The ability to comprehend phrases is an essential integrative property of the brain. Here, we evaluate the neural processes that enable the transition from single-word processing to a minimal compositional scheme. Previous research has reported conflicting timing effects of composition, and disagreement persists with respect to inferior frontal and posterior temporal contributions. To address these issues, 19 patients (10 male, 9 female) implanted with penetrating depth or surface subdural intracranial electrodes, heard auditory recordings of adjective-noun, pseudoword-noun, and adjective-pseudoword phrases and judged whether the phrase matched a picture. Stimulus-dependent alterations in broadband gamma activity, low-frequency power, and phase-locking values across the language-dominant left hemisphere were derived. This revealed a mosaic located on the lower bank of the posterior superior temporal sulcus (pSTS), in which closely neighboring cortical sites displayed exclusive sensitivity to either lexical...

Human APOER2 is a type I transmembrane protein with a large extracellular domain (ECD) and a short cytoplasmic tail. APOER2-ECD contains several ligand binding domains (LBD) that are organized into exons with aligning phase junctions, which allows for in-frame exon cassette splicing events. We have identified 25 human APOER2 isoforms from cerebral cortex using gene-specific APOER2 primers, where the majority are exon-skipping events within the N-terminal LBD regions compared to 6 identified in the heart. APOER2 undergoes proteolytic cleavage in response to ligand binding that releases a C-terminal fragment (CTF) and transcriptionally active intracellular domain (ICD). We tested whether the diversity of human brain-specific APOER2 variants affects APOER2 cleavage. We found isoforms with differing numbers of ligand binding repeats generated different amounts of CTFs compared to full-length APOER2 (APOER2-FL). Specifically, APOER2 isoforms lacking exons 5-8 (Δex5-8) and lacking exons 4-6 (Δex4-6) generated th...

We used the chromatic visual evoked potential, the cVEP, to study responses in human visual cortex evoked by equiluminant color stimuli for six male and 11 female observers. Large-area, colored squares were used to stimulate Single-Opponent cells preferentially, and fine color-checkerboard stimuli were used to activate Double-Opponent responses preferentially. Stimuli were modulated along two directions in color space: 1) the cardinal direction, L-M or M-L of DKL space; 2) the line from the white point to the color of the Red LED in the display screen, which was roughly intermediate between the L-M and -S directions in DKL space in cone-contrast coordinates. The amplitudes of cVEPs to large squares were smaller than those to checkerboards, and latency of the cVEP response to squares was significantly less than the checkerboard latency. The latency of cVEP responses to the squares varied little with cone-contrast unlike the steep reduction of latency with cone-contrast observed in responses to color checker...

It is widely accepted that activation of N-methyl-D-aspartate receptors (NMDAR) is necessary for the formation of fear memories in the basolateral amygdala complex (BLA). This acceptance is based on findings that blockade of NMDAR in the BLA disrupts Pavlovian fear conditioning in rodents when initially innocuous stimuli are paired with aversive and unexpected events (surprising foot shock). The present study challenges this acceptance by showing that the involvement of NMDAR in Pavlovian fear conditioning is determined by prediction errors in relation to aversive events. In the initial experiments, male rats received a BLA infusion of the NMDAR antagonist, D-AP5 and were then exposed to pairings of a novel target stimulus and foot shock. This infusion disrupted acquisition of fear to the target when the shock was surprising (Experiments 1a, 1b, 2a, 2b, 3a, 3b); but spared fear to the target when the shock was expected based on the context, time and other stimuli that were present (Experiments 1a, 1b). Und...

Temporal processing of complex sounds is a fundamental and complex task in hearing and a prerequisite for processing and understanding vocalization, speech, and prosody. Here we studied response properties of neurons in the inferior colliculus (IC) in mice lacking Cacna2d3 , a risk gene for autism spectrum disorders. The α2δ3 auxiliary Ca2+ channel subunit encoded by Cacna2d3 is essential for proper function of glutamatergic synapses in the auditory brainstem. Recent evidence has shown that much of auditory feature extraction is performed in the auditory brainstem and IC, including processing of amplitude modulation (AM). We determined both spectral and temporal properties of single- and multi-unit responses in the IC of anesthetized mice. IC units of α2δ3-/- mice showed normal tuning properties yet increased spontaneous rates compared with α2δ3+/+. When stimulated with AM tones, α2δ3-/- units exhibited less precise temporal coding and reduced evoked rates to higher modulation frequencies (fm). Whereas fir...

