Humans can seamlessly combine value signals from diverse motivational incentives, yet it is not well understood how these signals are “bundled” in the brain to modulate cognitive control. The dorsal ACC (dACC) is theorized to integrate motivational value dimensions in the service of goal-directed action, although this hypothesis has yet to receive rigorous confirmation. In the present study, we examined the role of human dACC in motivational incentive integration. Healthy young adult men and women were scanned with fMRI while engaged in an experimental paradigm that quantifies the combined effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. Monetary incentives modulated trial-by-trial dACC activation, whereas block-related effects of liquid incentives on dACC activity were observed. When bundled together, incentive-related dACC modulation predicted fluctuations in both cognitive performance and self-report motivation ratings. Statistical mediation anal...

Alpha-synuclein pathology is associated with dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's patients. Working across human and mouse models, we investigated mechanisms by which the accumulation of soluble α-synuclein oligomers leads to neurodegeneration. Biochemical analysis of the midbrain of α-synuclein overexpressing BAC-transgenic male and female mice revealed age- and region-dependent mitochondrial dysfunction and accumulation of damaged proteins downstream of the RE1 Silencing Transcription Factor (REST). Vulnerable SN dopaminergic neurons displayed low REST levels compared with neighboring protected SN GABAergic neurons, which correlated with the accumulation of α-synuclein oligomers and disrupted mitochondrial morphology. Consistent with a protective role, REST levels were reduced in patient induced pluripotent stem cell-derived dopaminergic neurons carrying the SNCA-Triplication mutation, which accumulated α-synuclein oligomers and mitochondrial damage, and displayed REST t...

Cochlear implant (CI) users with a prelingual onset of hearing loss show poor sensitivity to interaural time differences (ITDs), an important cue for sound localization and speech reception in noise. Similarly, neural ITD sensitivity in the inferior colliculus (IC) of neonatally-deafened animals is degraded compared with animals deafened as adults. Here, we show that chronic bilateral CI stimulation during development can partly reverse the effect of early-onset deafness on ITD sensitivity. The prevalence of ITD sensitive neurons was restored to the level of adult-deaf (AD) rabbits in the early-deaf rabbits of both sexes that received chronic stimulation and behavioral training with wearable bilateral sound processors during development. We also found a partial improvement in neural ITD sensitivity in the early-deaf and stimulated rabbits compared with unstimulated rabbits. In contrast, chronic CI stimulation did not improve temporal coding in early-deaf rabbits. The present study is the first report showi...

Schwann cells produce a considerable amount of lipids and proteins to form myelin in the peripheral nervous system (PNS). For this reason, the quality control of myelin proteins is crucial to ensure proper myelin synthesis. Deletion of serine 63 from P0 (P0S63del) protein in myelin forming Schwann cells causes Charcot-Marie-Tooth type 1B (CMT1B) neuropathy in humans and mice. Misfolded P0S63del accumulates in the endoplasmic reticulum (ER) of Schwann cells where it elicits the unfolded protein response (UPR). PERK is the UPR transducer that attenuates global translation and reduces ER stress by phosphorylating the translation initiation factor eIF2alpha. Paradoxically, Perk ablation in P0S63del Schwann cells (S63del/ PerkSCKO ) reduced the level of P-eIF2alpha, leaving UPR markers upregulated, yet unexpectedly improved S63del myelin defects in vivo . We therefore investigated the hypothesis that PERK may interfere with signals outside of the UPR and specifically with Calcineurin/NFATc4 pro-myelinating path...

Relapse susceptibility in women with substance use disorders has been linked to the estrogen, 17β-estradiol (E2). Our previous findings in female rats suggest that the influence of E2 on cocaine seeking can be localized to the prelimbic prefrontal cortex (PrL-PFC). Here we investigated the receptor mechanisms through which E2 regulates the reinstatement of extinguished cocaine seeking. Sexually mature female rats underwent intravenous cocaine self-administration (0.5 mg/inf; 14 x 2 hrs daily) and extinction, and then were ovariectomized prior to reinstatement testing. E2 (10 µg/kg, ip) alone did not reinstate cocaine seeking, but it potentiated reinstatement when combined with an otherwise subthreshold priming dose of cocaine. A similar effect was observed following intra-PrL-PFC micro-infusions of E2 and by systemic or intra-PrL-PFC administration of the estrogen receptor-β (ERβ) agonist, DPN, but not agonists at ERα or the G-protein coupled estrogen receptor (GPER1). By contrast, E2-potentiated reinstate...

