Modern molecular and biochemical neuroscience studies require analysis of specific cellular populations derived from brain tissue samples to disambiguate cell type-specific events. This is particularly true in the analysis of minority glial populations in the brain, such as microglia, which may be obscured in whole tissue analyses. Microglia have central functions in development, aging, and neurodegeneration and are a current focus of neuroscience research. A long-standing concern for glial biologists using in vivo models is whether cell isolation from CNS tissue could introduce ex vivo artifacts in microglia, which respond quickly to changes in the environment. Mouse microglia were purified by magnetic-activated cell sorting (MACS), as well as cytometer- and cartridge-based fluorescence-activated cell sorting (FACS) approaches to compare and contrast performance. The Cx3cr1-NuTRAP mouse model was used to provide an endogenous fluorescent microglial marker and a microglial-specific translatome profile as a...

Understanding the human brain is a ‘Grand Challenge’ for 21st century research. Computational approaches enable large and complex datasets to be addressed efficiently, supported by artificial neural networks, modeling and simulation. Dynamic generative multiscale models, which enable causation across scales and are guided by principles and theories of brain function, are instrumental to link brain structure and function. This integrated approach to neuroscientific discovery is framed within the BigBrain, which spatially anchors tissue models and data across different spatial scales and assures that multiscale models are supported by the data, making the bridge to both basic neuroscience and medicine. Research at the cross-over of neuroscience, computing and robotics has the potential to push neuro-inspired technologies, taking advantage of a growing body of insights into perception, plasticity and learning. To render data, tools and methods, theories, basic principles and concepts interoperable, the Human ...

Studying the temporal dynamics of perceptual decisions offers key insights into the cognitive processes contributing to it. Conducting such investigation in a genetically tractable animal model can facilitate the subsequent unpacking of the mechanistic basis of different stages in perceptual dynamics. Here, we investigated the time course as well as fundamental psychophysical constants governing visual perceptual decision-making in freely behaving mice. We did so by analyzing response accuracy against reaction time (i.e., conditional accuracy), in a series of 2-AFC orientation discrimination tasks in which we varied target size, luminance, duration, and presence of a foil. Our results quantified two distinct stages in the time course of mouse visual decision-making - a ‘sensory encoding’ stage, in which conditional accuracy exhibits a classic tradeoff with response speed, and a subsequent ‘short term memory (STM)-dependent’ stage in which conditional accuracy exhibits a classic asymptotic decay following s...

Working memory ability continues to mature into adulthood in humans and non-human primates. At the single neuron level, adolescent development is characterized by increased prefrontal firing rate in the delay period, but less is known about how coordinated activity between neurons is altered. Local field potentials (LFP) provide a window into the computations carried out by the local network. To address the effects of adolescent development on LFP activity, three male rhesus monkeys were trained to perform an oculomotor delayed response task and tested at both the adolescent and adult stage. Simultaneous single-unit and LFP signals were recorded from areas 8a and 46 of the dorsolateral prefrontal cortex. In both the cue and delay period, power relative to baseline increased in the gamma frequency range (32 - 128 Hz). The changes between developmental stages could not be accounted for by differences in performance and were observed in more posterior as well as more anterior recording sites. In the adult sta...

Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. In the present study, we find that the global Slack KO male mice exhibit anxious behaviors whereas the Slack Y777H male mice manifest anxiolytic behaviors. The expression of Slack channels is rich in BLA glutamatergic neurons and down-regulated in chronic corticosterone-treated mice. In addition, electrophysiological data show enhanced excitability of BLA glutamatergic neurons in the Slack KO mice and decreased excitability of these neurons in the Slack Y777H mice. Furthermore, the Slack channel deletion in BLA glutamatergic neurons is sufficient to result in enhanced avoidance behaviors while Kcnt1 gene expression in the BLA or BLA-vHPC glutamatergic projections reverses anxious behaviors of the Slack KO mice. Our study identifies the role of the Slack channel in controlling anxious behaviors by decreasing the excitability of BLA-vHPC glutamatergic projections, ...

