Attention often requires maintaining a stable mental state over time while simultaneously improving perceptual sensitivity. These requirements place conflicting demands on neural populations, as sensitivity implies robust response to perturbation by incoming stimuli, which is antithetical to stability. Functional specialization of cortical areas provides one potential mechanism to resolve this conflict. We reasoned that attention signals in executive control areas might be highly-stable over time, reflecting maintenance of the cognitive state, thereby freeing up sensory areas to be more sensitive to sensory input (i.e., unstable), which would be reflected by more dynamic attention signals in those areas. To test these predictions, we simultaneously recorded neural populations in prefrontal cortex (PFC) and visual cortical area V4 in rhesus macaque monkeys performing an endogenous spatial selective attention task. Using a decoding approach, we found that the neural code for attention states in PFC was subst...

Parvalbumin-containing (PV+) basket cells are specialized cortical interneurons that regulate the activity of local neuronal circuits with high temporal precision and reliability. To understand how the PV+ interneuron connectivity underlying these functional properties is established during development, we used array tomography to map pairs of synaptically connected PV+ interneurons and postsynaptic neurons from the neocortex of mice of both sexes. We focused on the axon-myelin unit of the PV+ interneuron and quantified the number of synapses onto the postsynaptic neuron, length of connecting axonal paths, and their myelination at different time points between 2 weeks and 7 months of age. We find that myelination of the proximal axon occurs very rapidly during the third and, to a lesser extent, fourth postnatal weeks. The number of synaptic contacts made by the PV+ interneuron on its postsynaptic partner meanwhile is significantly reduced to about one-third by the end of the first postnatal month. The numb...

At rest, mammalian brains display remarkable spatiotemporal complexity, evolving through recurrent functional connectivity states on a slow timescale of the order of tens of seconds. While the phenomenology of the resting state dynamics is valuable in distinguishing healthy and pathological brains, little is known about its underlying mechanisms. Here, we identify neuronal cascades as a potential mechanism. Using full-brain network modeling, we show that neuronal populations, coupled via a detailed structural connectome, give rise to large-scale cascades of firing rate fluctuations evolving at the same time scale of resting-state networks. The ignition and subsequent propagation of cascades depend upon the brain state and connectivity of each region. The largest cascades produce bursts of Blood-Oxygen-Level-Dependent (BOLD) co-fluctuations at pairs of regions across the brain, which shape the simulated resting-state network dynamics.We experimentally confirm these theoretical predictions. We demonstrate th...

Normal aging is associated with a decline in memory and motor learning ability. However, the exact form of these impairments (e.g., the short-term temporal stability and affected learning mechanisms) is largely unknown. Here, we utilized a sensorimotor adaptation task to examine changes in the temporal stability of two forms of learning (explicit and implicit) due to normal aging. Healthy young (ages 19-28, 20 individuals) and older human subjects (ages 63-85, 19 individuals) made reaching movements in response to altered visual feedback. On each trial subjects turned a rotation dial to select an explicit aiming direction. Once selected, the display was removed and subjects moved the cursor from the start position to the target. After initial training with the rotational feedback perturbation, subjects completed a series of probe trials at different delay periods to systematically assess the short-term retention of learning. For both groups the explicit aiming showed no significant decrease over 1.5 minute...

Numerous brain regions have been identified as contributing to withdrawal behaviors, but unclear is the way in which these brain regions as a whole lead to withdrawal. The search for a final common brain pathway that is involved in withdrawal remains elusive. To address this question, we implanted osmotic minipumps containing either saline, nicotine (24 mg/kg/day), cocaine (60 mg/kg/day), or methamphetamine (4 mg/kg/day) for 1 week in male C57BL/6J mice. After 1 week the minipumps were removed and brains collected 8 hours (saline, nicotine and cocaine) or 12 hours (methamphetamine) after removal. We then performed single-cell whole-brain imaging of neural activity during the withdrawal period when brains were collected. We used hierarchical clustering and graph theory to identify similarities and differences in brain functional architecture. Although methamphetamine and cocaine shared some network similarities, the main common neuroadaptation between these psychostimulant drugs was a dramatic decrease in m...

