Ventral tegmental area (VTA) glutamate neurons signal and participate in reward and aversion-based behaviors. However, the neurochemical mechanisms that underlie how these neurons contribute to motivated behaviors is unknown. We used a combination of optical sensors to identify how distinct neurochemical inputs to VTA glutamate neurons participate in motivated behavior within female and male transgenic mice. Activity of glutamate inputs to VTA glutamate neurons increased for both reward-predicting and aversion-predicting cues and aversive outcomes, but subpopulations of glutamate inputs were increased or decreased by reward. For both reward and aversion-based cues and outcomes, activity of GABA inputs to VTA glutamate neurons mostly decreased. GCaMP recordings showed overall population increases in VTA glutamate neuron intracellular calcium during reward and aversion-based cues and outcomes. Electrophysiological recordings of VTA VGluT2 neurons showed that glutamate receptor activation increases firing whi...

Neural activity is diverse, and varies depending on brain regions and sleep/wakefulness states. However, whether astrocyte activity differs between sleep/wakefulness states, and whether there are differences in astrocyte activity among brain regions remain poorly understood. Therefore, in this study, we recorded astrocyte intracellular calcium (Ca2+) concentrations of mice during sleep/wakefulness states in the cortex, hippocampus, hypothalamus, cerebellum, and pons using fiber photometry. For this purpose, male transgenic mice expressing the genetically encoded ratiometric Ca2+ sensor YCnano50 specifically in their astrocytes were used. We demonstrated that Ca2+ levels in astrocytes substantially decrease during rapid eye movement (REM) sleep, and increase after the onset of wakefulness. In contrast, differences in Ca2+ levels during non-REM (NREM) sleep were observed among the different brain regions, and no significant decrease was observed in the hypothalamus and pons. Further analyses focusing on the ...

People with strabismus acquired during childhood do not experience diplopia (double vision). To investigate how perception of the duplicate image is suppressed, we raised two male monkeys with alternating exotropia by disinserting the medial rectus muscle in each eye at age four weeks. Once the animals were mature, they were brought to the laboratory and trained to fixate a small spot while recordings were made in primary visual cortex (V1). Drifting gratings were presented to the receptive fields of 500 single neurons for eight interleaved conditions: (1) right eye monocular; (2) left eye monocular; (3) right eye's field, right eye fixating; (4) right eye's field, left eye fixating; (5) left eye's field, right eye fixating; (6) left eye's field, left eye fixating; (7) both eyes' fields, right eye fixating; (8) both eyes' fields, left eye fixating. As expected, ocular dominance histograms showed a monocular bias compared with normal animals, but many cells could still be driven via both eyes. Overall, neur...

The initiation and propagation of the action potential (AP) along an axon allows neurons to convey information rapidly and across distant sites. Although AP properties have typically been characterized at the soma and proximal axon, knowledge of the propagation of APs toward distal axonal domains of mammalian CNS neurons remains limited. We used genetically encoded voltage indicators (GEVIs) to image APs with submillisecond temporal resolution simultaneously at different locations along the long axons of dissociated hippocampal neurons from rat embryos of either sex. We found that APs became sharper and showed remarkable fidelity as they traveled toward distal axons, even during a high-frequency train. Blocking voltage-gated potassium channels (Kv) with 4-AP resulted in an increase in AP width in all compartments, which was stronger at distal locations and exacerbated during AP trains. We conclude that the higher levels of Kv channel activity in distal axons serve to sustain AP fidelity, conveying a reliab...

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 ...

Congenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by hearing loss that is not assessed on standard audiological exams, such as reduced temporal processing acuity. To assess whether sound therapy may improve these deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. The DBA/2J mouse strain develops rapid, base to apex, progressive sensorineural hearing loss (SNHL) beginning at birth and is functionally deaf by 6 months of age. Hearing sensitivity and auditory brainstem function was measured using otoacoustic emissions, auditory brainstem response and extracellular recording from the inferior colliculus in mice following exposure to 60 days of continuous AAE and in unexposed...

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...

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...