Motivational deficits characterized by an unwillingness to overcome effortful costs are a common feature of neuropsychiatric and neurological disorders that are insufficiently understood and treated. Dopamine (DA) signaling in the nucleus accumbens (NAc) facilitates goal-seeking, but how NAc DA release encodes motivationally-salient stimuli to influence effortful investment is not clear. Using fast-scan cyclic voltammetry (FSCV) in male and female mice, we find that NAc DA release diametrically responds to cues signaling increasing cost of reward, while DA release to the reward itself is unaffected by its cost. Because endocannabinoid (eCB) signaling facilitates goal-seeking and NAc DA release, we further investigated whether repeated augmentation of the eCB 2-arachidonoylglycerol (2-AG) with a low dose of a monoacylglycerol lipase (MAGL) inhibitor facilitates motivation and DA signaling without the development of tolerance. We find that chronic MAGL treatment stably facilitates goal-seeking and DA encodin...

Some of the most impressive functional specialization in the human brain is found in occipitotemporal cortex (OTC), where several areas exhibit selectivity for a small number of visual categories, such as faces and bodies, and spatially cluster based on stimulus animacy. Previous studies suggest this animacy organization reflects the representation of an intuitive taxonomic hierarchy, distinct from the presence of face- and body-selective areas in OTC. Using human fMRI, we investigated the independent contribution of these two factors – the face-body division and taxonomic hierarchy – in accounting for the animacy organization of OTC, and whether they might also be reflected in the architecture of several deep neural networks that have not been explicitly trained to differentiate taxonomic relations. We found that graded visual selectivity, based on animal resemblance to human faces and bodies, masquerades as an apparent animacy continuum, which suggests that taxonomy is not a separate factor underlying th...

Over the past decades, a plethora of studies have linked cortical γ oscillations (∼30–100 Hz) to neurocomputational mechanisms. Their functional relevance, however, is still passionately debated. Here, we asked whether endogenous γ oscillations in the human brain can be entrained by a rhythmic photic drive >50 Hz. A noninvasive modulation of endogenous brain rhythms allows conclusions about their causal involvement in neurocognition. To this end, we systematically investigated oscillatory responses to a rapid sinusoidal flicker in the absence and presence of endogenous γ oscillations using magnetoencephalography (MEG) in combination with a high-frequency projector. The photic drive produced a robust response over visual cortex to stimulation frequencies of up to 80 Hz. Strong, endogenous γ oscillations were induced using moving grating stimuli as repeatedly done in previous research. When superimposing the flicker and the gratings, there was no evidence for phase or frequency entrainment of the endogenous ...

Paternal care plays a critical role in the development of brain and behaviors in offspring in monogamous species. However, the neurobiological mechanisms, especially the neuronal circuity, underlying paternal care is largely unknown. Using socially monogamous male mandarin voles ( Microtus mandarinus ) with high levels of paternal care, we found that paraventricular nucleus of the hypothalamus (PVN) to ventral tegmental area (VTA) or nucleus accumbens (NAc) oxytocin (OT) neurons are activated during paternal care. Chemogenetic activation/inhibition of the PVN OT projection to VTA promoted/decreased paternal care, respectively. Chemogenetic inhibition of the PVN to VTA OT pathway reduced dopamine (DA) release in the NAc of male mandarin voles during licking and grooming of pups as revealed by in vivo fiber photometry. Optogenetic activation/inhibition of the VTA to NAc DA pathway possibly enhanced/suppressed paternal behaviors, respectively. Furthermore, chemogenetic activation/inhibition of PVN to NAc OT c...

