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Spreading depolarization (SD) is generated in the central nervous systems of both vertebrates and invertebrates. SD manifests as a propagating wave of electrical depression caused by a massive redistribution of ions. Mammalian SD underlies a continuum of human pathologies from migraine to stroke damage whereas insect SD is associated with environmental stress-induced neural shutdown. The general cellular mechanisms underlying SD seem to be evolutionarily conserved throughout the animal kingdom. In particular, SD in the CNS of Locusta migratoria and Drosophila melanogaster, has all the hallmarks of mammalian SD. Locust SD is easily induced and monitored within the metathoracic ganglion (MTG) and can be modulated both pharmacologically and by pre-conditioning treatments. The finding that the fly brain supports repetitive waves of SD is relatively recent but noteworthy as it provides a genetically tractable model system. Due to the human suffering caused by SD manifestations, elucidating control mechanisms that could ultimately attenuate brain susceptibility is essential. Here we review mechanisms of SD focusing on the similarities between mammalian and insect systems. Additionally we discuss advantages of using invertebrate model systems and propose insect SD as a valuable model for providing new insights to mammalian SD.
Computations performed by the visual pathway are constructed by neural circuits distributed over multiple stages of processing, and thus it is challenging to determine how different stages contribute based on recordings from single areas. Here, we address this problem in the lateral geniculate nucleus (LGN), using experiments combined with nonlinear modeling capable of isolating various circuit contributions. We recorded cat LGN neurons presented with temporally modulated spots of various sizes, which drove temporally precise LGN responses. We utilized simultaneously recorded S-potentials, corresponding to the primary retinal ganglion cell (RGC) input to each LGN cell, in order to distinguish the computations underlying temporal precision in the retina from those in the LGN. Nonlinear models with excitatory and delayed suppressive terms were sufficient to explain temporal precision in the LGN, and we found that models of the S-potentials were nearly identical, although with a lower threshold. To determine whether additional influences shaped the response at the level of the LGN, we extended this model to use the S-potential input in combination with stimulus-driven terms to predict the LGN response. We found that the S-potential input "explained away" the major excitatory and delayed suppressive terms responsible for temporal patterning of LGN spike trains, but revealed additional contributions - largely PULL suppression - to the LGN response. Using this novel combination of recordings and modeling, we were thus able to dissect multiple circuit contributions to LGN temporal responses across retina and LGN, and set the foundation for targeted study of each stage.
Motor unit activity in biceps brachii of left-handed humans during sustained contractions with two load types
Today, 23 Ιουνίου 2016, 8 hours ago | Gould, J. R., Cleland, B. T., Mani, D., Amiridis, I. G., Enoka, R. M.
The purpose of the study was to compare the discharge characteristics of single motor units during sustained isometric contractions that required either force or position control in left-handed individuals. The target force for the two sustained contractions (24.9 ± 10.5% maximal force) was identical for each biceps brachii motor unit (n = 32) and set at 4.7 ± 2.0% of maximal voluntary contraction (MVC) force above its recruitment threshold (range: 0.5-41.2% MVC force). The contractions were not sustained to task failure, but the duration (range: 60-330 s) was identical for each motor unit and the decline in MVC force immediately after the sustained contractions was similar for the two tasks (force: 11.1% ± 13.7%; position: 11.6% ± 9.9%). Despite a greater increase in the rating of perceived exertion during the position task (task x time interaction, P < 0.006), the amplitude of the surface-recorded electromyogram for the agonist and antagonist muscles increased similarly during the two tasks. Nonetheless, mean discharge rate of the biceps brachii motor units declined more during the position task (task x time interaction, P < 0.01) and the variability in discharge times (coefficient of variation for interspike interval) increased only during the position task (task x time interaction, P < 0.008). When combined with the results of an identical study on right-handers (Mottram et al. 2005), the findings indicate that handedness does not influence the adjustments in biceps brachii motor unit activity during sustained submaximal contractions requiring either force or position control.
