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Sleep is universal, tightly regulated, and its loss impairs cognition. But why does the brain need to disconnect from the environment for hours every day? The synaptic homeostasis hypothesis (SHY) proposes that sleep is the price the brain pays for plasticity. During a waking episode, learning statistical regularities about the current environment requires strengthening connections throughout the brain...
Molecular “hitchhiking” through receptor-mediated transcytosis at the blood-brain barrier is a CNS drug delivery strategy. In this issue of Neuron, Niewoehner et al. (2014) describe a modular anti-transferrin receptor Fab approach for shuttling therapeutic antibodies into the brain.
Structural plasticity in the adult brain is essential for adaptive behavior. We have found a remarkable anatomical plasticity in the basal ganglia of adult mice that is regulated by dopamine D2 receptors (D2Rs). By modulating neuronal excitability, striatal D2Rs bidirectionally control the density of direct pathway collaterals in the globus pallidus that bridge the direct pathway with the functionally...
Although biotherapeutics have vast potential for treating brain disorders, their use has been limited due to low exposure across the blood-brain barrier (BBB). We report that by manipulating the binding mode of an antibody fragment to the transferrin receptor (TfR), we have developed a Brain Shuttle module, which can be engineered into a standard therapeutic antibody for successful BBB transcytosis...
Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated...
Theta-gamma network oscillations are thought to represent key reference signals for information processing in neuronal ensembles, but the underlying synaptic mechanisms remain unclear. To address this question, we performed whole-cell (WC) patch-clamp recordings from mature hippocampal granule cells (GCs) in vivo in the dentate gyrus of anesthetized and awake rats. GCs in vivo fired action potentials...
Our choice is influenced by choices we made in the past, but the mechanism responsible for the choice bias remains elusive. Here we show that the history-dependent choice bias can be explained by an autonomous learning rule whereby an estimate of the likelihood of a choice to be made is updated in each trial by comparing between the actual and expected choices. We found that in perceptual decision...
The maintenance of goal-directed behavior relies upon a cascade of covert mental actions including motor imagery and planning. Here we investigated how cues imbued with motivational salience can invigorate motor imagery networks preceding action. We adapted the Pavlovian-to-instrumental (PIT) paradigm to explore this by substituting motor action with motor imagery. Thus, reward was contingent upon...
Voltage-gated ion channels exhibit complex properties, which can be targeted in pharmacological therapies for disease. Here, we report that the pro-oxidant, tert-butyl dihydroquinone (BHQ), modulates Cav2.1 Ca2+ channels in ways that oppose defects in channel gating and synaptic transmission resulting from a familial hemiplegic migraine mutation (S218L). BHQ slows deactivation, inhibits voltage-dependent...
Perceptual decisions involve distributed cortical activity. Does information flow sequentially from one cortical area to another, or do networks of interconnected areas contribute at the same time? Here we delineate when and how activity in specific areas drives a whisker-based decision in mice. A short-term memory component temporally separated tactile “sensation” and “action” (licking). Using optogenetic...
Musk odorants are used widely in cosmetic industries because of their fascinating animalic scent. However, how this aroma is perceived in the mammalian olfactory system remains a great mystery. Here, we show that muscone, one musk odor secreted by various animals from stink glands, activates a few glomeruli clustered in a neuroanatomically unique anteromedial olfactory bulb. The muscone-responsive...
Successful graduate training benefits from committed mentors and motivated students. Because scientific research involves investigating unexplored territory, however, each student’s experience will necessarily be unique, making it rarely possible to conform to an idealized training sequence. To approach this inherently uncontrolled situation constructively, students are encouraged, first, to become...
The propagation of visual signals from individual cone photoreceptors through parallel neural circuits was examined in the primate retina. Targeted stimulation of individual cones was combined with simultaneous recording from multiple retinal ganglion cells of identified types. The visual signal initiated by an individual cone produced strong responses with different kinetics in three of the four...
Layer 5 pyramidal neurons comprise at least two subtypes: thick-tufted, subcortically projecting type A neurons, with prominent h-current, and thin-tufted, callosally projecting type B neurons, which lack prominent h-current. Using optogenetic stimulation, we find that these subtypes receive distinct forms of input that could subserve divergent functions. Repeatedly stimulating callosal inputs evokes...
In this issue of Neuron, Guo et al. (2014) optogenetically probe contributions of different cortical regions to tactile sensory perception, finding that somatosensory cortex is necessary for acquisition of sensory information and frontal cortex is necessary for planning motor output.
Censor et al. (2014) combine behavioral, TMS, and neuroimaging to identify task-free neural signatures that relate to modification of motor memories. Modulation of memories using TMS may provide a powerful approach to improve human brain function in neurorehabilitation and cognitive neuroscience.
Female eutherian mammals use X chromosome inactivation (XCI) to epigenetically regulate gene expression from ∼4% of the genome. To quantitatively map the topography of XCI for defined cell types at single cell resolution, we have generated female mice that carry X-linked, Cre-activated, and nuclear-localized fluorescent reporters—GFP on one X chromosome and tdTomato on the other. Using these reporters...
Inhibitory microcircuits are wired with a precision that underlies their complex regulatory roles in neural information processing. In the spinal cord, one specialized class of GABAergic interneurons (GABApre) mediates presynaptic inhibitory control of sensory-motor synapses. The synaptic targeting of these GABAergic neurons exhibits an absolute dependence on proprioceptive sensory terminals, yet...
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