Recent branching (100 MYA) of the mammalian evolutionary tree has enhanced brain complexity and functions at the putative cost of increased emotional circuitry vulnerability. Thus, to better understand psychopathology, a burden for the modern society, novel approaches should exploit evolutionary aspects of psychiatric-relevant molecular pathways. A handful of genes is nowadays tightly associated to psychiatric disorders. Among them, neuronal-enriched RbFOX1 modifies the activity of synaptic regulators in response to neuronal activity, keeping excitability within healthy domains. We here dissect a higher primates-restricted interaction between RbFOX1 and the transcriptional corepressor Lysine Specific Demethylase 1 (LSD1/KDM1A). A single nucleotide variation (AA to AG) in LSD1 gene appeared in higher primates and humans, endowing RbFOX1 with the ability to promote the alternative usage of a novel 3′ AG splice site, which extends LSD1 exon E9 in the upstream intron (E9-long). Exon E9-long regulates LSD1 leve...

Beta oscillations (13-30Hz) are ubiquitous in the human motor nervous system. Yet, their origins and roles are unknown. Traditionally, beta activity has been treated as a stationary signal. However, recent studies observed that cortical beta occurs in ‘bursting events’, which are transmitted to muscles. This short-lived nature of beta events makes it possible to study the main mechanism of beta activity found in the muscles in relation to cortical beta. Here, we assessed if muscle beta activity mainly results from cortical projections. We ran two experiments in healthy humans of both sexes (N=15 and N=13, respectively) to characterize beta activity at the cortical and motor unit (MU) levels during isometric contractions of the tibialis anterior muscle. We found that beta rhythms observed at the cortical and MU levels are indeed in bursts. These bursts appeared to be time-locked and had comparable average durations (40-80ms) and rates (∼3-4 bursts/second). To further confirm that cortical and MU beta have t...

The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been associated with the expression of adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, reported effects of mPFC manipulations on cue-elicited natural reward-seeking and inhibition thereof have been varied, with few studies examining cortico-striatal contributions in tasks that require adaptive responding to cues signalling reward and punishment within the same session. The current study aimed to better elucidate the role of mPFC and NAc subdivisions, and their functional connectivity in cue-elicited adaptive responding using a novel discriminative cue responding task. Male Long Evans rats learned to lever-press on a VR5 schedule for a discriminative cue signalling reward, and to avoid pressing the same lever in the presence of another cue signalling punishment. Post-acquisition, prelimbic (PL) and infralimbic (IL) areas of the mPFC, NAc core, shell, PL-core or IL-shell circuits were pharmacolo...

Although the cerebellum has been traditionally considered to be exclusively involved in motor control, recent anatomic and clinical studies show that it also has a role in reward-processing. However, the way in which the movement-related and the reward-related neural activity interact at the level of the cerebellar cortex and contribute toward learning is still unclear. Here, we studied the simple spike activity of Purkinje cells in the mid-lateral cerebellum when 2 male monkeys learned to associate a right or left-hand movement with one of two visual symbolic cues. These cells had distinctly different discharge patterns between an overtrained symbol–hand association and a novel symbol–hand association, responding in association with the movement of both hands, although the kinematics of the movement did not change between the two conditions. The activity change was not related to the pattern of the visual symbols, the movement kinematics, the monkeys’ reaction times, or the novelty of the visual symbols. ...

Reaching movements are known to have large condition-independent neural activity and cyclic neural dynamics. A new precision center-out task was performed by rhesus macaques to test the hypothesis that cyclic, condition-independent neural activity in the primary motor cortex (M1) occurs not only during initial reaching movements but also during subsequent corrective movements. Corrective movements were observed to be discrete with time courses and bell-shaped speed profiles similar to the initial movements. Condition-independent cyclic neural trajectories were similar and repeated for initial and each additional corrective submovement. The phase of the cyclic condition-independent neural activity predicted the time of peak movement speed more accurately than regression of instantaneous firing rate, even when the subject made multiple corrective movements. Rather than being controlled as continuations of the initial reach, a discrete cycle of motor cortex activity encodes each corrective submovement. Signi...