'Real-time' imaging of cortical and subcortical sites of cardiovascular control: concurrent recordings of sympathetic nerve activity and fMRI in awake subjects
We review our approach to functionally identifying cortical and subcortical areas involved in the generation of spontaneous fluctuations in sympathetic outflow to muscle or skin. We record muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA), via a tungsten microelectrode inserted percutaneously into the common peroneal nerve, at the same time as performing functional magnetic resonance imaging (fMRI) of the brain. By taking advantage of the neurovascular coupling delay associated with BOLD (Blood Oxygen Level Dependent) fMRI, and the delay associated with conduction of a burst of sympathetic impulses to the peripheral recording site, we can identify structures in which BOLD signal intensity covaries with MSNA or SSNA. Using this approach we have shown that signal intensity and MSNA were positively correlated in the left mid-insula, bilateral dorsolateral prefrontal cortex, bilateral posterior cingulate cortex, bilateral precuneus, left dorsomedial hypothalamus, bilateral ventromedial hypothalamus and bilateral rostral ventrolateral medualla. Conversely, spontaneous bursts of SSNA covaried with BOLD signal intensity in the left ventromedial thalamus, the left posterior and right anterior insula, the right orbitofrontal cortex, right frontal cortex, and bilaterally in the mid-cingulate cortex and precuneus. These results emphasize the contributions of cortical regions of the brain to sympathetic outflow in awake human subjects, and the extensive interactions between cortical and subcortical regions in the ongoing regulation of sympathetic nerve activity to muscle and skin in awake human subjects.
Today, 23 Ιουνίου 2016, 8 hours ago | MacDougall, M., Nummela, S. U., Coop, S., Disney, A., Mitchell, J. F., Miller, C. T.
Optogenetics has revolutionized the study of functional neuronal circuitry (Boyden et al. 2005; Deisseroth 2011). Although these techniques have been most successfully implemented in rodent models, they have the potential to be similarly impactful in studies of nonhuman primate brains (Diester et al. 2011; Han et al. 2009). Common marmosets (Callithrix jacchus) have recently emerged as a candidate primate model for gene editing, providing a potentially powerful model for studies of neural circuitry and disease in primates (Belmonte et al. 2015; Sasaki et al. 2009). The application of viral transduction methods in marmosets for identifying and manipulating neuronal circuitry is a crucial step in developing this species for neuroscience research. Here we employed a novel, chronic method to successfully induce rapid photostimulation in individual cortical neurons transduced by AAV to express channel-rhodopsin (ChR2) in awake marmosets. We found that a large proportions of neurons could be effectively photoactivated following viral transduction and that this procedure could be repeated for several months. These data suggest that techniques for viral transduction and optical manipulation of neuronal populations are suitable for marmosets and can be combined with existing behavioral preparations in the species (Miller et al. 2015; Mitchell et al. 2014; Osmanski et al. 2013; Song et al. 2016) in order to elucidate the functional neural circuitry underlying perceptual and cognitive processes.
The cerebellum's role in non-motor processes is now well accepted, but cerebellar interaction with cerebral targets is not well understood. Complex cognitive tasks activate cerebellar, parietal, and frontal regions; but the effective connectivity between these regions has never been tested. To this end, we used psycho-physiological interactions analysis (PPI) to test connectivity changes of cerebellar and parietal seed regions in complex (2-digit by 1-digit multiplication, e.g., 12 x 3) versus simple (1-digit by 1-digit multiplication, e.g., 4 x 3) task conditions ('complex - simple'). For cerebellar seed-regions (lobule VI, hemisphere and vermis), we found significantly decreased cerebellar-parietal, cerebellar-cingulate, and cerebellar-frontal connectivity in complex multiplication. For parietal seed regions (PFcm, PFop, PFm) we found significantly increased parietal-parietal and parietal-frontal connectivity in complex multiplication. These results suggest decreased cerebellar-cerebral connectivity contributes to complex task performance. Interestingly, BOLD activity contrasts revealed partially overlapping parietal areas of increased BOLD activity but decreased cerebellar-parietal PPI connectivity.
