Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy.

BackgroundHistone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac diseases. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle (SV) heart disease of right ventricular morphology, as well as in a rodent model of right ventricular hypertrophy (RVH).MethodsHomogenates of right ventricle (RV) explants from non-failing controls and children born with a SV were assayed for HDAC catalytic activity and HDAC isoform expression. Postnatal 1-day-old rat pups were placed in hypoxic conditions, and echocardiographic analysis, gene expression, HDAC catalytic activity, and isoform expression studies of the RV were performed.ResultsClass I, IIa, and IIb HDAC catalytic activity and protein expression were elevated in the hearts of children born with a SV. Hypoxic neonatal rats demonstrated RVH, abnormal gene expression, elevated class I and class IIb HDAC catalytic activity, and protein expression in the RV compared with those in the control.ConclusionsThese data suggest that myocardial HDAC adaptations occur in the SV heart and could represent a novel therapeutic target. Although further characterization of the hypoxic neonatal rat is needed, this animal model may be suitable for preclinical investigations of pediatric RV disease and could serve as a useful model for future mechanistic studies

It's in the loop: shared sub-surface foot kinematics in birds and other dinosaurs shed light on a new dimension of fossil track diversity

The feet of ground-dwelling birds retain many features of their dinosaurian ancestry. Experiments with living species offer insights into the complex interplay among anatomy, kinematics and substrate during the formation of Mesozoic footprints. However, a key aspect of the track-making process, sub-surface foot movement, is hindered by substrate opacity. Here, we use biplanar X-rays to image guineafowl walking through radiolucent substrates of different consistency (solid, dry granular, firm to semi-liquid muds). Despite substantial kinematic variation, the foot consistently moves in a looping pattern below ground. As the foot sinks and then withdraws, the claws of the three main toes create entry and exit paths in different locations. Sampling these paths at incremental horizons captures two-dimensional features just as fossil tracks do, allowing depth-based zones to be characterized by the presence and relative position of digit impressions. Examination of deep, penetrative tracks from the Early Jurassic confirms that bipeds had an equivalent looping response to soft substrates approximately 200 Ma. Our integration of extant and extinct evidence demonstrates the influence of substrate properties on sinking depth and sub-surface foot motion, both of which are significant sources of track variation in the fossil record of dinosaurs

Voluntary exercise can strengthen the circadian system in aged mice

Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2luc/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and >18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age-related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (>21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption

BK Channels Regulate Spontaneous Action Potential Rhythmicity in the Suprachiasmatic Nucleus

Background: Circadian (,24 hr) rhythms are generated by the central pacemaker localized to the suprachiasmatic nucleus (SCN) of the hypothalamus. Although the basis for intrinsic rhythmicity is generally understood to rely on transcription factors encoded by ‘‘clock genes’’, less is known about the daily regulation of SCN neuronal activity patterns that communicate a circadian time signal to downstream behaviors and physiological systems. Action potentials in the SCN are necessary for the circadian timing of behavior, and individual SCN neurons modulate their spontaneous firing rate (SFR) over the daily cycle, suggesting that the circadian patterning of neuronal activity is necessary for normal behavioral rhythm expression. The BK K + channel plays an important role in suppressing spontaneous firing at night in SCN neurons. Deletion of the Kcnma1 gene, encoding the BK channel, causes degradation of circadian behavioral and physiological rhythms. Methodology/Principal Findings: To test the hypothesis that loss of robust behavioral rhythmicity in Kcnma1 2/2 mice is due to the disruption of SFR rhythms in the SCN, we used multi-electrode arrays to record extracellular action potentials from acute wild-type (WT) and Kcnma1 2/2 slices. Patterns of activity in the SCN were tracked simultaneously for up to 3 days, and the phase, period, and synchronization of SFR rhythms were examined. Loss of BK channels increased arrhythmicity but also altered the amplitude and period of rhythmic activity. Unexpectedly, Kcnma1 2/2 SCNs showed increased variability in the timing of the daily SFR peak

