Neuronal activity initiates signaling cascades that culminate in diverse outcomes including structural and functional neuronal plasticity, and metabolic changes. While studies have revealed activity-dependent neuronal cell type specific transcriptional changes, unbiased quantitative analysis of cell specific activity-induced dynamics in newly synthesized proteins synthesis in vivo has been complicated by the brain’s cellular heterogeneity and relative low abundance of newly synthetized proteins (NSP) within the proteome. Here we combined targeted expression of mutant MetRS in genetically defined cortical glutamatergic neurons with tight temporal control of treatment with the non-canonical amino acid, azidonorleucine, ANL, to biotinylate NSPs within a short period after pharmacologically-induced seizure in male and female mice. By purifying peptides tagged with heavy or light biotin-alkynes and using direct MS/MS detection of biotinylated peptides, we quantified activity-induced changes in cortical glutamat...

Mutations in PTEN-induced kinase 1 (PINK1) contribute to autosomal recessive Parkinson’s disease with cognitive and neuropsychiatric comorbidities. Disturbances in dendritic and spine architecture are hallmarks of neurodegenerative and neuropsychiatric conditions, but little is known of the impact of PINK1 on these structures. We utilized Pink1-/- mice to study the role of endogenous PINK1 in regulating dendritic architecture, spine density and spine maturation. Pink1-/- cortical neurons of unknown sex showed decreased dendritic arborization, affecting both apical and basal arbors. Dendritic simplification in Pink1-/- neurons was primarily driven by diminished branching with smaller effects on branch lengths. Pink1-/- neurons showed reduced spine density with a shift in morphology to favor filopodia at the expense of mushroom spines. Electrophysiology revealed significant reductions in miniature excitatory postsynaptic current (mEPSC) frequency in Pink1-/- neurons, consistent with the observation of decrea...

Forelimb-related areas of the motor cortex communicate directly to downstream areas in the brainstem and spinal cord via axons that project to and through the pyramidal tract. To better understand the diversity of the brainstem branching patterns of these pyramidal tract projections, we used MAPseq, a molecular barcode technique for population-scale sampling with single-axon resolution. In experiments using mice of both sexes, we first confirmed prior results demonstrating the basic efficacy of axonal barcode identification of M1 pyramidal-tract type (PT) axons, including corticobulbar (CBULB) and corticospinal (CSPI) subclasses. We then used multiplexed MAPseq to analyze projections from M1 and M2 (caudal and rostral forelimb areas). The four basic axon subclasses comprising these projections (M1-CSPI, M1-CBULB, M2-CSPI, M2-CBULB) showed a complex mix of differences and similarities in their brainstem projection profiles. This included relatively abundant branching by all classes in the dorsal midbrain, b...

Midfrontal theta (FMθ) in the human EEG is commonly viewed as a generic and homogeneous mechanism of cognitive control in general and conflict processing in particular. However, the role of FMθ in approach-avoidance conflicts and its cross-task relationship to simpler stimulus-response conflicts remain to be examined more closely. Therefore, we recorded EEG data while 59 healthy participants (49 female, 10 male) completed both, an approach-avoidance task and a Flanker task. Participants showed significant increases in FMθ power in response to conflicts in both tasks. To our knowledge, this is the first study to show a direct relationship between FMθ and approach-avoidance conflicts. Crucially, FMθ activity was task dependent and showed no cross-task correlation. To assess the possibility of multiple FMθ sources, we applied source separation (Generalized Eigendecomposition; GED) to distinguish independent FMθ generators. The component’s activity showed a similar pattern and was again task-specific. However,...

We are able to temporally organize multiple movements in a purposeful manner in everyday life. Both the dorsal premotor (PMd) area and pre-supplementary motor area (pre-SMA) are known to be involved in the performance of motor sequences. However, it is unclear how each area differentially contributes to controlling multiple motor sequences. To address this issue, we recorded single-unit activity in both areas while monkeys (one male, one female) performed sixteen motor sequences. Each sequence comprised either a series of two identical movements (repetition) or two different movements (nonrepetition). The sequence was initially instructed with visual signals but had to be remembered thereafter. Here, we showed that the activity of single neurons in both areas transitioned from reactive- to predictive encoding while motor sequences were memorized. In the memory-guided trials, in particular, the activity of PMd cells preferentially represented the second movement (2M) in the sequence leading to a reward gene...