Accurate timing is critical for a wide range of cognitive processes and behaviors. In addition, complex environments frequently necessitate the simultaneous timing of multiple intervals, and behavioral performance in concurrent timing can constrain formal models of timing behavior and provide important insights into the corresponding neural mechanisms. However, the accuracy of such concurrent timing has not been rigorously examined. We developed a novel behavioral paradigm in which rhesus monkeys were incentivized to time two independent intervals. The onset asynchrony of two overlapping intervals varied randomly, thereby discouraging the animals from adopting any habitual responses. We found that only the first response for each interval was strongly indicative of the internal timing of that interval, consistent with previous findings and a two-stage model. In addition, the temporal precision of the first response was comparable in the single-interval and concurrent-interval conditions, although the first saccade to the second interval tended to occur sooner than in the single-interval condition. Finally, behavioral responses during concurrent timing could be well accounted for by a race between two independent stochastic processes resembling those in the single-interval condition. The fact that monkeys can simultaneously monitor and respond to multiple temporal intervals indicates that the neural mechanisms for interval timing must be sufficiently flexible for concurrent timing.
Relationship of membrane properties, spike burst responses, laminar location and functional class of dorsal horn neurons recorded in vitro
Input-output and discharge properties of neurons are shaped by both passive and active electrophysiological membrane properties. Whole-cell patch clamp recordings in lamina I-III neurons in an isolated preparation of the whole spinal cord of juvenile rats with attached dorsal roots and dorsal root ganglia was used to further define which of these properties provides the most impactful classification strategy. A total of 95 neurons were recorded in segment L5 and were classified based on the responses to L4 dorsal root stimulation. The results showed that high threshold and silent neurons had higher membrane resistance and more negative resting membrane potential than low threshold or wide dynamic range neurons. Rheobase in low threshold and wide dynamic range neurons was significantly lower than that of high threshold or silent neurons. Four types of firing patterns were identified in response to depolarizing current injections. Low threshold cells most frequently showed a phasic firing pattern characterized by a short initial burst of action potentials, single-spiking or irregular firing bursts at the onset of a depolarizing pulse. High threshold and wide dynamic range neurons were characterized by tonic firing with trains of spikes occurring at regular intervals throughout the current pulse. The majority of silent neurons displayed a delayed onset of firing in response to current injection. These results indicate that passive membrane properties of spinal neurons are tuned to optimize the responses to particular subsets of afferent stimuli.
Thresholds and biases of human motion perception were determined for yaw rotation, sway (left-right), and surge (fore-aft) translation independently and in combination. Stimuli were 1 Hz sinusoid in acceleration with a peak velocity of 14°/s or cm/s. Test stimuli were adjusted based on prior responses while the distracting stimulus was constant. Seventeen human subjects between the age of 20 and 83 completed the experiments and were divided into 2 groups younger and older than 50. Both sway and surge translation thresholds significantly increased when combined with yaw rotation. Rotation thresholds were not significantly increased by the presence of translation. Presence of a yaw distractor significantly biased perception of sway translation such that during 14°/s leftward rotation, the point of subjective equality (PSE) occurred with sway of 3.2±0.7 (mean±SE) cm/s to the right. Similarly, during 14°/s rightward motion the PSE was with sway of 2.9±0.7 cm/s to the left. A sway distractor did not bias rotation perception. When subjects were asked to report the direction of translation while varying the axis of yaw rotation, the PSE at which translation was equally likely to be perceived in either direction was 29±11 cm anterior to the midline. These results demonstrated that rotation biased translation perception such that it is minimized when rotating about an axis anterior to head. Since the combination of translation and rotation during ambulation is consistent with an axis anterior to the head, this may reflect a mechanism by which movements outside the pattern that occurs during ambulation are perceived.