A two-neuron system for adaptive goal-directed decision-making in Lymnaea

During goal-directed decision-making, animals must integrate information from the external environment and their internal state to maximize resource localization while minimizing energy expenditure. How this complex problem is solved by the nervous system remains poorly understood. Here, using a combined behavioural and neurophysiological approach, we demonstrate that the mollusc Lymnaea performs a sophisticated form of decision-making during food-searching behaviour, using a core system consisting of just two neuron types. The first reports the presence of food and the second encodes motivational state acting as a gain controller for adaptive behaviour in the absence of food. Using an in vitro analogue of the decision-making process, we show that the system employs an energy management strategy, switching between a low- and high-use mode depending on the outcome of the decision. Our study reveals a parsimonious mechanism that drives a complex decision-making process via regulation of levels of tonic inhibition and phasic excitation

Diurnal Rhythms in Neurexins Transcripts and Inhibitory/Excitatory Synapse Scaffold Proteins in the Biological Clock

The neurexin genes (NRXN1/2/3) encode two families (α and β) of highly polymorphic presynaptic proteins that are involved in excitatory/inhibitory synaptic balance. Recent studies indicate that neuronal activation and memory formation affect NRXN1/2/3α expression and alternative splicing at splice sites 3 and 4 (SS#3/SS#4). Neurons in the biological clock residing in the suprachiasmatic nuclei of the hypothalamus (SCN) act as self-sustained oscillators, generating rhythms in gene expression and electrical activity, to entrain circadian bodily rhythms to the 24 hours day/night cycles. Cell autonomous oscillations in NRXN1/2/3α expression and SS#3/SS#4 exons splicing and their links to rhythms in excitatory/inhibitory synaptic balance in the circadian clock were explored. NRXN1/2/3α expression and SS#3/SS#4 splicing, levels of neurexin-2α and the synaptic scaffolding proteins PSD-95 and gephyrin (representing excitatory and inhibitory synapses, respectively) were studied in mRNA and protein extracts obtained from SCN of C3H/J mice at different times of the 24 hours day/night cycle. Further studies explored the circadian oscillations in these components and causality relationships in immortalized rat SCN2.2 cells. Diurnal rhythms in mNRXN1α and mNRXN2α transcription, SS#3/SS#4 exon-inclusion and PSD-95 gephyrin and neurexin-2α levels were found in the SCN in vivo. No such rhythms were found with mNRXN3α. SCN2.2 cells also exhibited autonomous circadian rhythms in rNRXN1/2 expression SS#3/SS#4 exon inclusion and PSD-95, gephyrin and neurexin-2α levels. rNRXN3α and rNRXN1/2β were not expressed. Causal relationships were demonstrated, by use of specific siRNAs, between rNRXN2α SS#3 exon included transcripts and gephyrin levels in the SCN2.2 cells. These results show for the first time dynamic, cell autonomous, diurnal rhythms in expression and splicing of NRXN1/2 and subsequent effects on the expression of neurexin-2α and postsynaptic scaffolding proteins in SCN across the 24-h cycle. NRXNs gene transcripts may have a role in coupling the circadian clock to diurnal rhythms in excitatory/inhibitory synaptic balance

Neurophysiologic effects of spinal manipulation in patients with chronic low back pain