Understanding masseter muscle (MM) innervation is critical for the study of cell-specific mechanisms of pain induced by temporomandibular disorder or after facial surgery. Here, we identified trigeminal (TG) sensory neuronal subtypes (MM TG neurons) innervating masseter muscle fibers, masseteric fascia, tendons, and adjusted tissues. A combination of patch clamp electrophysiology and immunohistochemistry on TG neurons backtraced from reporter mouse MM found 9 distinct subtypes of MM TG neurons. Of these neurons, 24% belonged to non-peptidergic IB-4+/TRPA1- or IB-4+/TRPA1+ groups, while two TRPV1+ small-sized neuronal groups were classified as peptidergic/CGRP+. One small-sized CGRP+ neuronal group had a unique electrophysiological profile and were recorded from Nav1.8- or trkC+ neurons. The remaining CGRP+ neurons were medium-sized, could be divided into Nav1.8-/trkC- and Nav1.8low/trkC+ clusters, and showed large 5HT-induced current. The final two MM TG neuronal groups were trkC+ and had no Nav1.8 and CGR...

Epilepsy-Aphasia Syndromes (EAS) are a spectrum of childhood epileptic, cognitive, and language disorders of unknown etiology. CNKSR2 is a strong X-linked candidate gene implicated in EAS, however, there have been no studies of genetic models to dissect how its absence may lead to EAS. Here we develop a novel Cnksr2 knockout (KO) mouse line and show that male mice exhibit increased neural activity and have spontaneous electrographic seizures. Cnksr2 KO mice also display significantly increased anxiety, impaired learning and memory, and a progressive and dramatic loss of ultrasonic vocalizations. We find that Cnksr2 is expressed in cortical, striatal, and cerebellar regions and is localized at both excitatory and inhibitory postsynapses. Proteomics analysis reveals Cnksr2 anchors key binding partners at synapses, and its loss results in significant alterations of the synaptic proteome, including proteins implicated in epilepsy disorders. Our results validate that loss of CNKSR2 leads to EAS and highlights t...

Older adults tend to display greater brain activation in the non-dominant hemisphere during even basic sensorimotor responses. It is debated whether this Hemispheric Asymmetry Reduction in Older Adults (HAROLD) reflects a compensatory mechanism. Across two independent fMRI experiments involving adult-lifespan human samples (N = 586 and N = 81; approximately half female) who performed right hand finger responses, we distinguished between these hypotheses using behavioural and multivariate Bayes (MVB) decoding approaches. Standard univariate analyses replicated a HAROLD pattern in motor cortex, but in- and out-of-scanner behavioural results both demonstrated evidence against a compensatory relationship, in that reaction time measures of task performance in older adults did not relate to ipsilateral motor activity. Likewise, MVB showed that this increased ipsilateral activity in older adults did not carry additional information, and if anything, combining ipsilateral with contralateral activity patterns reduc...

Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years due to its role in social memory formation. However, the role of cholinergic inputs to the CA2 area for the regulation of synaptic plasticity remains to be fully understood. We show that cholinergic receptor activation with the non-selective cholinergic agonist, carbachol (CCh), triggers a protein synthesis-dependent and NMDAR-independent long-term synaptic depression (CCh-LTD) at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses in the hippocampus of adult male Wistar rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of CCh-LTD with the results suggesting an involvement of M3 and M1 mAChRs in the early facilitation of CCh-LTD, while nicotinic acetylcholine receptor activation plays a role in the late maintenance of CCh-LTD at CA2 synapses. Remarkably, we find that CCh priming lowers the thresh...

Two novel short-interval intracortical inhibition (SICI) protocols, assessing SICI across a range of interstimulus intervals (ISI) using either parallel threshold-tracking transcranial magnetic stimulation (TT-TMS) or automated conventional TMS (cTMS), were recently introduced. However, the test-retest reliability of these protocols has not been investigated, which is important if they are to be introduced in the clinic. SICI was recorded in 18 healthy subjects using TT-TMS (T-SICI) and cTMS (A-SICI). All subjects were examined at four identical sessions, i.e. morning and afternoon sessions on two days, five to seven days apart. Both SICI protocols were performed twice at each session by the same observer. In one of the sessions, another observer performed additional examinations. Neither intra- nor inter-observer measures of SICI differed significantly between examinations, except for T-SICI at ISI 3ms (P=0.00035) and A-SICI at ISI 2.5ms (P=0.0103). Intra-day reliability was poor-to-good for A-SICI and m...