Electron microscopy-based connectomes provide important insights into how visual circuitry of fruit fly Drosophila computes various visual features, guiding and complementing behavioral and physiological studies. However, connectomic analyses of the lobula, a neuropil putatively dedicated to detecting object-like features, remains underdeveloped, largely because of incomplete data on the inputs to the brain region. Here, we attempted to map the columnar inputs into the Drosophila lobula neuropil by performing connectivity- and morphology-based clustering on a densely reconstructed connectome dataset. While the dataset mostly lacked visual neuropils other than lobula, which would normally help identify inputs to lobula, our clustering analysis successfully extracted clusters of cells with homogeneous connectivity and morphology, likely representing genuine cell types. We were able to draw a correspondence between the resulting clusters and previously identified cell types, revealing previously undocumented ...

Intracranial electroencephalographic (icEEG) recordings provide invaluable insights into neural dynamics in humans due to their unmatched spatiotemporal resolution. Yet, such recordings reflect the combined activity of multiple underlying generators, confounding the ability to resolve spatially distinct neural sources. To empirically quantify the listening zone of icEEG recordings, we computed correlations between signals as a function of distance (full width at half maximum; FWHM) between 8,752 recording sites in 71 patients (33 female) implanted with either subdural electrodes (SDE), stereo-encephalography electrodes (sEEG), or high-density sEEG electrodes. As expected, for both SDEs and sEEGs, higher frequency signals exhibited a sharper fall off relative to lower frequency signals. For broadband high gamma (BHG) activity, the mean FWHM of SDEs (6.6 ± 2.5 mm) and sEEGs in gray matter (7.14 ± 1.7 mm) was not significantly different, however FWHM for low frequencies recorded by sEEGs was 2.45 mm smaller t...

The development of mathematical skills in early childhood relies on number sense, the foundational ability to discriminate between quantities. Number sense in early childhood is predictive of academic and professional success, and deficits in number sense are thought to underlie lifelong impairments in mathematical abilities. Despite its importance, the brain circuit mechanisms that support number sense learning remain poorly understood. Here, we designed a theoretically motivated training program to determine brain circuit mechanisms underlying foundational number sense learning in female and male elementary school-aged children (ages 7-10). Our four-week integrative number sense training program gradually strengthened the understanding of the relations between symbolic (Arabic numerals) and non-symbolic (sets of items) representations of quantity. We found that our number sense training program improved symbolic quantity discrimination ability in children across a wide a range of math abilities including...

Neurons in posterior parietal cortex (PPC) encode many aspects of the sensory world (e.g., scene structure), the posture of the body, and plans for action. For a downstream computation, however, only some of these dimensions are relevant; the rest are “nuisance variables”, because their influence on neural activity changes with sensory and behavioral context, potentially corrupting the read-out of relevant information. Here we show that a key postural variable for vision – eye position – is represented robustly in male macaque PPC across a range of contexts, even though the tuning of single neurons depended strongly on context. Contexts were defined by different stages of a visually guided reaching task, including ( i ) a visually sparse epoch; ( ii ) a visually rich epoch; ( iii ) a “go” epoch in which the reach was cued; and ( iv ) during the reach itself. Eye position was constant within trials but varied across trials in a 3 × 3 grid spanning 24° × 24°. Using demixed principal component analysis of neu...

The neural processes that enable healthy humans to orient attention to sudden visual events are poorly understood because they are tightly intertwined with purely sensory processes. Here we isolated visually guided orienting activity from sensory activity using event-related potentials (ERPs). By recording ERPs to a lateral stimulus and comparing waveforms obtained under conditions of attention and inattention, we identified an early positive deflection over the ipsilateral visual cortex that was associated with the covert orienting of visual attention to the stimulus. Across five experiments with male and female adults participants, this ipsilateral visual orienting activity (VOA) could be distinguished from purely sensory-evoked activity and from other top-down spatial attention effects. The VOA was linked with behavioral measures of orienting, being significantly larger when the stimulus was detected rapidly than when it was detected more slowly, and its presence was independent of saccadic eye movement...