Traumatic brain injury (TBI) triggers a plethora of inflammatory events in the brain that aggravate secondary injury and impede tissue repair. Resident microglia (Mi) and blood-borne infiltrating macrophages (MΦ) are major players of inflammatory responses in the post-TBI brain and possess high functional heterogeneity. However, the plasticity of these cells has yet to be exploited to develop therapies that can mitigate brain inflammation and improve the outcome after TBI. This study investigated the transcription factor STAT1 as a key determinant of proinflammatory Mi/MΦ responses and aimed to develop STAT1 as a novel therapeutic target for TBI using a controlled cortical impact model of TBI on adult male mice. TBI induced robust upregulation of STAT1 in the brain at the subacute injury stage, which occurred primarily in Mi/MΦ. Intraperitoneal administration of fludarabine, a selective STAT1 inhibitor, markedly alleviated proinflammatory Mi/MΦ responses and brain inflammation burden after TBI. Such phenot...

Habituation is a conserved adaptive process essential for incoming information assessment, which drives the behavioral response decrement to recurrent inconsequential stimuli and does not involve sensory adaptation or fatigue. Although the molecular mechanisms underlying the process are not well understood, habituation has been reported to be defective in a number of disorders including schizophrenia. We demonstrate that loss of furin1 , the Drosophila homolog of a gene whose transcriptional downregulation has been linked to schizophrenia, results in defective habituation to recurrent footshocks in mixed sex populations. The deficit is reversible by transgenic expression of the Drosophila or human Furin in adult α′/β′ mushroom body neurons and by acute oral delivery of the typical antipsychotic haloperidol and the atypical clozapine, which are commonly used to treat schizophrenic patients. The results validate the proposed contribution of Furin downregulation in schizophrenia and suggest that defective foo...

To understand language, we must infer structured meanings from real-time auditory or visual signals. Researchers have long focused on word-by-word structure building in working memory as a mechanism that might enable this feat. However, some have argued that language processing does not typically involve rich word-by-word structure building, and/or that apparent working memory effects are underlyingly driven by surprisal (how predictable a word is in context). Consistent with this alternative, some recent behavioral studies of naturalistic language processing that control for surprisal have not shown clear working memory effects. In this fMRI study, we investigate a range of theory-driven predictors of word-by-word working memory demand during naturalistic language comprehension in humans of both sexes under rigorous surprisal controls. In addition, we address a related debate about whether the working memory mechanisms involved in language comprehension are language specialized or domain general. To do so...

Tactile sensations can bias visual perception in the awake state while visual sensitivity is known to be facilitated by sleep. It remains unknown, however, whether the tactile sensation during sleep can bias the visual improvement after sleep. Here, we performed nap experiments in human participants ( n = 56, 18 males, 38 females) to demonstrate that repetitive tactile motion stimulation on the fingertip during slow wave sleep selectively enhanced subsequent visual motion detection. The visual improvement was associated with slow wave activity. The high activation at the high beta frequency was found in the occipital electrodes after the tactile motion stimulation during sleep, indicating a visual-tactile cross-modal interaction during sleep. Furthermore, a second experiment ( n = 14, 14 females) to examine whether a hand- or head-centered coordination is dominant for the interpretation of tactile motion direction showed that the biasing effect on visual improvement occurs according to the hand-centered co...

Autophagy and endocytic trafficking are two key pathways that regulate the composition and integrity of the neuronal proteome. Alterations in these pathways are sufficient to cause neurodevelopmental and neurodegenerative disorders. Thus, defining how autophagy and endocytic pathways are organized in neurons remains a key area of investigation. These pathways share many features and converge on lysosomes for cargo degradation, but what remains unclear is the degree to which the identity of each pathway is preserved in each compartment of the neuron. Here, we elucidate the degree of intersection between autophagic and endocytic pathways in axons of primary mouse cortical neurons of both sexes. Using microfluidic chambers, we labeled newly-generated bulk endosomes and signaling endosomes in the distal axon, and systematically tracked their trajectories, molecular composition, and functional characteristics relative to autophagosomes. We find that newly-formed endosomes and autophagosomes both undergo retrogr...

Psychology and neuroscience research have shown that fractioning operations between several individuals along a hierarchical chain allows diffusing responsibility between components of the chain, which has the potential to disinhibit antisocial actions. Here, we present two studies, one using fMRI (Study 1) and one using EEG (Study 2), designed to help understand how commanding or being in an intermediary position impacts the sense of agency and empathy for pain. In the age of military drones, we also explored whether commanding a human or robot agent influences these measures. This was done within a single behavioral paradigm in which participants could freely decide whether or not to send painful shocks to another participant in exchange for money. In Study 1, fMRI reveals that activation in social cognition and empathy-related brain regions was equally low when witnessing a victim receive a painful shock while participants were either commander or simple intermediary transmitting an order, compared to b...

Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid system and the brain's fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3mg/kg) from gestational day (GD) 7 until GD22. Anxiety-like, depressive-like, and reward-seeking behaviour, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted laser...

While recent studies have revealed an involvement of hippocampal interneurons in learning the association among time-separated events, its underlying cellular mechanisms remained not fully clarified. Here, we combined multi-channel recording and optogenetics to elucidate how the hippocampal parvalbumin-expressing interneurons (PV-IN) support associative learning. To address this issue, we trained the mice (box sexes) to learn hippocampus-dependent trace eyeblink conditioning (tEBC) where they associated a light flash conditioned stimulus (CS) with a corneal airpuff unconditioned stimuli (US) separated by a 250-ms time interval. We found that the hippocampal PV-INs exhibited learning-associated sustained activity at the early stage of tEBC acquisition. Moreover, the PV-IN sustained activity was positively correlated with the occurrence of conditioned eyeblink responses at the early learning stage. Suppression of the PV-IN sustained activity impaired the acquisition of tEBC, whereas the PV-IN activity suppre...

Phosphodiesterase (PDE) inhibitors have been safely and effectively used in the clinic and increase the concentration of intracellular cyclic nucleotides (cAMP/cGMP). These molecules activate downstream mediators, including the cAMP-response-element binding (CREB) protein, which controls neuronal excitability and growth responses. CREB gain of function enhances learning, and allocates neurons into memory engrams. CREB was also controls recovery after stroke. PDE-inhibitors are linked to recovery from neural damage and to stroke recovery in specific sites within the brain. PDE2A is enriched in cortex. In the present study, we use a mouse cortical stroke model in young adult and aged male mice to test the effect of PDE2A inhibition on functional recovery, and on downstream mechanisms of axonal sprouting, tissue repair and the functional connectivity of neurons in recovering cortex. Stroke causes deficits in use of the contralateral forelimb, loss of axonal projections in cortex adjacent to the infarct and fu...

It has been suggested that the dorsomedial striatum (DMS) is engaged in the early stages of motor learning for goal-directed actions, whereas at later stages, control is transferred to the dorsolateral striatum (DLS), a process that enables learned motor actions to become a skill or habit. It is not known if these striatal regions are simultaneously active while the expertise is acquired. To address this question, we developed a mouse “treadmill training task” that tracks changes in mouse locomotor coordination during running practice and simultaneously provides a means to measure local neuronal activity using photometry. To measure change in motor coordination over treadmill practice sessions, we used DeepLabCut and custom-built code to analyze body position and paw movements. By evaluating improvements in motor coordination during training with simultaneous neuronal calcium activity in the striatum, we found that DMS direct pathway neurons exhibited decreased activity as the mouse gained proficiency at r...