BackgroundThe biological process underlying axonal myelination is complex and often prone to injury and disease. The ratio of the inner axonal diameter to the total outer diameter or g-ratio is widely utilized as a functional and structural index of optimal axonal myelination. Based on the speed of fiber conduction, Rushton was the first to derive a theoretical estimate of the optimal g-ratio of 0.6 [1]. This theoretical limit nicely explains the experimental data for myelinated axons obtained for some peripheral fibers but appears significantly lower than that found for CNS fibers. This is, however, hardly surprising given that in the CNS, axonal myelination must achieve multiple goals including reducing conduction delays, promoting conduction fidelity, lowering energy costs, and saving space.Methodology/Principal FindingsIn this study we explore the notion that a balanced set-point can be achieved at a functional level as the micro-structure of individual axons becomes optimized, particularly for the central system where axons tend to be smaller and their myelin sheath thinner. We used an intuitive yet novel theoretical approach based on the fundamental biophysical properties describing axonal structure and function to show that an optimal g-ratio can be defined for the central nervous system (≈0.77). Furthermore, by reducing the influence of volume constraints on structural design by about 40%, this approach can also predict the g-ratio observed in some peripheral fibers (≈0.6).Conclusions/SignificanceThese results support the notion of optimization theory in nervous system design and construction and may also help explain why the central and peripheral systems have evolved different g-ratios as a result of volume constraints.

This study explored the viability and efficacy of integrating cadence-matched, salient music into a walking intervention for patients with Parkinson's disease (PD). Twenty-two people with PD were randomised to a control (CTRL, n = 11) or experimental (MUSIC, n = 11) group. MUSIC subjects walked with an individualised music playlist three times a week for the intervention period. Playlists were designed to meet subject's musical preferences. In addition, the tempo of the music closely matched (±10–15 bpm) the subject's preferred cadence. CTRL subjects continued with their regular activities during the intervention. The effects of training accompanied by “walking songs” were evaluated using objective measures of gait score. The MUSIC group improved gait velocity, stride time, cadence, and motor symptom severity following the intervention. This is the first study to demonstrate that music listening can be safely implemented amongst PD patients during home exercise.

SUMMARY1. Intracellular recordings were obtained from 112 supraoptic nucleus magnocellular neurosecretory cells (MNCs) in superfused explants of rat hypothalamus maintained in vitro. The effects of glutamate receptor agonists and antagonists were examined at 32-34°C.2. In control solutions, spontaneously active (> 5 Hz) phasic or continuous neurones showed interspike interval distributions slightly skewed toward short intervals, but did not feature pauses in the 0 4-2 s range. Current injection to alter the rate of cell discharge shifted the histograms according to the mean firing rate, but failed to induce intermittent pauses in the 0 4-2 s range.3. Application ofN-methyl-D-aspartate (NMDA) induced a mode of firing in which bimodal interspike interval distributions reflected a high incidence of clusters of short interspike intervals (0 5-1 5 s) recurring every 1-3 s. In contrast, firing evoked by application of D,L-a-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid (AMPA) was not associated with a clustering of impulse discharge.4. The putative endogenous excitatory amino acid transmitters L-glutamate, Laspartate and quinolinate all mimicked the effects of NMDA. Clustered spiking responses to these agents were reversibly blocked by D,L-2-amino-5-phosphonovalerate (APV), but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In contrast, the non-NMDA receptor ligands kainate and quisqualate caused CNQXsensitive increases in firing rate, but these responses were not associated with the appearance of clustered activity.5. When applied to cells showing negative resting potentials ( <-70 mV), or to neurones hyperpolarized by current injection, responses to NMDA consisted of rhythmic ( 1 Hz) voltage oscillations associated with bursts of spike discharge. In the presence of TTX, NMDA could induce subthreshold voltage oscillations in the absence of action potentials.6. Application of a voltage clamp to potentials between -75 and -55 mV during rhythmic bursting responses failed to reveal any rhythmic oscillation of the

