds at Wexford and adult birds elsewhere fluctuated over the 29-year study period, but were not identifiably different. However, per capita recruitment rates at Wexford in later years (post-1995) were identifiably lower than in earlier years (pre-1995). The observed persistence of the Wexford subpopulation was only possible with high rates of immigration, which exceeded emigration in each year. Thus, despite its apparent stability, Wexford has functioned as a sink over the entire study period. These results demonstrate that even large subpopulations can potentially be sinks, and that movement dynamics (e.g. immigration) among winters can dramatically obscure key processes driving subpopulation size. Further, novel population models which integrate capture-mark-recapture, census and recruitment data are essential to correctly ascribing source-sink status and accurately informing development of site-safeguard networks.This research was funded through a joint PhD studentship to M.D.W. from the Wildfowl & Wetlands Trust and the University of Exeter, and through a NERC grant (NE/L007770/1) to D.J.

Should I stay or should I go? Fitness costs and benefits of prolonged parent-offspring and sibling-sibling associations in an Arctic-nesting goose population.

This is the final version of the article. Available from the publisher via the DOI in this record.Theory predicts persistence of long-term family relationships in vertebrates will occur until perceived fitness costs exceed benefits to either parents or offspring. We examined whether increased breeding probability and survival were associated with prolonged parent-offspring and sibling-sibling relationships in a long-lived Arctic migrant herbivore, the Greenland white-fronted goose (Anser albifrons flavirostris). Although offspring associated with parents for 1-13 years, 79 % of these associations lasted two or less years. Only 65 (9.9 %) of the 656 marked offspring bred once in their lifetime, and just 16 (2.4 %) bred twice or more. The probability of birds with siblings breeding successfully in a subsequent year was credibly greater than that of independent birds at ages 5, 6, and 7. Survival of offspring with parents was credibly greater than that of independent/nonbreeder birds at all possible ages (i.e., ages 2-7+). A cost-benefit matrix model utilizing breeding and survival probabilities showed that staying with family groups was favored over leaving until age 3, after which there were no credible differences between staying and leaving strategies until the oldest ages, when leaving family groups was favored. Thus, most birds in this study either departed family groups early (e.g., at age 2, when the "stay" strategy was favored) or as predicted by our cost-benefit model (i.e., at age 3). Although extended family associations are a feature of this population, we contend that the survival benefits are not sufficient enough to yield clear fitness benefits, and associations only persist because parents and offspring mutually benefit from their persistence.This research was funded through a joint PhD studentship from the Wildfowl & Wetlands Trust and the University of Exeter undertaken by MDW

Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer's disease.

This is the author accepted manuscriptRecently, increased neuronal activity in nucleus reuniens (Re) has been linked to hyperexcitability within hippocampal-thalamo-cortical networks in the J20 mouse model of amyloidopathy. Here in vitro whole-cell patch clamp recordings were used to compare old pathology-bearing J20 mice and wild-type controls to examine whether altered intrinsic electrophysiological properties could contribute to the amyloidopathy-associated Re hyperactivity. A greater proportion of Re neurons display hyperpolarized membrane potentials in J20 mice without changes to the incidence or frequency of spontaneous action potentials. Re neurons recorded from J20 mice did not exhibit increased action potential generation in response to depolarizing current stimuli but an increased propensity to rebound burst following hyperpolarizing current stimuli. Increased rebound firing did not appear to result from alterations to T-type Ca2+ channels. Finally, in J20 mice, there was an ~8% reduction in spike width, similar to what has been reported in CA1 pyramidal neurons from multiple amyloidopathy mice. We conclude that alterations to the intrinsic properties of Re neurons may contribute to hippocampal-thalmo-cortical hyperexcitability observed under pathological beta-amyloid load.Alzheimer´s Research UKEli Lilly and Company Limited (T/A Lilly

CO destruction in protoplanetary disk midplanes: Inside versus outside the CO snow surface

Context: The total gas mass is one of the most fundamental properties of disks around young stars, because it controls their evolution and their potential to form planets. To measure disk gas masses, CO has long been thought to be the best tracer as it is readily detected at (sub)mm wavelengths in many disks. However, inferred gas masses from CO in recent ALMA observations of large samples of disks in the 1–5 Myr age range seem inconsistent with their inferred dust masses. The derived gas-to-dust mass ratios from CO are between one and two orders of magnitude lower than the ISM value of ~100 even if photodissociation and freeze-out are included. In contrast, Herschel measurements of hydrogen deuteride line emission of a few disks imply gas masses in line with gas-to-dust mass ratios of 100. This suggests that at least one additional mechanism is removing CO from the gas phase. Aims: Here we test the suggestion that the bulk of the CO is chemically processed and that the carbon is sequestered into less volatile species such as CO2, CH3OH, and CH4 in the dense, shielded midplane regions of the disk. This study therefore also addresses the carbon reservoir of the material which ultimately becomes incorporated into planetesimals. Methods: Using our gas-grain chemical code, we performed a parameter exploration and follow the CO abundance evolution over a range of conditions representative of shielded disk midplanes. Results: Consistent with previous studies, we find that no chemical processing of CO takes place on 1–3 Myr timescales for low cosmic-ray ionisation rates, <5 × 10−18 s−1. Assuming an ionisation rate of 10−17 s−1, more than 90% of the CO is converted into other species, but only in the cold parts of the disk below 30 K. This order of magnitude destruction of CO is robust against the choice of grain-surface reaction rate parameters, such as the tunnelling efficiency and diffusion barrier height, for temperatures between 20 and 30 K. Below 20 K there is a strong dependence on the assumed efficiency of H tunnelling. Conclusions: The low temperatures needed for CO chemical processing indicate that the exact disk temperature structure is important, with warm disks around luminous Herbig stars expected to have little to no CO conversion. In contrast, for cold disks around sun-like T Tauri stars, a large fraction of the emitting CO layer is affected unless the disks are young (<1 Myr). This can lead to inferred gas masses that are up to two orders of magnitude lower. Moreover, unless CO is locked up early in large grains, the volatile carbon composition of the icy pebbles and planetesimals forming in the midplane and drifting to the inner disk will be dominated by CH3OH, CO2 and/or hydrocarbons