In severely affected stroke survivors, cortico-muscular control is disturbed and volitional upper limb movements often absent. Mental rehearsal of the impaired movement in conjunction with sensory feedback provision are suggested as promising rehabilitation exercises. Knowledge about the underlying neural processes, however, remains vague. In male and female chronic stroke patients with hand paralysis, a brain-computer interface controlled a robotic orthosis and turned sensorimotor β-band desynchronization during motor imagery (MI) of finger extension into contingent hand opening. Healthy control subjects performed the same task and received the same proprioceptive feedback with a robotic orthosis or visual feedback only. Only when proprioceptive feedback was provided, cortico-muscular coherence (CMC) increased with a predominant information flow from the sensorimotor cortex to the finger extensors. This effect (1) was specific to the β frequency band, (2) transferred to a motor task (MT), (3) was proporti...

Humans form impressions toward individuals of their own social groups (ingroup members) and of different social groups (outgroup members). Outgroup-focused theories predict that intergroup impressions are mainly shaped by experiences with outgroup individuals, while ingroup-focused theories predict that ingroup experiences play a dominant role. Here we test predictions from these two psychological theories by estimating how intergroup impressions are dynamically shaped when people learn from both ingroup and outgroup experiences. While undergoing fMRI, male participants had identical experiences with different ingroup or outgroup members and rated their social closeness and impressions toward the ingroup and the outgroup. Behavioral results showed an initial ingroup bias in impression ratings which was significantly reduced over the course of learning, with larger effects in individuals with stronger ingroup identification. Computational learning models revealed that these changes in intergroup impressions...

fMRI plays a key role in the study of attention. However, there remains a puzzling discrepancy between attention effects measured with fMRI and with electrophysiological methods. While electrophysiological studies find that attention increases sensory gain, amplifying stimulus-evoked neural responses by multiplicatively scaling the contrast-response function (CRF), fMRI appears to be insensitive to these multiplicative effects. Instead, fMRI studies typically find that attention produces an additive baseline shift in the BOLD signal. These findings suggest that attentional effects measured with fMRI reflect top-down inputs to visual cortex, rather than the modulation of sensory gain. If true, this drastically limits what fMRI can tell us about how attention improves sensory coding. Here, we examined whether fMRI is sensitive to multiplicative effects of attention using a feature-based attention paradigm designed to preclude any possible additive effects. We measured BOLD activity evoked by a probe stimulus...

In Drosophila melanogaster , the pacemaker located in the brain plays the main role in maintaining circadian rhythms; however, peripheral oscillators including glial cells, are also crucial components of the circadian network. In the present study, we investigated an impact of oscillators located in astrocyte-like glia, the chiasm giant glia of the optic lobe, epithelial and subperineurial glia on sleep of Drosophila males. We described that oscillators located in astrocyte-like glia and chiasm giant glia are necessary to maintain daily changes in clock neurons arborizations, while those located in epithelial glia regulate amplitude of these changes. Finally, we showed that communication between glia and neurons through tripartite synapses formed by epithelial glia and, in effect, neurotransmission regulation plays important role in wake-promoting during the day. SIGNIFICANCE STATEMENT Circadian clock or pacemaker regulates many aspects of animals' physiology and behavior. The pacemaker is located in the ...

There are five cloned muscarinic acetylcholine receptors (M1–M5). Of these, the muscarinic type 5 receptor (M5) is the only one localized to dopamine neurons in the ventral tegmental area and substantia nigra. Unlike M1–M4, the M5 receptor has relatively restricted expression in the brain, making it an attractive therapeutic target. Here, we performed an in-depth characterization of M5-dependent potentiation of dopamine transmission in the nucleus accumbens and accompanying exploratory behaviors in male and female mice. We show that M5 receptors potentiate dopamine transmission by acting directly on the terminals within the nucleus accumbens. Using the muscarinic agonist oxotremorine, we revealed a unique concentration–response curve and a sensitivity to repeated forced swim stress or restraint stress exposure. We found that constitutive deletion of M5 receptors reduced exploration of the center of an open field while at the same time impairing normal habituation only in male mice. In addition, M5 deletion...