Stereotaxic access to brain areas underneath the superior sagittal sinus (SSS) is notoriously challenging. As a major drainage vessel, covering the whole extension of the sagittal fissure, the SSS impedes direct bilateral access to underlying regions for recording and stimulation probes, drug-delivery cannulas, and injection devices. We now describe a new method for transection and retraction of the SSS in rats, that allows the accurate placement of microinjection devices, or chronic electrode probes, while avoiding hemorrhage and the ensuing deleterious consequences for local structures, animal health, and behavior. To demonstrate the feasibility of this approach we evaluated its consequences acutely during surgery, and thereafter during surgical survival, recovery, behavioral testing, as well as postmortem analysis of histological impact in the related brain structures of male rats. This method provides a new approach enabling direct access for manipulation and recording of activity in brain areas previo...

Our current understanding of synergistic muscle control is based on the analysis of muscle activities. Modules (synergies) in muscle coordination are extracted from electromyographic signal envelopes. Each envelope indirectly reflects the neural drive received by a muscle, therefore it carries information on the overall activity of the innervating motor neurons. However, it is not known whether the output of spinal motor neurons, whose number is orders of magnitude greater than the muscles they innervate, is organized in a low-dimensional fashion when performing complex tasks. Here, we hypothesized that motor neuron activities exhibit a synergistic organization in complex tasks and therefore that the common input to motor neurons results in a large dimensionality reduction in motor neuron outputs. To test this hypothesis, we factorized the output spike trains of motor neurons innervating 14 intrinsic and extrinsic hand muscles and analyzed the dimensionality of control when healthy individuals exerted isom...

Early studies in mouse neurodevelopment led to the discovery of the RE1 Silencing Transcription Factor (REST) and its role as a master repressor of neuronal gene expression. Recently, REST was reported to also repress neuronal genes in the human adult brain. These genes were found to be involved in pro-apoptotic pathways and their repression, associated with increased REST levels during aging, were found to be neuroprotective and conserved across species. However, direct genome-wide REST binding profiles for REST in adult brain have not been identified for any species. Here, we apply this approach to mouse and human hippocampus. We find an expansion of REST binding sites in the human hippocampus that are lacking in both mouse hippocampus and other human non-neuronal cell types. The unique human REST binding sites are associated with genes involved in innate immunity processes and inflammation signaling which, on the basis of histology and recent public transcriptomic analyses, suggest that these new target...

Adult neural plasticity is an important and intriguing phenomenon in the brain, and adult hippocampal neurogenesis is directly involved in modulating neural plasticity by mechanisms that are only partially understood. We have performed gain- and loss-of-function experiments to study Smad2, a transcription factor selected from genes that are demethylated after exercise through the analysis of an array of physical activity-induced factors, and its corresponding gene expression, and an efficient inducer of plasticity. In these studies, changes in cell number and morphology were analyzed in the hippocampal dentate gyrus (cell proliferation and survival -including regional distribution-, and structural maturation/differentiation -including arborization, dendritic spines and neurotransmitter-specific vesicles-) of sedentary male mice, after evaluation in a battery of behavioral tests. As a result, we reveal a role for Smad2 in the balance of proliferation vs. maturation of differentiating immature cells (Smad2 s...

Following stroke, the survival of neurons and their ability to re-establish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABAA receptors (GABAAR). Conversely, in the late phase, negative allosteric modulation of GABAAR can correct the sub-optimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAAR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which make it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermor...

How does the brain anticipate information in language? When people perceive speech, low-frequency (<10 Hz) activity in the brain synchronizes with bursts of sound and visual motion. This phenomenon, called cortical stimulus-tracking, is thought to be one way that the brain predicts the timing of upcoming words, phrases, and syllables. In this study, we test whether stimulus-tracking depends on domain-general expertise or on language-specific prediction mechanisms. We go on to examine how the effects of expertise differ between frontal and sensory cortex. We recorded electroencephalography (EEG) from human participants who were experts in either sign language or ballet, and we compared stimulus-tracking between groups while participants watched videos of sign language or ballet. We measured stimulus-tracking by computing coherence between EEG recordings and visual motion in the videos. Results showed that stimulus-tracking depends on domain-general expertise, and not on language-specific prediction mechanis...