Inhibition of the amygdala slows down acquisition of conditioned eyeblink responses (CRs). Based on the two-stage or two-factor theory of aversive conditioning, amygdala-dependent conditioned fear is a necessary prerequisite to acquire eyeblink CRs but is no longer needed after eyeblink CRs are attained. According to the sensory gating hypothesis of the amygdala, on the other hand, the amygdala modulates the salience of unconditioned stimuli (USs) and conditioned stimuli (CSs) in eyeblink conditioning. We tested these two opposing assumptions in five groups of 20 young and healthy men. On day 1, three groups underwent fear acquisition training followed by acquisition of eyeblink CRs. On the next day (day 2), extinction was tested. In group 1, fear and eyeblink extinction trials overlapped; in group 2, fear and eyeblink extinction trials alternated; and in group 3, fear extinction trials were followed by eyeblink extinction trials. Groups 4 and 5 were control conditions testing fear and eyeblink conditionin...

Oligodendrocytes in the central nervous system (CNS) produce myelin sheaths that insulate axons to facilitate efficient electrical conduction. These myelin sheaths contain lamellar microtubules that enable vesicular transport into the inner sheath. Mechanistically, oligodendrocytes rely on Golgi outpost organelles and the associated protein tubulin polymerization promoting protein (TPPP) to nucleate or form new microtubules outside of the cell body. Consequently, elongation of lamellar microtubules is defective in Tppp knock-out (KO) mice, which have thinner and shorter myelin sheaths. We now explore the behavioral phenotypes of Tppp KO mice using a number of different assays. In open-field assays, Tppp KO mice display similar activity levels and movement patterns as wild-type mice, indicating that they do not display anxiety behavior. However, Tppp KO mice lack fear responses by two types of assays, traditional fear-conditioning assays and looming fear assays, which test for innate fear responses. Deficit...

Hypofunction of the prefrontal cortex (PFC) contributes to stress-related neuropsychiatric illnesses. Mechanisms leading to prefrontal hypoactivity remain to be determined. Prior evidence suggests that chronic stress leads to an increase in activity of parvalbumin (PV) expressing GABAergic interneurons (INs) in the PFC. The purpose of the study was to determine whether reducing PV IN activity in the Infralimbic (IL) PFC would prevent stress-related phenotypes. We used a chemogenetic approach to inhibit IL PFC PV INs during stress. Mice were first tested in the tail suspension test (TST) to determine the impact of PV IN inhibition on behavioral responses to acute stress. The long-term impact of PV IN inhibition during a modified chronic variable stress (CVS) was tested in the forced swim test (FST). Acute PV IN inhibition reduced active (struggling) and increased passive coping behaviors (immobility) in the TST. In contrast, inhibition of PV INs during CVS increased active and reduced passive coping behavio...

Small ubiquitin-like modifier (SUMO) is a widespread regulatory mechanism of post-translational modification (PTM) that induces rapid and reversible changes in protein function and stability. Using SUMO conjugase Ubc9-overexpressing or knock-down cells in Parkinson’s disease (PD) models, we demonstrate that SUMOylation protects dopaminergic cells against MPP+ or preformed fibrils (PFFs) of α-synuclein (α-syn)-induced toxicities in cell viability and cytotoxicity assays. In the mechanism of protection, Ubc9 overexpression significantly suppressed the MPP+ or PFF-induced reactive oxygen species (ROS) generation, while Ubc9-RNAi enhanced the toxicity-induced ROS production. Further, PFF-mediated protein aggregation was exacerbated by Ubc9-RNAi in thioflavin T staining, compared with NC1 controls. In cycloheximide (Chx)-based protein stability assays, higher protein level of α-syn was identified in Ubc9-enhanced green fluorescent protein (EGFP) than in EGFP cells. Since there was no difference in endogenous mR...

Cognitive control is a mental process, which underlies adaptive goal-directed decisions. Previous studies have linked cognitive control to electrophysiological fluctuations in the θ band and θ-γ cross-frequency coupling (CFC) arising from the cingulate and frontal cortices. However, to date, the behavioral consequences of different forms of θ-γ CFC remain elusive. Here, we studied the behavioral effects of the θ-γ CFC via transcranial alternating current stimulation (tACS) designed to stimulate the frontal and cingulate cortices in humans. Using a double-blind, randomized, repeated measures study design, 24 healthy participants were subjected to three active and one control CFC-tACS conditions. In the active conditions, 80-Hz γ tACS was coupled to 4-Hz θ tACS. Specifically, in two of the active conditions, short γ bursts were coupled to the delivered θ cycle to coincide with either its peaks or troughs. In the third active condition, the phase of a θ cycle modulated the amplitude of the γ oscillation. In t...

