Mossy fiber-evoked subthreshold responses induce timing-dependent plasticity at hippocampal CA3 recurrent synapses

Dentate granule cells exhibit exceptionally low levels of activity and rarely elicit action potentials in targeted CA3 pyramidal cells. It is thus unclear how such weak input from the granule cells sustains adequate levels of synaptic plasticity in the targeted CA3 network. We report that subthreshold potentials evoked by mossy fibers are sufficient to induce synaptic plasticity between CA3 pyramidal cells, thereby complementing the sparse action potential discharge. Repetitive pairing of a CA3–CA3 recurrent synaptic response with a subsequent subthreshold mossy fiber response induced long-term potentiation at CA3 recurrent synapses in rat hippocampus in vitro. Reversing the timing of the inputs induced long-term depression. The underlying mechanism depends on a passively conducted giant excitatory postsynaptic potential evoked by a mossy fiber that enhances NMDA receptor-mediated current at active CA3 recurrent synapses by relieving magnesium block. The resulting NMDA spike generates a supralinear depolarization that contributes to synaptic plasticity in hippocampal neuronal ensembles implicated in memory.The CA3 area of the hippocampus exhibits a distinctive, highly recurrent circuitry proposed to support autoassociative memory representation (1, 2). This prediction has been confirmed by experimental work demonstrating the pattern completion capabilities of CA3 networks (3), as well as their roles in the spatial tuning of CA1 pyramidal cells, in one-trial contextual learning (4) and in certain forms of memory consolidation (5). CA3 pyramidal cells receive, via the mossy fibers, information processed by granule cells important for both pattern separation (6, 7) and pattern completion functions (7). The faithful transmission of mossy fiber input appears to be ensured by giant synapses composed of presynaptic boutons with up to 45 release sites (8) that target massive spines, the thorny excrescences, on the apical dendrite of CA3 pyramidal cells. Thus, the mossy fiber synapse is often referred to as a detonator synapse (9). In fact, mossy fiber signaling is more compatible with a gatekeeper function than a high-throughput data relay. Although high-frequency bursts of action potentials in a hippocampal granule cell can discharge a targeted CA3 pyramidal cell, the majority of responses evoked by granule cells in CA3 pyramidal cells do not attain the firing threshold (10). Nevertheless, mossy fibers generate powerful signals evoking subthreshold responses that are much larger than typical synaptic events in the brain, with excitatory postsynaptic potentials (EPSPs) and excitatory postsynaptic currents (EPSCs) reaching amplitudes of 10 mV and 1 nA, respectively (11). Here we examined in rat slice cultures how EPSPs generated at mossy fiber synapses are processed in CA3 pyramidal cell dendrites, and evaluated whether subthreshold synaptic responses evoked by mossy fiber stimulation can act as instructive signals to induce plasticity at the pyramidal cell synapses forming the CA3 recurrent network.     

Eating disorders and associated mental health comorbidities in female veterans

Eating disorders (EDs) remain understudied among veterans, possibly due to the perception that primarily male population does not suffer from EDs. However, previous research suggests that male and female veterans do experience EDs. The high rates of posttraumatic stress disorder (PTSD), depression, and obesity observed among veterans may make this group vulnerable to disordered eating. Retrospective chart review was used to obtain data from 492 female veterans who were presented to a women?s primary care center at a large, urban VA medical center between 2007 and 2009. A total of 2.8% of this sample had been diagnosed with an ED. In bivariate analyses, presence of PTSD and depression were significantly associated with having an ED diagnosis. However, when these two disorders were included in a multivariate model controlling for age, only depression diagnosis and lower age were significantly related to ED status. In sum, the rate of EDs in this sample is comparable to prevalence estimates of EDs in the general population. Current findings underscore the importance of assessing for EDs among VA patients and the need for further research among veterans.     

The effect of β-alanine and NaHCO3 co-ingestion on buffering capacity and exercise performance with high-intensity exercise in healthy males

Introduction

β-alanine (BAl) and NaHCO₃ (SB) ingestion may provide performance benefits by enhancing concentrations of their respective physiochemical buffer counterparts, muscle carnosine and blood bicarbonate, counteracting acidosis during intense exercise. This study examined the effect of BAl and SB co-supplementation as an ergogenic strategy during high-intensity exercise.

Methods

Eight healthy males ingested either BAl (4.8 g day^?1 for 4 weeks, increased to 6.4 g day^?1 for 2 weeks) or placebo (Pl) (CaCO₃) for 6 weeks, in a crossover design (6-week washout between supplements). After each chronic supplementation period participants performed two trials, each consisting of two intense exercise tests performed over consecutive days. Trials were separated by 1 week and consisted of a repeated sprint ability (RSA) test and cycling capacity test at 110 % Wmax (CCT_110 %). Placebo (Pl) or SB (300 mg kgbw^?1) was ingested prior to exercise in a crossover design to creating four supplement conditions (BAl-Pl, BAl-SB, Pl–Pl, Pl-SB).

