Sleep spindles, bursts of electroencephalogram (EEG) activity in the sigma-frequency (11-16 Hz) range, may be biomarkers of cortical development. Studies capturing the transition to adolescence are needed to delineate age-, sex- and pubertal-related changes in sleep spindles at the population-level. We analyzed the sleep EEG of 572 subjects 6-21y (48% female) and 332 subjects 5-12y (46% female) followed-up at 12-22y. From 6y to 21y, spindle density (p-quadratic=0.019) and fast (12-16 Hz) spindle percent (p-quadratic=0.016) showed inverted U-shaped trajectories, with plateaus after 15y and 19y, respectively. Spindle frequency increased (p-linear<0.001), while spindle power decreased (p-linear<0.001) from 6y to 21y. The trajectories of spindle density, frequency and fast spindle percent diverged between females and males, in whom density plateaued by 14y, fast spindle percent by 16y, and frequency by 18y, while fast spindle percent and spindle frequency continued to increase until 21y in females. Males exper...

Cells in the entorhinal cortex (EC) contain rich spatial information and project strongly to the hippocampus where a cognitive map is supposedly created. These cells range from cells with structured spatial selectivity, such as grid cells in the medial entorhinal cortex (MEC) that are selective to an array of spatial locations that form a hexagonal grid, to weakly spatial cells, such as non-grid cells in the MEC and lateral entorhinal cortex (LEC) that contain spatial information but have no structured spatial selectivity. However, in a small environment, place cells in the hippocampus are generally selective to a single location of the environment, while granule cells in the dentate gyrus of the hippocampus have multiple discrete firing locations but lack spatial periodicity. Given the anatomical connection from the EC to the hippocampus, how the hippocampus retrieves information from upstream EC remains unclear. Here, we propose a unified learning model that can describe the spatial tuning properties of ...

Listening to vocal music has been recently shown to improve language recovery in stroke survivors. The neuroplasticity mechanisms supporting this effect are, however, still unknown. Using data from a three-arm single-blind randomized controlled trial including acute stroke patients (N=38) and a 3-month follow-up, we set out to compare the neuroplasticity effects of daily listening to self-selected vocal music, instrumental music, and audiobooks on both brain activity and structural connectivity of the language network. Using deterministic tractography we show that the 3-month intervention induced an enhancement of the microstructural properties of the left frontal aslant tract (FAT) for the vocal music group as compared to the audiobook group. Importantly, this increase in the strength of the structural connectivity of the left FAT correlated with improved language skills. Analyses of stimulus-specific activation changes showed that the vocal music group exhibited increased activations in the frontal termi...

Understanding the bioenergetics of axon extension and maintenance has wide ranging implications for neurodevelopment and disease states. Glycolysis is a pathway consisting of ten enzymes and separated into preparatory and payoff phases, the latter producing ATP. Using embryonic chicken sensory neurons, we report that glycolytic enzymes are found through the axon and the growth cone. Pharmacological inhibition of glycolysis in the presence of NGF impairs axon extension and growth cone dynamics within minutes without affecting axon maintenance. Experiments using microfluidic chambers show the effect of inhibiting glycolysis on axon extension is local along distal axons and can be reversed by promoting mitochondrial respiration. Knock down of GAPDH simplifies growth cone morphology and is rescued by shRNA resistant GAPDH expression. Rescue of GAPDH using killer red (KR) fused to GAPDH followed by localized chromophore assisted light inactivation of KR-GAPDH in distal axons halts growth cone dynamics. Consider...

Systemic treatment with resiniferatoxin (RTX) induces small-fiber sensory neuropathy by damaging TRPV1-expressing primary sensory neurons and causes distinct thermal sensory impairment and tactile allodynia, which resemble the unique clinical features of postherpetic neuralgia. However, the synaptic plasticity associated with RTX-induced tactile allodynia remains unknown. In this study, we found that RTX-induced neuropathy is associated with α2δ-1 upregulation in the dorsal root ganglion (DRG) and increased physical interaction between α2δ-1 and GluN1 in the spinal cord synaptosomes. RNAscope in situ hybridization showed that RTX treatment significantly increased α2δ-1 expression in DRG neurons labeled with CGRP, IB4, NF200, and tyrosine hydroxylase. Electrophysiological recordings revealed that RTX treatment augmented the frequency of miniature excitatory postsynaptic currents (mEPSCs) and the amplitude of evoked EPSCs in spinal dorsal horn neurons, and these effects were reversed by blocking of NMDA rece...

