Humans show a pervasive bias for processing self- over other-related information, including in working memory (WM), where people prioritize the maintenance of self- (over other-) associated cues. To elucidate the neural mechanisms underlying this self-bias, we paired a self- versus other-associated spatial WM task with fMRI and transcranial direct current stimulation (tDCS) of human participants of both sexes. Maintaining self- (over other-) associated cues resulted in enhanced activity in classic WM regions (frontoparietal cortex), and in superior multivoxel pattern decoding of the cue locations from visual cortex. Moreover, ventromedial PFC (VMPFC) displayed enhanced functional connectivity with WM regions during maintenance of self-associated cues, which predicted individuals' behavioral self-prioritization effects. In a follow-up tDCS experiment, we targeted VMPFC with excitatory (anodal), inhibitory (cathodal), or sham tDCS. Cathodal tDCS eliminated the self-prioritization effect. These findings provi...

DYT1 dystonia is a hereditary neurologic movement disorder characterized by uncontrollable muscle contractions. It is caused by a heterozygous mutation in Torsin A ( TOR1A ), a gene encoding a membrane-embedded ATPase. While animal models provide insights into disease mechanisms, significant species-dependent differences exist since animals with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-specific cholinergic motor neurons (MNs) that are generated through either direct conversion of patients' skin fibroblasts or differentiation of induced pluripotent stem cells (iPSCs). These human MNs with the heterozygous TOR1A mutation show reduced neurite length and branches, markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport (NCT) of mRNAs and proteins, whereas they lack the perinuclear “blebs” that are often observed in animal models. Furthermore, we uncover that the nuclear lamina protein LMNB1 is upregu...

Cocaine experience generates AMPA receptor (AMPAR)-silent synapses in the nucleus accumbens (NAc), which are thought to be new synaptic contacts enriched in GluN2B-containing NMDA receptors (NMDARs). After drug withdrawal, some of these synapses mature by recruiting AMPARs, strengthening the newly established synaptic transmission. Silent synapse generation and maturation are two consecutive cellular steps through which NAc circuits are profoundly remodeled to promote cue-induced cocaine seeking after drug withdrawal. However, the basic cellular processes that mediate these two critical steps remains underexplored. Using a combination of electrophysiology, viral-mediated gene transfer, and confocal imaging in male rats as well as knock-in (KI) mice of both sexes, our current study characterized the dynamic roles played by AMPARs and NMDARs in generation and maturation of silent synapses on NAc medium spiny neurons after cocaine self-administration and withdrawal. We report that cocaine-induced generation o...

The primary motor hand area (M1HAND) and adjacent dorsal premotor cortex (PMd) form the so-called motor hand knob in the precentral gyrus. M1HAND and PMd are critical for dexterous hand use and are densely inter-connected via cortico-cortical axons, lacking a sharp demarcating border. In 24 young right-handed volunteers, we performed multi-modal mapping to delineate the relationship between structure and function in the right motor hand knob. Quantitative structural magnetic resonance imaging (MRI) at 3 Tesla yielded regional R1-maps as a proxy of cortical myelin content. Participants also underwent functional MRI. We mapped task-related activation and temporal precision, while they performed a visuo-motor synchronization task requiring visually cued abduction movements with the left index or little finger. We also performed sulcus-aligned transcranial magnetic stimulation (TMS) of the motor hand knob to localize the optimal site (hotspot) for evoking a motor evoked potential (MEP) in two intrinsic hand mu...

Past work has demonstrated that active suppression of salient distractors is a critical part of visual selection. Evidence for goal-driven suppression includes below-baseline visual encoding at the position of salient distractors (Gaspelin and Luck, 2015) and neural signals such as the Pd that track the position and number of distractors in the visual field (Feldmann-Wustefeld and Vogel, 2019). One basic question regarding distractor suppression is whether it is inherently spatial or nonspatial in character. Indeed, past work has shown that distractors evoke both spatial (Theeuwes, 1992) and nonspatial forms of interference (Folk and Remington, 1998), motivating a direct examination of whether space is integral to goal-driven distractor suppression. Here, we use behavioral and EEG data from adult humans (male and female) to provide clear evidence for a spatial gradient of suppression surrounding salient singleton distractors. Replicating past work, both reaction time and neural indices of target selection ...

