Pain-related sensory input is processed in the spinal dorsal horn (SDH) before being relayed to the brain. That processing profoundly influences whether stimuli are correctly or incorrectly perceived as painful. Significant advances have been made in identifying the types of excitatory and inhibitory neurons that comprise the SDH, and there is some information about how neuron types are connected, but it remains unclear how the overall circuit processes sensory input or how that processing is disrupted under chronic pain conditions. To explore SDH function, we developed a computational model of the circuit that is tightly constrained by experimental data. Our model comprises conductance-based neuron models that reproduce the characteristic firing patterns of spinal neurons. Excitatory and inhibitory neuron populations, defined by their expression of genetic markers, spiking pattern, or morphology, were synaptically connected according to available qualitative data. Using a genetic algorithm, synaptic weigh...

The human dorsolateral prefrontal cortex (DLPFC; approximately corresponding to Brodmann areas 9 and 46) has demonstrable roles in diverse executive functions such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. However, it remains unclear whether this is the result of one functionally homogeneous region or whether there are functional subdivisions within the DLPFC. Here, we divided the DLPFC into seven areas along rostral-caudal and dorsal-ventral axes anatomically and explored their respective patterns of structural and functional connectivity. In vivo probabilistic tractography (11 females and 13 males) and resting-state functional magnetic resonance imaging (fMRI; 57 females and 21 males) were employed to map out the patterns of connectivity from each DLPFC subregion. Structural connectivity demonstrated graded intraregional connectivity within the DLPFC. The patterns of structural connectivity between the DLPFC subregions and other cortical areas revealed that t...

The multiple demand (MD) system is a network of fronto-parietal brain regions active during the organization and control of diverse cognitive operations. It has been argued that this activation may be a nonspecific signal of task difficulty. However, here we provide convergent evidence for a causal role for the MD network in the “simple task” of automatic auditory change detection, through the impairment of top-down control mechanisms. We employ independent structure-function mapping, dynamic causal modeling (DCM), and frequency-resolved functional connectivity analyses of MRI and magnetoencephalography (MEG) from 75 mixed-sex human patients across four neurodegenerative syndromes [behavioral variant fronto-temporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), posterior cortical atrophy (PCA), and Alzheimer's disease mild cognitive impairment with positive amyloid imaging (ADMCI)] and 48 age-matched controls. We show that atrophy of any MD node is sufficient to impair auditory ...

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...

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...

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...