Emergent oscillations in networks of stochastic spiking neurons

Networks of neurons produce diverse patterns of oscillations, arising from the network's global properties, the propensity of individual neurons to oscillate, or a mixture of the two. Here we describe noisy limit cycles and quasi-cycles, two related mechanisms underlying emergent oscillations in neuronal networks whose individual components, stochastic spiking neurons, do not themselves oscillate. Both mechanisms are shown to produce gamma band oscillations at the population level while individual neurons fire at a rate much lower than the population frequency. Spike trains in a network undergoing noisy limit cycles display a preferred period which is not found in the case of quasi-cycles, due to the even faster decay of phase information in quasi-cycles. These oscillations persist in sparsely connected networks, and variation of the network's connectivity results in variation of the oscillation frequency. A network of such neurons behaves as a stochastic perturbation of the deterministic Wilson-Cowan equations, and the network undergoes noisy limit cycles or quasi-cycles depending on whether these have limit cycles or a weakly stable focus. These mechanisms provide a new perspective on the emergence of rhythmic firing in neural networks, showing the coexistence of population-level oscillations with very irregular individual spike trains in a simple and general framework.     

Insulin resistance in non-obese subjects is associated with activation of the JNK pathway and impaired insulin signaling in skeletal muscle

Background

The pathogenesis of insulin resistance in the absence of obesity is unknown. In obesity, multiple stress kinases have been identified that impair the insulin signaling pathway via serine phosphorylation of key second messenger proteins. These stress kinases are activated through various mechanisms related to lipid oversupply locally in insulin target tissues and in various adipose depots.

Methodology/Principal Findings

To explore whether specific stress kinases that have been implicated in the insulin resistance of obesity are potentially contributing to insulin resistance in non-obese individuals, twenty healthy, non-obese, normoglycemic subjects identified as insulin sensitive or resistant were studied. Vastus lateralis muscle biopsies obtained during euglycemic, hyperinsulinemic clamp were evaluated for insulin signaling and for activation of stress kinase pathways. Total and regional adipose stores and intramyocellular lipids (IMCL) were assessed by DXA, MRI and ¹H-MRS. In muscle of resistant subjects, phosphorylation of JNK was increased (1.36±0.23 vs. 0.78±0.10 OD units, P<0.05), while there was no evidence for activation of p38 MAPK or IKKβ. IRS-1 serine phosphorylation was increased (1.30±0.09 vs. 0.22±0.03 OD units, P<0.005) while insulin-stimulated tyrosine phosphorylation decreased (10.97±0.95 vs. 0.89±0.50 OD units, P<0.005). IMCL levels were twice as high in insulin resistant subjects (3.26±0.48 vs. 1.58±0.35% H₂O peak, P<0.05), who also displayed increased total fat and abdominal fat when compared to insulin sensitive controls.

Conclusions

This is the first report demonstrating that insulin resistance in non-obese, normoglycemic subjects is associated with activation of the JNK pathway related to increased IMCL and higher total body and abdominal adipose stores. While JNK activation is consistent with a primary impact of muscle lipid accumulation on metabolic stress, further work is necessary to determine the relative contributions of the various mediators of impaired insulin signaling in this population.     

Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding

Background

The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address “food-abuse” disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.

Methodology/Principal Findings

We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.

Conclusions/Significance

Acquired disruption of brain insulin action may confer risk for and/or underlie “food-abuse” disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to “the fast food lifestyle” creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.     

Effects of light intensity and spectrum on fish behaviour in laboratory aquaria

Teleost fish are commonly used as model species in laboratory studies of behaviour and ecology. In comparison to other groups of vertebrates used routinely in such studies, however, relatively little attention has been paid to their environmental requirements from a welfare perspective. Fish naturally inhabit a wide variety of aquatic habitats that differ enormously in the range of light environments they provide, and light regime has enormous potential to affect behaviour. Yet the level and quality of illumination (in terms of intensity and wavelength spectrum) provided in experimental studies of fish behaviour is generally designed to maximize ease of recording by the observer. In addition, display or home aquaria provide illumination that maximizes the ‘viewing pleasure’ of the observer, and specialist lighting tubes are available to stimulate rapid plant growth and to ‘show off’ the colours of fish, rather than to provide ‘natural’ light environments. Here we present the results of three studies designed to examine the effects of light intensity, wavelength spectrum and their interactions on the behaviour of a model species commonly used in behavioural studies, the three‐spined stickleback Gasterosteus aculeatus. Our aims are to determine whether unnatural light environments, generated by manipulating light intensity and wavelength spectrum, affect behaviour in ways that may lead to concern for the welfare of fish as research animals or pets.     