N-methyl-D-aspartate receptors (NMDARs) are important for synaptic plasticity associated with many physiological functions and neurological disorders. Protein kinase C (PKC) activation increases the phosphorylation and activity of NMDARs, and α2δ-1 is a critical NMDAR-interacting protein and controls synaptic trafficking of NMDARs. In this study, we determined the relative roles of PKC and α2δ-1 in the control of NMDAR activity. We found that α2δ-1 coexpression significantly increased NMDAR activity in HEK293 cells transfected with GluN1/GluN2A or GluN1/GluN2B. PKC activation with phorbol 12-myristate 13-acetate (PMA) increased receptor activity only in cells coexpressing GluN1/GluN2A and α2δ-1. Remarkably, PKC inhibition with Gӧ6983 abolished α2δ-1 coexpression–induced potentiation of NMDAR activity in cells transfected with GluN1/GluN2A or GluN1/GluN2B. Treatment with PMA increased the α2δ-1–GluN1 interaction and promoted α2δ-1 and GluN1 cell surface trafficking. PMA also significantly increased NMDAR ac...

New information is rarely learned in isolation, instead most of what we experience can be incorporated into or uses previous knowledge networks in some form. Previous knowledge in form of a cognitive map can facilitate knowledge acquisition and will influence how we learn new spatial information. Here, we developed a new spatial navigation task where food locations are learned in a large, gangway maze to test how mice learn a large spatial map over a longer time period – the HexMaze. Analysing performance across sessions as well as on specific trials, we can show simple memory effects as well as multiple effects of previous knowledge of the map accelerating both online learning and performance increases over offline periods when incorporating new information. We could identify three main phases: 1) Learning the initial goal location, 2) faster learning after two weeks when learning a new goal location and then 3) the ability to express one-session learning leading to long-term memory effect after 12 weeks....

Cognitive dysfunction is among the hallmark symptoms of Neurofibromatosis 1, and accordingly, loss of the Drosophila melanogaster ortholog of Neurofibromin 1 (dNf1) precipitates associative learning deficits. However, the affected circuitry in the adult CNS remained unclear and the compromised mechanisms debatable. Although the main evolutionarily conserved function attributed to Nf1 is to inactivate Ras, decreased cAMP signaling on its loss has been thought to underlie impaired learning. Using mixed sex populations, we determine that dNf1 loss results in excess GABAergic signaling to the central for associative learning mushroom body (MB) neurons, apparently suppressing learning. dNf1 is necessary and sufficient for learning within these non-MB neurons, as a dAlk and Ras1-dependent, but PKA-independent modulator of GABAergic neurotransmission. Surprisingly, we also uncovered and discuss a postsynaptic Ras1-dependent, but dNf1-independnet signaling within the MBs that apparently responds to presynaptic GAB...

We developed a method for single-cell resolution longitudinal bioluminescence imaging of PERIOD (PER) protein and TIMELESS (TIM) oscillations in cultured male adult Drosophila brains that captures circadian circuit-wide cycling under simulated day/night cycles. Light input analysis confirms that CRYPTOCHROME (CRY) is the primary circadian photoreceptor and mediates clock disruption by constant light (LL), and that eye light input is redundant to CRY; 3-h light phase delays (Friday) followed by 3-h light phase advances (Monday morning) simulate the common practice of staying up later at night on weekends, sleeping in later on weekend days then returning to standard schedule Monday morning [weekend light shift (WLS)]. PER and TIM oscillations are highly synchronous across all major circadian neuronal subgroups in unshifted light schedules for 11 d. In contrast, WLS significantly dampens PER oscillator synchrony and rhythmicity in most circadian neurons during and after exposure. Lateral ventral neuron (LNv) ...