Much evidence supports a fundamental role for the subthalamic nucleus (STN) in rapidly stopping behavior when a stop signal or surprising event occurs, but the extent to which the STN may be involved in stopping cognitive processes is less clear. Here, we used an optogenetic approach to control STN activity in a delayed-match-to-position (DMTP) task where mice had to recall a response location after a delay. We first demonstrated that a surprising event impaired performance by both slowing the latency to respond and increasing the rate of errors. We next showed that these effects could be mimicked by brief optogenetic activation of the STN. Further, inhibiting STN during surprise blocked surprise-induced slowing, although without changing surprise-induced errors. These data are consistent with the hypothesis that STN is recruited by surprise to slow responding and that this can also interrupt cognitive processes. Under normal conditions STN-mediated stopping of behavior may slow or stop ongoing cognition t...

The dorsal raphe (DR) is an evolutionarily conserved brain structure that is involved in aggressive behavior. It projects onto numerous cortical and limbic areas underlying attack behavior. The specific neurocircuit through which the DR regulates aggression, however, is largely unclear. In this study we show that DR neurons expressing CaMKIIα are activated by attack behavior in mice. These neurons project to the medial aspect of the orbitofrontal cortex (OFC; MeOC) and the medial amygdala (MeA), two key regions within the neural circuit known to control aggressive behavior. Using an in vivo optogenetic approach, we show that attack bouts are shortened by inhibiting CaMKIIα+ neurons in the DR and their axons at the MeOC and prolonged by stimulating the DR-MeOC axons during an attack. By contrast, stimulating the axons of CaMKIIα+ DR neurons at the MeA shortens attack. Notably, neither the DR-MeOC or DR-MeA pathway initiates attack when stimulated. These results indicate that the DR-MeOC and DR-MeA pathways ...

The self is a distinct entity from the rest of the world, and actions and sensory feedback are our channels of interaction with the external world. This study examined how the sense of control influences people’s perception of sensorimotor input under the framework of categorical perception. Twenty human participants (18 males, two females) took part in both experiments. Experiment 1 showed that the sensitivity (d′) of detecting a 20% change in control from no change was higher when the changes occurred at the control-category boundary than within each category. Experiment 2 showed that the control categories greatly affected early attention allocation, even when the judgment of control was unnecessary to the task. Taken together, these results showed that our perceptual and cognitive systems are highly sensitive to small changes in control that build up to a determinant change in the control category within a relatively narrow boundary zone between categories, compared with a continuous, gradual physical ...

There are several distinct areas in the granular part of the lateral frontal cortex, and these areas provide high-level regulation of cognitive processing. Lesions of the dorsolateral frontal cortex that include area 8A in the human brain and lesions restricted to area 8A in the macaque monkey have demonstrated impairments in tasks requiring selection between visual targets based on rules, such as conditional if/then rules. These same subjects show no impairment in the ability to discriminate between visual stimuli nor in the ability to learn selection rules in general. Area 8A can be considered as a key area for the top-down control of attentional selection. The present functional neuroimaging study demonstrates that activity in area 8A that lies on the posterior part of the middle frontal gyrus underlies the trial-to-trial selection between competing visual targets based on previously acquired conditional rules. Critically, the activity of area 8A could clearly be dissociated from activity related to the...

The resting human brain exhibits spontaneous patterns of activity that reflect features of the underlying neural substrate. Examination of interareal coupling of resting-state oscillatory activity has revealed that the brain’s resting activity is composed of functional networks, whose topographies differ depending on oscillatory frequency, suggesting a role for carrier frequency as a means of creating multiplexed, or functionally segregated, communication channels between brain areas. Using canonical correlation analysis (CCA), we examined spectrally resolved resting-state connectivity patterns derived from magnetoencephalography (MEG) recordings to determine the relationship between connectivity intrinsic to different frequency channels and a battery of over a hundred behavioral and demographic indicators, in a group of 89 young healthy participants. We demonstrate that each of the classical frequency bands in the range 1–40 Hz (δ, θ, α, β, and γ) delineates a subnetwork that is behaviorally relevant, spa...