1. Vasopressin-secreting neurones in the rat hypothalamic supraoptic nucleus display patterned spontaneous phasic activity, which is apparently maintained in vivo through yet unidentified neurotransmitter system(s). The present investigation used extracellular recording techniques in anaesthetized Long-Evans rats to evaluate whether the neurotransmitter mechanism underlying phasic firing is provided via a family of ionotropic glutamate receptors. 2. N-Methyl-D-aspartate (NMDA) reliably evoked bursts of activity in twenty-seven of twenty-eight phasic neurones. Amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and kainate also elicited pronounced excitations in twenty-one of twenty-one and and fourteen of fifteen phasic cells, respectively. 3. A rapid blockade of on-going phasic activity was consistently induced following brief applications of both NMDA and non-NMDA receptor antagonists; extended application of antagonists resulted in prolonged silent periods, during which phasic activity failed to recur for minutes. Neither saline nor a cholecystokinin receptor antagonist influenced cell firing. 4. In contrast to putative vasopressin cells, application of NMDA receptor ligands did not affect the spontaneous activity in most putative oxytocin-secreting neurones, whereas kainate and AMPA potently excited seven of nine and four of five putative oxytocin cells, respectively. 5. These results imply that the maintenance of spontaneous phasic discharges in vivo in supraoptic vasopressin-secreting neurones requires tonic synaptic activation involving both NMDA and non-NMDA glutamate receptors. In putative oxytocin-secreting neurones, spontaneous firing appears to be predominantly regulated by non-NMDA receptors.

Thalamic nuclei of the mammalian auditory system exhibit remarkable parallelism in their anatomical pathways and the patterns of synaptic signalling. This has led to the theory that lemniscal, or core thalamocortical projection, carries tonotopically organized and auditory specific information whereas the nonlemniscal thalamocortical pathway forms part of an integrative system that plays an important role in polysensory integration, temporal pattern recognition, and certain forms of learning. Recent experimental evidence derived from molecular, cellular and behavioural studies indeed supports the conjecture that lemniscal and nonlemniscal pathways are involved in distinctive auditory functions.

Though most experimental evidence indicates that the corticothalamic (CT) pathway would exert a direct excitatory action on thalamic relay neurons, the electrophysiological features of this excitation have never been clearly described. A methodological problem in previous electrophysiological studies was that direct corticofugal effects on relay cells could not be separated from those mediated by collateral activation of reticular thalamic neurons. In the present study, the reticular complex was lesioned by kainic acid and the CT response of relay neurons of the ventral lateral nucleus was recorded intracellularly in cats under pentobarbital or urethane anaesthesia. Following reticular thalamic lesions, a prominent depolarization was triggered in thalamic relay cells by stimulation of the CT pathway. This depolarization strongly drove spike discharges, and its amplitude augmented when the stimulation rate exceeded 2 Hz. Tetanizing the CT input with short trains (100 - 200 Hz for 200 - 300 ms) produced a similar augmentation to test volleys for 15 - 30 s after the tetanos. The CT excitation and its frequency-dependent augmentation were depressed by ketamine injection or by local application of N-methyl-D-aspartate (NMDA) antagonists. The augmenting phenomenon appeared strictly homosynaptic. For instance, it did not appear during repetitive stimulation of the cerebellar input, nor did the CT input potentiate subthreshold synaptic potentials of cerebellar origin during a conditioning procedure. Conversely, the cerebellar excitation was depressed when it occurred during the CT depolarization. It is concluded that the direct synaptic responses induced by CT fibres in relay neurons are mediated at least partly by the activation of NMDA receptors. Moreover, the marked non-linear additivity of cerebellar and CT synaptic potentials raises questions concerning the presumed improvement of thalamic transmission of peripheral informations ensured by the CT input. Instead, both inputs could compete for control of the firing of thalamic neurons. The numerical importance of CT fibres and the strong augmenting mechanism operating at synaptic sites in the thalamus suggest that the role of the thalamus is not only to transfer peripheral informations toward the cortex, but also and mainly to feed back to the cortex a modified copy of its own neuronal constructs.

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TWIK-related acid-sensitive K(+) (K(2P) 9.1, TASK-3) ion channels have the capacity to regulate the activity of neuronal pathways by influencing the resting membrane potential of neurons on which they are expressed. The central nervous system (CNS) expression of these channels suggests potential roles in neurologic disorders, and it is believed that the development of TASK-3 antagonists could lead to the therapeutic treatment of a number of neurological conditions. While a therapeutic potential for TASK-3 channel modulation exists, there are only a few documented examples of potent and selective small-molecule channel blockers. Herein, we describe the discovery and lead optimization efforts for a novel series of TASK-3 channel antagonists based on a 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine high-throughput screening lead from which a subseries of potent and selective inhibitors were identified. One compound was profiled in detail with respect to its physical properties and demonstrated pharmacological target engagement as indicated by its ability to modulate sleep architecture in rodent electroencephalogram (EEG) telemetry models.