Selective attention allows organisms to extract behaviorally relevant information while ignoring distracting stimuli that compete for the limited resources of their central nervous systems. Attention is highly flexible, and it can be harnessed to select information based on sensory modality, within-modality feature(s), spatial location, object identity, and/or temporal properties. In this review, we discuss the body of work devoted to understanding mechanisms of selective attention in the somatosensory system. In particular, we describe the effects of attention on tactile behavior and corresponding neural activity in somatosensory cortex. Our focus is on neural mechanisms that select tactile stimuli based on their location on the body (somatotopic-based attention) or their sensory feature (feature-based attention). We highlight parallels between selection mechanisms in touch and other sensory systems, and discuss several putative neural coding schemes employed by cortical populations to signal the behavioral relevance of sensory inputs. Specifically, we contrast the advantages and disadvantages of using a gain vs. spike-spike correlation code for representing attended sensory stimuli. We favor a neural network model of tactile attention that is composed of frontal, parietal and sub-cortical areas, which controls somatosensory cells encoding the relevant stimulus features to enable preferential processing throughout the somatosensory hierarchy. Our review is based on data from non-invasive electrophysiological and imaging data in humans as well as single-unit recordings in non-human primates.
Effect of coordinate frame compatibility on the transfer of implicit and explicit learning across limbs
Insights into the neural representation of motor learning can be obtained by investigating how learning transfers to novel task conditions. We recently demonstrated that visuomotor rotation learning transferred strongly between left and right limbs when the task was performed in a sagittal workspace, which afforded a consistent remapping for the two limbs in both extrinsic and joint-based coordinates. In contrast, transfer was absent when performed in horizontal workspace, where the extrinsically-defined perturbation required conflicting joint-based remapping for the left and right limbs. As visuomotor learning is thought to be supported by both implicit and explicit forms of learning, however, it is unclear to what extent these distinct forms of learning contribute to inter-limb transfer. Here, we assessed the degree to which inter-limb transfer, following visuomotor rotation training, reflects explicit versus implicit learning, by obtaining verbal reports of participants' aiming direction before each movement. We also determined the extent to which these distinct components of learning are constrained by the compatibility of coordinate systems, by comparing transfer between groups who reached to targets arranged in the horizontal and sagittal planes. Both sagittal and horizontal conditions displayed complete transfer of explicit learning to the untrained limb. In contrast, transfer of implicit learning was incomplete, but the sagittal condition showed greater transfer than the horizontal condition. These findings suggest that explicit strategies developed with one limb can be fully implemented in the opposite limb, while implicit transfer depends on the degree to which new sensorimotor maps are spatially compatible for the two limbs.
A simple approach to ignoring irrelevant variables by population decoding based on multisensory neurons
Today, 23 Ιουνίου 2016, 8 hours ago | Kim, H. R., Pitkow, X., Angelaki, D. E., DeAngelis, G. C.
Sensory input reflects events that occur in the environment, but multiple events may be confounded in sensory signals. For example, under many natural viewing conditions, retinal image motion reflects some combination of self-motion and movement of objects in the world. To estimate one stimulus event and ignore others, the brain can perform marginalization operations, but the neural bases of these operations are poorly understood. Using computational modelling, we examine how multisensory signals may be processed to estimate the direction of self-motion (i.e., heading) and to marginalize out effects of object motion. Multisensory neurons represent heading based on both visual and vestibular inputs and come in two basic types: 'congruent' and 'opposite' cells. Congruent cells have matched heading tuning for visual and vestibular cues, and have been linked to perceptual benefits of cue integration during heading discrimination. Opposite cells have mismatched visual and vestibular heading preferences, and are ill-suited for cue integration. We show that decoding a mixed population of congruent and opposite cells substantially reduces errors in heading estimation caused by object motion. In addition, we present a general formulation of an optimal linear decoding scheme that approximates marginalization and can be implemented biologically by simple reinforcement learning mechanisms. We also show that neural response correlations induced by task-irrelevant variables may greatly exceed intrinsic noise correlations. Overall, our findings suggest a general computational strategy by which neurons with mismatched tuning for two different sensory cues may be decoded to perform marginalization operations that dissociate possible causes of sensory inputs.