In the mammalian brain, perivascular astrocytes (PAs) closely juxtapose blood vessels and are postulated to have important roles in the control of vascular physiology, including regulation of the blood–brain barrier (BBB). Deciphering specific functions for PAs in BBB biology, however, has been limited by the ability to distinguish these cells from other astrocyte populations. In order to characterize selective roles for PAs in vivo , a new mouse model has been generated in which the endogenous megalencephalic leukoencephalopathy with subcortical cysts 1 (Mlc1) gene drives expression of Cre fused to a mutated estrogen ligand-binding domain (Mlc1-T2A-CreERT2). This knock-in mouse model, which we term MLCT, allows for selective identification and tracking of PAs in the postnatal brain. We also demonstrate that MLCT-mediated ablation of PAs causes severe defects in BBB integrity, resulting in premature death. PA loss results in aberrant localization of Claudin 5 and -VE-Cadherin in endothelial cell junctions ...

Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen α3 VI (COL6A3) C-terminal domain (CTD). These Col6a3 CTT mice showed a recessive dystonia-like phenotype in both sexes. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3 CTT mice of both sexes have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid (eCB) signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3 CTT mice of both sexes was improved by CB1R agonist treatment. Our fi...

Synaptic vesicle (SV) recycling is essential for the maintenance of neurotransmission, with a number of neurodevelopmental disorders linked to defects in this process. Fragile X syndrome (FXS) results from a loss of fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. Hyperexcitability of neuronal circuits is a key feature of FXS, therefore we investigated whether SV recycling was affected by the absence of FMRP during increased neuronal activity. We revealed that primary neuronal cultures from male Fmr1 knock-out (KO) rats display a specific defect in activity-dependent bulk endocytosis (ADBE). ADBE is dominant during intense neuronal activity, and this defect resulted in an inability of Fmr1 KO neurons to sustain SV recycling during trains of high-frequency stimulation. Using a molecular replacement strategy, we also revealed that a human FMRP mutant that cannot bind BK channels failed to correct ADBE dysfunction in KO neurons, however this dysfunction was corrected by BK channel agonist...

The axon initial segment (AIS), nodes of Ranvier, and the oligodendrocyte-derived myelin sheath have significant influence on the firing patterns of neurons and the faithful, coordinated transmission of action potentials (APs) to downstream brain regions. In the olfactory bulb (OB), olfactory discrimination tasks lead to adaptive changes in cell firing patterns, and the output signals must reliably travel large distances to other brain regions along highly myelinated tracts. Whether myelinated axons adapt to facilitate olfactory sensory processing is unknown. Here, we investigate the morphology and physiology of mitral cell (MC) axons in the olfactory system of adult male and female mice and show that unilateral sensory deprivation causes system-wide adaptations in axonal morphology and myelin thickness. MC spiking patterns and APs also adapted to sensory deprivation. Strikingly, myelination and MC physiology were altered on both the deprived and nondeprived sides, indicating system level adaptations to re...

Economic choice is thought to involve the elicitation of the subjective values of the choice options. Thus far, value estimation in animals has relied on stochastic choices between multiple options presented in repeated trials and expressed from averages of dozens of trials. However, subjective reward valuations are made moment-to-moment and do not always require alternative options; their consequences are usually felt immediately. Here, we describe a Becker–DeGroot–Marschak (BDM) auction-like mechanism that provides more direct and simple valuations with immediate consequences. The BDM encourages agents to truthfully reveal their true subjective value in individual choices (“incentive compatibility”). Male monkeys reliably placed well-ranked BDM bids for up to five juice volumes while paying from a water budget. The bids closely approximated the average subjective values estimated with conventional binary choices (BCs), thus demonstrating procedural invariance and aligning with the wealth of knowledge acq...