Although moving sound-sources abound in natural auditory scenes, it is not clear how the human brain processes auditory motion. Previous studies have indicated that, although ocular localization responses to stationary sounds are quite accurate, ocular smooth pursuit of moving sounds is very poor. We here demonstrate that human subjects faithfully track a sound’s unpredictable movements in the horizontal plane with smooth-pursuit responses of the head. Our analysis revealed that the stimulus–response relation was well described by an under-damped passive, second-order low-pass filter in series with an idiosyncratic, fixed, pure delay. The model contained only two free parameters: the system’s damping coefficient, and its central (resonance) frequency. We found that the latter remained constant at about 0.6 Hz throughout the experiment for all subjects. Interestingly, the damping coefficient systematically increased with trial number, suggesting the presence of an adaptive mechanism in the auditory pursuit ...

In humans, finely tuned gamma synchronization (60-90 Hz) rapidly appears at movement onset in a motor control network involving primary motor cortex, the basals ganglia and motor thalamus. Yet the functional consequences of brief movement-related synchronization are still unclear. Distinct synchronization phenomena have also been linked to different forms of motor inhibition, including relaxing antagonist muscles, rapid movement interruption and stabilizing network dynamics for sustained contractions. Here I will introduce detailed hypotheses about how intra- and inter-site synchronization could interact with firing rate changes in different parts of the network to enable flexible action control. The here proposed cause-and-effect relationships shine a spotlight on potential key mechanisms of cortico-basal ganglia-thalamo-cortical communication. Confirming or revising these hypotheses will be critical in understanding the neuronal basis of flexible movement initiation, invigoration and inhibition. Ultimate...

Taste neurons are functionally and molecularly diverse, but their morphological diversity remains completely unexplored. Using sparse cell genetic labeling, we provide the first reconstructions of peripheral taste neurons. The branching characteristics across 96 taste neurons show surprising diversity in their complexities. Individual neurons had 1 to 17 separate arbors entering between 1 to 7 taste buds, 18 of these neurons also innervated non-taste epithelia. Axon branching characteristics are similar in gustatory neurons from male and female mice. Cluster analysis separated the neurons into four groups according to branch complexity. The primary difference between clusters was the amount of the nerve fiber within the taste bud available to contact taste-transducing cells. Consistently, we found that the maximum number of taste-transducing cells capable of providing convergent input onto individual gustatory neurons varied with a range of 1-22 taste-transducing cells. Differences in branching characteris...

Different species of animals can discriminate numerosity, the countable number of objects in a set. The representations of countable numerosities have been deciphered down to the level of single neurons. However, despite its importance for human number theory, a special numerical quantity, the empty set (numerosity zero), has remained largely unexplored. We explored the behavioral and neuronal representation of the empty set in carrion crows. Crows were trained to discriminate small numerosities including the empty set. Performance data showed a numerical distance effect for the empty set in one crow, suggesting that the empty set and countable numerosities are represented along the crows’ ‘mental number line’. Single-cell recordings in the endbrain region nidopallium caudolaterale (NCL) showed a considerable proportion of NCL neurons tuned to the preferred numerosity zero. As evidenced by neuronal distance and size effects, NCL neurons integrated the empty set in the neural number line. A subsequent neuro...

Although moving sound-sources abound in natural auditory scenes, it is not clear how the human brain processes auditory motion. Previous studies have indicated that, although ocular localization responses to stationary sounds are quite accurate, ocular smooth pursuit of moving sounds is very poor. We here demonstrate that human subjects faithfully track a sound’s unpredictable movements in the horizontal plane with smooth-pursuit responses of the head. Our analysis revealed that the stimulus–response relation was well described by an under-damped passive, second-order low-pass filter in series with an idiosyncratic, fixed, pure delay. The model contained only two free parameters: the system’s damping coefficient, and its central (resonance) frequency. We found that the latter remained constant at about 0.6 Hz throughout the experiment for all subjects. Interestingly, the damping coefficient systematically increased with trial number, suggesting the presence of an adaptive mechanism in the auditory pursuit ...