The functional role of input from primary motor cortex (M1) to primary somatosensory cortex (S1) is unclear; one key to understanding this pathway may lie in elucidating the cell-type specific microcircuits that connect S1 and M1. Recently, we discovered that a subset of pyramidal neurons in the infragranular layers of S1 receive especially strong input from M1 (Kinnischtzke et al., 2013), suggesting that M1 may affect specific classes of pyramidal neurons differently. Here, using combined optogenetic and retrograde labeling approaches in the mouse, we examined the strengths of M1 inputs to five classes of infragranular S1 neurons categorized by their projections to particular cortical and subcortical targets. We find that the magnitude of M1 synaptic input to S1 pyramidal neurons varies greatly depending on the projection target of the post-synaptic neuron. Of the populations examined, M1-projecting corticocortical neurons in L6 received the strongest M1 inputs whereas VPM-projecting corticothalamic neurons, also located in L6, received the weakest. Each population also possessed distinct intrinsic properties. Results suggest that M1 differentially engages specific classes of S1 projection neurons, thereby regulating the motor-related influence S1 exerts over subcortical structures.
Intramuscular MAPK signaling following high volume and high intensity resistance exercise protocols in trained men
PurposeTo examine the mitogen-activated protein kinase (MAPK) family of signaling proteins following typical high volume (HV) and high intensity (HI) lower body resistance exercise protocols in resistance-trained men.
MethodsTen resistance-trained men (24.7 ± 3.4 year; 90.1 ± 11.3 kg; 176.0 ± 4.9 cm) performed each resistance exercise protocol in a random, counterbalanced order. The HV protocol utilized a load of 70 % 1-RM for sets of 10–12 repetitions with a 1-min rest period length between sets and exercises. The HI protocol utilized a load of 90 % 1-RM for sets of 3–5 repetitions with a 3-min rest period length between sets and exercises. Both protocols included six sets of barbell back squats and four sets of bilateral leg press, bilateral hamstring curls, bilateral leg extensions, and seated calf raises. Fine needle muscle biopsies of the vastus lateralis were completed at baseline (BL) and 1-h post exercise (1H).
ResultsNo significant differences over time were noted for phosphorylation of MEK1, ERK1/2, p38, MSK1, ATF2, p53, or c-Jun (p > 0.05). No significance between trial interactions was noted for phosphorylation of MAPK signaling proteins, including MEK1, ERK1/2, p38, JNK, MSK1, ATF2, STAT1, p53, c-Jun, or HSP27 (p > 0.05). However, significant time effects were observed for phosphorylation of JNK (p < 0.01), HSP27 (p < 0.01), and STAT1 (p = 0.03). Phosphorylation of JNK, HSP27, and STAT1 was significantly elevated from BL at 1H for both HV and HI.
ConclusionsHV and HI lower body resistance exercise protocols appear to elicit similar MAPK activation in resistance-trained men.
Oral nitrate and citrulline decrease blood pressure and increase vascular conductance in young adults: a potential therapy for heart failure
PurposeBoth inorganic nitrate and citrulline are known to alter the arginine–nitric oxide–nitrate system to increase the bioavailability of nitric oxide with potential benefits in the treatment of heart failure. However, their effects on cardiac electrical activity, vascular compliance and peripheral conductance are less well understood. This study examined the effect of nitrate and citrulline on cardiac electrical activity and blood flow.
MethodsYoung adult subjects (n = 12) were recruited to investigate the effects of acute oral nitrate consumption (8 mg/kg) and chronic citrulline consumption (3 g/day) on cardiac electrical activity measured by ECG recording and blood pressure. Blood flow and vascular compliance were measured by IR-plethysmography at the thumb and the hallux.