Upper extremity biomechanics in computer tasks differ by gender

ObjectivesThis laboratory study examined gender differences in upper extremity postures, applied forces, and muscle activity when a computer workstation was adjusted to individual anthropometry according to current guidelines.MethodsFifteen men and 15 women completed five standardized computer tasks: touch-typing, completing a form, editing text, sorting and resizing graphical objects and navigating intranet pages. Subjects worked at a height-adjustable workstation with the keyboard on top of the work surface and the mouse to the right. Subjects repeated the text editing task with the mouse in two other locations: a “high” mouse position, which simulated using a keyboard drawer with the mouse on the primary work surface, and “center” mouse position with the mouse between the keyboard and the body, centered with the body’s center line. Surface electromyography measured muscle activity; electrogoniometric and magnetic motion analysis system measured wrist, forearm and upper arm postures; load-cells measured typing forces; and a force-sensing mouse measured applied forces.ResultsRelative forces applied to the keyboard, normalized muscle activity of two forearm muscles, range of motion for the wrist and shoulder joints and external rotation of the shoulder were higher for women (p < 0.05). When subjects were dichotomized instead by anthropometry (either large/small shoulder width or arm length), the differences in forces, muscle activity of the shoulder and wrist posture and shoulder posture became more pronounced with smaller subjects having higher values. Postural differences between the genders increased in the high mouse position and decreased in the center mouse location.ConclusionsWhen a workstation is adjusted per current guidelines differences in upper extremity force, muscle activity and postural factors still exist between genders. However, these were often stronger when subjects were grouped by anthropometry suggesting that perhaps the computer input devices themselves should be scaled to be more in proportion with the anthropometry and strength of the user.     

COMPARISON OF POPULATION STRUCTURE IN CHROMOSOMALLY POLYTYPIC AND MONOTYPIC SPECIES OF SCELOPORUS (SAURIA: IGUANIDAE) IN RELATION TO CHROMOSOMALLY-MEDIATED SPECIATION

Sceloporus grammicus has been used as an example of stasipatric speciation, and some models of chromosomal speciation have assumed that the fission rearrangements which distinguish the chromosome races within this complex are negatively heterotic in the heterozygous state. Consequently, such rearrangements are assumed to be fixed by drift in small, inbred populations. Allelic variation at 19 presumptive gene loci was examined in 13 samples of a chromosomally conservative congener, Sceloporus graciosus, and was compared to an equivalent data set for the chromosomally polytypic S. grammicus. Several estimates of population variability and structure were calculated, and results were inconsistent with models of extreme population subdivision and/or frequent bottlenecks and extinction-colonization events in S. grammicus. For example, mean level of heterozygosity and mean number of alleles per locus were significantly higher in S. grammicus than in S. graciosus, while the average genetic distance (D) was significantly higher in S. graciosus. These results are considered in light of expected “Wrightian” population genetic parameters, and we conclude that S. grammicus does not seem to have the population structure necessary for the fixation of strongly negatively heterotic rearrangements.     

High fidelity TNA synthesis by Therminator polymerase

Therminator DNA polymerase is an efficient DNA-dependent TNA polymerase capable of polymerizing TNA oligomers of at least 80 nt in length. In order for Therminator to be useful for the in vitro selection of functional TNA sequences, its TNA synthesis fidelity must be high enough to preserve successful sequences. We used sequencing to examine the fidelity of Therminator-catalyzed TNA synthesis at different temperatures, incubation times, tNTP ratios and primer/template combinations. TNA synthesis by Therminator exhibits high fidelity under optimal conditions; the observed fidelity is sufficient to allow in vitro selection with TNA libraries of at least 200 nt in length.