Finding the link between behaviors and their regulatory molecular pathways is a major obstacle in treating neuropsychiatric disorders. The immediate early gene EGR1 is implicated in the etiology of neuropsychiatric disorders, and is linked to gene pathways associated with social behavior. Despite extensive knowledge of EGR1 gene regulation at the molecular level, it remains unclear how EGR1 deficits might affect the social component of these disorders. Here we examined the social behavior of zebrafish with a mutation in the homologous gene egr1 . Mutant fish exhibited reduced social approach and orienting, whereas other sensorimotor behaviors were unaffected. On a molecular level, expression of the dopaminergic biosynthetic enzyme, tyrosine hydroxylase (TH), was strongly decreased in TH-positive neurons of the anterior parvocellular preoptic nucleus. These neurons are connected with basal forebrain neurons associated with social behavior. Chemo-genetic ablation of around 30% of TH-positive neurons in this ...

Working memory, a core function underlying many higher-level cognitive processes, requires cooperation of multiple brain regions. White matter refers to myelinated axons, which are critical to inter-regional brain communication. Past studies on the association between white-matter integrity and working memory have yielded mixed findings. Using voxel-wise tract-based spatial statistics analysis, we investigated this relationship in a sample of 328 healthy adults from 25 to 80 years of age. Given the important role of dopamine (DA) in working-memory functioning and white matter, we also analyzed the effects of dopamine-related genes on them. There were associations between white-matter integrity and working memory in multiple tracts, indicating that working-memory functioning relies on global connections between different brain areas across the adult lifespan. Moreover, a mediation analysis suggested that white-matter integrity contributes to age-related differences in working memory. Finally, there was an e...

Speech perception in noise is a challenging everyday task with which many listeners have difficulty. Here, we report a case in which electrical brain stimulation of implanted intracranial electrodes in the left planum temporale (PT) of a neurosurgical patient significantly and reliably improved subjective quality (up to 50%) and objective intelligibility (up to 97%) of speech in noise perception. Stimulation resulted in a selective enhancement of speech sounds compared with the background noises. The receptive fields of the PT sites whose stimulation improved speech perception were tuned to spectrally broad and rapidly changing sounds. Corticocortical evoked potential analysis revealed that the PT sites were located between the sites in Heschl’s gyrus and the superior temporal gyrus. Moreover, the discriminability of speech from nonspeech sounds increased in population neural responses from Heschl’s gyrus to the PT to the superior temporal gyrus sites. These findings causally implicate the PT in background...

Cannabinoid receptor 1 (CB1R) has strong effects on neurogenesis and axon pathfinding in the prenatal brain. Endocannabinoids that activate CB1R are abundant in the early postnatal brain and in mother’s milk, but few studies have investigated their function in newborns. We examined postnatal CB1R expression in the major striatonigral circuit from striosomes of the striatum to the dopamine-containing neurons of the substantia nigra. CB1R enrichment was first detectable between postnatal days 5 and 7, and this timing coincided with the formation of ‘striosome-dendron bouquets’, the elaborate anatomical structures by which striosomal neurons control dopaminergic cell activity through inhibitory synapses. In Cnr1−/− knockouts lacking CB1R expression, striosome-dendron bouquets were markedly disorganized by postnatal day 11 and at adulthood, suggesting a postnatal pathfinding connectivity function for CB1R in connecting striosomal axons and dopaminergic neurons analogous to CB1R’s prenatal function in other bra...

Humans can perform complex movements with speed and agility in the face of constantly changing task demands. To accomplish this, motor plans are adapted to account for errors in our movements due to changes in our body (e.g., growth or injury) or in the environment (e.g., walking on sand vs. ice). It has been suggested that adaptation that occurs in response to changes in the state of our body will generalize across different movement contexts and environments, whereas adaptation that occurs with alterations in the external environment will be context-specific. Here we asked if the ability to form generalizable versus context-specific motor memories develops during childhood. We performed a cross-sectional study of context-specific locomotor adaptation in 35 children (3-18 years old) and 7 adults (19-31 years old). Subjects first adapted their gait and learned a new walking pattern on a split-belt treadmill, which has two belts that move each leg at a different speed. Then, subjects walked overground to as...