ResultsNitrate (p < 0.05) and citrulline (p < 0.01) consumption both decreased diastolic blood pressure but had no effect on either pulse pressure or rate-pressure product (NS for both). Citrulline also decreased systolic pressure (p < 0.01). Nitrate and citrulline both decreased vascular compliance (p < 0.05 for both) prior to isometric grip exercise, but this was increased for nitrate following exercise (NS). Citrulline decreased R–R interval 9 % (p < 0.05) at rest and increased heart rate (p < 0.05) in addition to significantly decreasing pulse transit duration (6 %; p < 0.05). QRS duration was also decreased by 5 % for citrulline (p < 0.05) with the reduction in R–R interval.
ConclusionBoth nitrate and citrulline supplementation decreased vascular tone at rest but citrulline also altered sympathovagal balance to increase sympathetic tone. We suggest that both oral nitrate and citrulline may be suitable adjuvants for patients with heart failure to improve peripheral tissue oxygenation.
Differential impact of acute and prolonged cAMP agonist exposure on protein kinase A activation and human myometrium contractile activity
Acute cAMP elevation inhibits myometrial contractility, but the mechanisms responsible are not fully defined and the long-term effects uncertain. These need to be defined in pregnant human myometrium before the therapeutic potential of cAMP-elevating agents in the prevention of preterm labour can be realised. In the present study, we tested the hypotheses that PKA activity is necessary for cAMP-induced myometrial relaxation and prolonged cAMP elevation can prevent myometrial contractions. Myometrial tissues obtained from term, pre-labour elective Caesarean sections were exposed to receptor-independent cAMP agonists to determine the relationship between myometrial contractility (spontaneous and oxytocin-induced), PKA activity, HSP20 phosphorylation and expression of contraction-associated and cAMP signalling proteins. Acute (1 h) application of cAMP agonists promoted myometrial relaxation but this was weakly related to PKA activation. PKA-specific activator, 6-Bnz-cAMP, increased PKA activity (6.8 ± 2.0 mean fold versus vehicle; P = 0.0313) without inducing myometrial relaxation. Spontaneous myometrial contractility declined after 24 h but was less marked when tissues were constantly exposed to cAMP agonists, especially for 8-bromo-cAMP (4.3 ± 1.2 mean fold versus vehicle; P = 0.0043); this was associated with changes to calponin, cofilin and HSP20 phosphorylated/total protein levels. Oxytocin-induced contractions were unaffected by pre-incubation with cAMP agonists despite treatments being able to enhance PKA activity and HSP20 phosphorylation. These data suggest that cAMP-induced myometrial relaxation is not solely dependent on PKA activity and the ability of cAMP agonists to repress myometrial contractility is lost with prolonged exposure. We conclude that cAMP agonist treatment alone may not prevent preterm labour.
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Yesterday, 22 Ιουνίου 2016, 12:17:07 μμ | Marcio Luiz Escorcio-Bezerra, Agessandro Abrahao, Isac de Castro, Marco Antonio Troccoli Chieia, Lyamara Apostolico de Azevedo, Denise Spinola Pinheiro, Nadia Iandoli de Oliveira Braga, Acary Souza Bulle de Oliveira, Gilberto Mastrocola Manzano
Motor Unit Number Index (MUNIX) analysis is a technique, developed by Nanadedkar et al. (Nandedkar et al., 2004), that provides an index directly correlated with the number of motor units. Thus, unlike the motor unit estimation (MUNE) methods, it does not directly count or estimate the number of functioning motor neurons (Bromberg et al., 2007). Compared to existing MUNE methods, MUNIX is faster and easier, which can potentially represent a practical advantage. For a given muscle, MUNIX requires the compound muscle action potential (CMAP) and progressive grades of voluntary muscle contractions recorded in surface electromyography (EMG) epochs, the surface interference pattern (SIP).