<p>Abstract</p> <p>Background</p> <p>While there is growing evidence for the efficacy of SM to treat LBP, little is known on the mechanisms and physiologic effects of these treatments. Accordingly, the purpose of this study was to determine whether SM alters the amplitude of the motor evoked potential (MEP) or the short-latency stretch reflex of the erector spinae muscles, and whether these physiologic responses depend on whether SM causes an audible joint sound.</p> <p>Methods</p> <p>We used transcranial magnetic stimulation to elicit MEPs and electromechanical tapping to elicit short-latency stretch reflexes in 10 patients with chronic LBP and 10 asymptomatic controls. Neurophysiologic outcomes were measured before and after SM. Changes in MEP and stretch reflex amplitude were examined based on patient grouping (LBP vs. controls), and whether SM caused an audible joint sound.</p> <p>Results</p> <p>SM did not alter the erector spinae MEP amplitude in patients with LBP (0.80 ± 0.33 vs. 0.80 ± 0.30 μV) or in asymptomatic controls (0.56 ± 0.09 vs. 0.57 ± 0.06 μV). Similarly, SM did not alter the erector spinae stretch reflex amplitude in patients with LBP (0.66 ± 0.12 vs. 0.66 ± 0.15 μV) or in asymptomatic controls (0.60 ± 0.09 vs. 0.55 ± 0.08 μV). Interestingly, study participants exhibiting an audible response exhibited a 20% decrease in the stretch reflex (p < 0.05).</p> <p>Conclusions</p> <p>These findings suggest that a single SM treatment does not systematically alter corticospinal or stretch reflex excitability of the erector spinae muscles (when assessed ~ 10-minutes following SM); however, they do indicate that the stretch reflex is attenuated when SM causes an audible response. This finding provides insight into the mechanisms of SM, and suggests that SM that produces an audible response may mechanistically act to decrease the sensitivity of the muscle spindles and/or the various segmental sites of the Ia reflex pathway.</p

Prokineticin 2 Regulates the Electrical Activity of Rat Suprachiasmatic Nuclei Neurons

Neuropeptide signaling plays roles in coordinating cellular activities and maintaining robust oscillations within the mammalian suprachiasmatic nucleus (SCN). Prokineticin2 (PK2) is a signaling molecule from the SCN and involves in the generation of circadian locomotor activity. Prokineticin receptor 2 (PKR2), a receptor for PK2, has been shown to be expressed in the SCN. However, very little is known about the cellular action of PK2 within the SCN. In the present study, we investigated the effect of PK2 on spontaneous firing and miniature inhibitory postsynaptic currents (mIPSCs) using whole cell patch-clamp recording in the SCN slices. PK2 dose-dependently increased spontaneous firing rates in most neurons from the dorsal SCN. PK2 acted postsynaptically to reduce γ-aminobutyric acid (GABA)-ergic function within the SCN, and PK2 reduced the amplitude but not frequency of mIPSCs. Furthermore, PK2 also suppressed exogenous GABA-induced currents. And the inhibitory effect of PK2 required PKC activation in the postsynaptic cells. Our data suggest that PK2 could alter cellular activities within the SCN and may influence behavioral and physiological rhythms

Cognitive frailty: rational and definition from an (I.A.N.A./I.A.G.G.) international consensus group.

The frailty syndrome has recently attracted attention of the scientific community and public health organizations as precursor and contributor of age-related conditions (particularly disability) in older persons. in parallel, dementia and cognitive disorders also represent major healthcare and social priorities. although physical frailty and cognitive impairment have shown to be related in epidemiological studies, their pathophysiological mechanisms have been usually studied separately. an international Consensus Group on “Cognitive Frailty” was organized by the international academy on nutrition and aging (i.a.n.a) and the international association of Gerontology and Geriatrics (i.a.G.G) on april 16th, 2013 in toulouse (France). the present report describes the results of the Consensus Group and provides the first definition of a “Cognitive Frailty” condition in older adults. specific aim of this approach was to facilitate the design of future personalized preventive interventions in older persons. Finally, the Group discussed the use of multidomain interventions focused on the physical, nutritional, cognitive and psychological domains for improving the well-being and quality of life in the elderly. the consensus panel proposed the identification of the so-called “cognitive frailty” as an heterogeneous clinical manifestation characterized by the simultaneous presence of both physical frailty and cognitive impairment. in particular, the key factors defining such a condition include: 1) presence of physical frailty and cognitive impairment (Cdr=0.5); and 2) exclusion of concurrent ad dementia or other dementias. under different circumstances, cognitive frailty may represent a precursor of neurodegenerative processes. a potential for reversibility may also characterize this entity. a psychological component of the condition is evident and concurs at increasing the vulnerability of the individual to stressors