Recurrent seizures intensely activate GABAA receptors (GABAA-Rs), which induces transient neuronal chloride ([Cl–]i) elevations and depolarizing GABA responses that contribute to the failure of inhibition that engenders further seizures and anticonvulsant resistance. The K+-Cl– cotransporter KCC2 is responsible for Cl– extrusion and restoration of [Cl–]i equilibrium (ECl) after synaptic activity, but at the cost of increased extracellular potassium which may retard K+-Cl– extrusion, depolarize neurons, and potentiate seizures. Thus, KCC2 may either diminish or facilitate seizure activity, and both proconvulsant and anticonvulsant effects of KCC2 inhibition have been reported. It is now necessary to identify the loci of these divergent responses by assaying both the electrographic effects and the ionic effects of KCC2 manipulation. We therefore determined the net effects of KCC2 transport activity on cytoplasmic chloride elevation and Cl– extrusion rates during spontaneous recurrent ictal-like epileptiform ...

Inhibition plays important roles in modulating the neural activities of sensory and motor systems at different levels from synapses to brain regions. To achieve coordinated movement, motor systems produce alternating contractions of antagonist muscles, whether along the body axis or within and among limbs, which often involves direct or indirect cross-inhibitory pathways. In the nematode Caenorhabditis elegans , a small network involving excitatory cholinergic and inhibitory GABAergic motoneurons generates the dorsoventral alternation of body-wall muscles that supports undulatory locomotion. Inhibition has been suggested to be necessary for backward undulation because mutants that are defective in GABA transmission exhibit a shrinking phenotype in response to a harsh touch to the head, whereas wild-type animals produce a backward escape response. Here, we demonstrate that the shrinking phenotype is exhibited by wild-type as well as mutant animals in response to harsh touch to the head or tail, but only GAB...

Excitatory synaptic transmission in many neurons is mediated by two coexpressed ionotropic glutamate receptor subtypes, AMPA and NMDA receptors, that differ in kinetics, ion selectivity, and voltage-sensitivity. AMPA receptors have fast kinetics and are voltage-insensitive, while NMDA receptors have slower kinetics and increased conductance at depolarized membrane potentials. Here, we report that the voltage dependency and kinetics of NMDA receptors act synergistically to stabilize synaptic integration of EPSPs across spatial and voltage domains. Simulations of synaptic integration in simplified and morphologically realistic dendritic trees revealed that the combined presence of AMPA and NMDA conductances reduce the variability of somatic responses to spatiotemporal patterns of excitatory synaptic input presented at different initial membrane potentials and/or in different dendritic domains. This moderating effect of the NMDA conductance on synaptic integration was robust across a wide range of AMPA-to-NMD...

While it is well established that there are robust circadian rhythms of arginine vasopressin (AVP) in the cerebrospinal fluid (CSF), the route whereby the peptide reaches the CSF is not clear. A , AVP neurons constitute the largest fraction of the SCN neuronal population. Here, we show that processes of AVP-expressing SCN neurons cross the epithelium of the 3rd ventricular wall to reach the CSF (black arrows). Additionally, we report rostro-caudal differences in AVP neuron size and demonstrate that the localization of cells expressing the clock protein PER2 extend beyond the AVP population, thereby indicating that the size of this nucleus is somewhat larger than previously understood. B , Following lateral ventricle (LV) injection of cholera toxin β subunit (CTβ ; magenta) the retrograde tracer is seen in AVP neurons of the SCN, supporting the anatomical evidence that AVP neuronal processes directly contact the CSF. Arginine vasopressin (AVP) expressing neurons form the major population in the brain’s cir...

What role does color play in the neural representation of complex shapes? We approached the question by measuring color responses of face-selective neurons, using fMRI-guided microelectrode recording of the middle and anterior face patches of inferior temporal cortex (IT) in rhesus macaques. Face-selective cells responded weakly to pure color (equiluminant) photographs of faces. But many of the cells nonetheless showed a bias for warm colors when assessed using images that preserved the luminance contrast relationships of the original photographs. This bias was also found for non-face-selective neurons. Fourier analysis uncovered two components: the first harmonic, accounting for most of the tuning, was biased toward reddish colors, corresponding to the L>M pole of the L-M cardinal axis. The second harmonic showed a bias for modulation between blue and yellow colors axis, corresponding to the S-cone axis. To test what role face-selective cells play in behavior, we related the information content of the neu...