Results

Carnosine increased in the gastrocnemius (n = 5) (p = 0.03) and soleus (n = 5) (p = 0.02) following BAl supplementation, and Pl-SB and BAl-SB ingestion elevated blood HCO₃ ^? concentrations (p < 0.01). Although buffering capacity was elevated following both BAl and SB ingestion, performance improvement was only observed with BAl-Pl and BAl-SB increasing time to exhaustion of the CCT_110 % test 14 and 16 %, respectively, compared to Pl–Pl (p < 0.01).

Conclusion

Supplementation of BAl and SB elevated buffering potential by increasing muscle carnosine and blood bicarbonate levels, respectively. BAl ingestion improved performance during the CCT_110 %, with no aggregating effect of SB supplementation (p > 0.05). Performance was not different between treatments during the RSA test.     

High-intensity intermittent cycling increases purine loss compared with workload-matched continuous moderate intensity cycling

Purpose

Exercise at 50–60 % of peak oxygen consumption (VO_{2 peak}) stimulates maximal fat oxidation rates. Despite a lower estimated work performed; high-intensity intermittent exercise (HIIE) training produces greater fat mass reductions when compared with workload-matched continuous (CON) steady state exercise. No metabolic basis has been documented nor mechanisms offered to explain this anomaly. This study investigated the physiological and metabolic responses of two different workload-matched exercise protocols.

Methods

On separate occasions and at least 1 week apart, eight apparently healthy males cycled for 30 min at either 50 % VO_{2 peak} (CON) or performed repeated 20 s bouts of supramaximal exercise at 150 %VO_{2 peak} separated by 40 s rest (HIIE).

Results

The average heart rate, oxygen consumption, plasma glycerol and free fatty acid concentrations were not different during exercise and recovery between the trials. Plasma lactate and hypoxanthine (Hx) concentrations were elevated and urinary excretion rates of Hx and uric acid were greater following HIIE as compared to CON (P < 0.05).

Conclusion

Exercise-induced plasma Hx accumulation and urinary purine excretion are greater following HIIE and indirectly represents a net loss of adenosine triphosphate (ATP) from the muscle. The subsequent restorative processes required for intramuscular de novo replacement of ATP may contribute to a negative energy balance and in part, account for the potential accelerated fat loss observed with HIIE when compared with CON training programs.     

Long-term subcutaneous morphine administration after surgery in newborns

AIM: To analyze the management of newborns after major surgery receiving morphine subcutaneously and to identify possible side effects. METHODS: Morphine was administered via a subcutaneous catheter (Insuflon) in 20 newborns after major surgery. Side effects like hypotension, pain during morphine administration and local infection were noted. Morphine dose was adjusted according to the hospital guidelines with the Neonatal Infant Pain Score (NIPS) and the Finnegan withdrawal score. RESULTS: Surgery was performed at the median age of 38 5/7 weeks (range: 32 1/7-49 5/7 weeks). Before starting subcutaneous morphine administration, patients received intravenous morphine for a median of two weeks (range six days to seven weeks). All patients showed good pain relief with no severe side effects. Three patients reacted with crying to the first dose of subcutaneous morphine. No other side effects occurred. CONCLUSION: Subcutaneous application of morphine with the Insuflon catheter is an alternative to intravenous treatment of postoperative pain in neonates. In this small group pain relief was good and side effects were harmless.     

Length of ovarian stimulation does not impact live birth rate in fresh donor oocyte cycles: a SART CORS study

PurposeTo evaluate the effect of controlled ovarian hyperstimulation length and total gonadotropin (GN) dose on recipient live birth rate (LBR) in fresh donor oocyte cycles.MethodsData was obtained from SART CORS on all fresh donor oocyte GnRH antagonist cycles (n = 1049) between 2014 and 2015 which resulted in a single embryo transferred. Donor and recipient demographic information and cycle characteristics were extracted. Binomial regression was used to estimate LBR with respect to days of stimulation (DOS) and total GN dose. Multivariate analysis was performed to evaluate these relationships after controlling for confounders.ResultsOverall LBR in fresh donor oocyte cycles was 57%. Average stimulation length was 14.3 ± 4.9 days, and total GN dose was 2464 ± 1062 IU. On univariate analysis, neither days of stimulation (p = 0.5) nor total GN dose (p = 0.57) was independently correlated with LBR. However, in prolonged stimulations (> 15 days) with high total GN dose (> 3000 IU), as both the cycle length and total GN dose increased, LBR significantly decreased from 63.81 to 48.15% (p = 0.02) and from 67.61 to 48.15% (p = 0.01), respectively. Multivariate analysis showed no significant effect of either DOS or total GN dose on LBR.ConclusionsLBR is significantly decreased in fresh donor oocyte cycles when cycles are prolonged with high total GN dose. However, after controlling for confounders neither DOS nor total GN dose significantly affects LBR.