Undergraduate medical textbooks do not provide adequate information on intravenous fluid therapy: a systematic survey and suggestions for improvement

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Inappropriate prescribing of intravenous (IV) fluid, particularly 0.9% sodium chloride, causes post-operative complications. Fluid prescription is often left to junior medical staff and is frequently poorly managed. One reason for poor intravenous fluid prescribing practices could be inadequate coverage of this topic in the textbooks that are used.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt;&lt;p&gt;&lt;/p&gt; We formulated a comprehensive set of topics, related to important common clinical situations involving IV fluid therapy, (routine fluid replacement, fluid loss, fluids overload) to assess the adequacy of textbooks in common use. We assessed 29 medical textbooks widely available to students in the UK, scoring the presence of information provided by each book on each of the topics. The scores indicated how fully the topics were considered: not at all, partly, and adequately. No attempt was made to judge the quality of the information, because there is no consensus on these topics.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt;&lt;p&gt;&lt;/p&gt; The maximum score that a book could achieve was 52. Three of the topics we chose were not considered by any of the books. Discounting these topics as “too esoteric”, the maximum possible score became 46. One textbook gained a score of 45, but the general score was poor (median 11, quartiles 4, 21). In particular, coverage of routine postoperative management was inadequate.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Textbooks for undergraduates cover the topic of intravenous therapy badly, which may partly explain the poor knowledge and performance of junior doctors in this important field. Systematic revision of current textbooks might improve knowledge and practice by junior doctors. Careful definition of the remit and content of textbooks should be applied more widely to ensure quality and “fitness for purpose”, and avoid omission of vital knowledge

Pre-treatment preferences and characteristics among patients seeking in vitro fertilisation

BACKGROUND: This study sought to describe patient features before beginning fertility treatment, and to ascertain their perceptions relative to risk of twin pregnancy outcomes associated with such therapy. METHODS: Data on readiness for twin pregnancy outcome from in vitro fertilisation (IVF) was gathered from men and women before initiating fertility treatment by anonymous questionnaire. RESULTS: A total of 206 women and 204 men were sampled. Mean (+/- SD) age for women and men being 35.5 +/- 5 and 37.3 +/- 7 yrs, respectively. At least one IVF cycle had been attempted by 27.2% of patients and 33.9% of this subgroup had initiated &gt;/=3 cycles, reflecting an increase in previous failed cycles over five years. Good agreement was noted between husbands and wives with respect to readiness for twins from IVF (77% agreement; Cohen's K = 0.61; 95% CI 0.53 to 0.70). CONCLUSION: Most patients contemplating IVF already have ideas about particular outcomes even before treatment begins, and suggests that husbands and wives are in general agreement on their readiness for twin pregnancy from IVF. However, fertility patients now may represent a more refractory population and therefore carry a more guarded prognosis. Patient preferences identified before IVF remain important, but further studies comparing pre- and post-treatment perceptions are needed

Are bisphosphonates effective in the treatment of osteoarthritis pain? A meta-analysis and systematic review.

Osteoarthritis (OA) is the most common form of arthritis worldwide. Pain and reduced function are the main symptoms in this prevalent disease. There are currently no treatments for OA that modify disease progression; therefore analgesic drugs and joint replacement for larger joints are the standard of care. In light of several recent studies reporting the use of bisphosphonates for OA treatment, our work aimed to evaluate published literature to assess the effectiveness of bisphosphonates in OA treatment

Differential electrographic signatures generated by mechanistically-diverse seizurogenic compounds in the larval zebrafish brain.

This is the final version. Available from the Society for Neuroscience via the DOI in this record. We assessed similarities and differences in the electrographic signatures of local field potentials (LFPs) evoked by different pharmacological agents in zebrafish larvae. We then compared and contrasted these characteristics with what is known from electrophysiological studies of seizures and epilepsy in mammals, including humans. Ultimately, our aim was to phenotype neurophysiological features of drug-induced seizures in larval zebrafish for expanding knowledge on the translational potential of this valuable alternative to mammalian models. LFPs were recorded from the midbrain of 4-d-old zebrafish larvae exposed to a pharmacologically diverse panel of seizurogenic compounds, and the outputs of these recordings were assessed using frequency domain analysis. This included analysis of changes occurring within various spectral frequency bands of relevance to mammalian CNS circuit pathophysiology. From these analyses, there were clear differences in the frequency spectra of drug-exposed LFPs, relative to controls, many of which shared notable similarities with the signatures exhibited by mammalian CNS circuits. These similarities included the presence of specific frequency components comparable to those observed in mammalian studies of seizures and epilepsy. Collectively, the data presented provide important information to support the value of larval zebrafish as an alternative model for the study of seizures and epilepsy. These data also provide further insight into the electrophysiological characteristics of seizures generated in nonmammalian species by the action of neuroactive drugs.National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs