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Cytokines produced during infection/inflammation activate adaptive central nervous system (CNS) responses, including acute stress responses mediated by the hypothalamo-pituitary-adrenal (HPA) axis. The mechanisms by which cytokines engage HPA control circuitry remain unclear, though stimulated release of prostanoids from neighboring vascular cells has been implicated in this regard. How specific vascular...
Arousal is fundamental to many behaviors, but whether it is unitary or whether there are different types of behavior-specific arousal has not been clear. In Drosophila, dopamine promotes sleep-wake arousal. However, there is conflicting evidence regarding its influence on environmentally stimulated arousal. Here we show that loss-of-function mutations in the D1 dopamine receptor DopR enhance repetitive...
The entorhinal cortex (EC) is regarded as the gateway to the hippocampus and thus is essential for learning and memory. Whereas the EC expresses a high density of GABA B receptors, the functions of these receptors in this region remain unexplored. Here, we examined the effects of GABA B receptor activation on neuronal excitability in the EC and spatial learning. Application of baclofen,...
Our understanding of the evolution, formation, and pathological disruption of human brain circuits is impeded by a lack of comprehensive data on the developing brain transcriptome. A whole-genome, exon-level expression analysis of 13 regions from left and right sides of the mid-fetal human brain revealed that 76% of genes are expressed, and 44% of these are differentially regulated. These data reveal...
Some synapses transmit strongly to action potentials (APs), but weaken with repeated activation; others transmit feebly at first, but strengthen with sustained activity. We measured synchronous and asynchronous transmitter release at “phasic” crayfish neuromuscular junctions (NMJs) showing depression and at facilitating “tonic” junctions, and define the kinetics of depression and facilitation. We...
Availability of genome-scale in situ hybridization data allows systematic analysis of genetic neuroanatomical architecture. Within the hippocampus, electrophysiology and lesion and imaging studies demonstrate functional heterogeneity along the septotemporal axis, although precise underlying circuitry and molecular substrates remain uncharacterized. Application of unbiased statistical component analyses...
Decision making with several choice options is central to cognition. To elucidate the neural mechanisms of such decisions, we investigated a recurrent cortical circuit model in which fluctuating spiking neural dynamics underlie trial-by-trial stochastic decisions. The model encodes a continuous analog stimulus feature and is thus applicable to multiple-choice decisions. Importantly, the continuous...
Although rod and cone photoreceptor cells in the vertebrate retina are anatomically connected or coupled by gap junctions, a type of electrical synapse, rod-cone electrical coupling is thought to be weak. Using tracer labeling and electrical recording in the goldfish retina and tracer labeling in the mouse retina, we show that the retinal circadian clock, and not the retinal response to the visual...
The role of cell size and shape in controlling local intracellular signaling reactions, and how this spatial information originates and is propagated, is not well understood. We have used partial differential equations to model the flow of spatial information from the β-adrenergic receptor to MAPK1,2 through the cAMP/PKA/B-Raf/MAPK1,2 network in neurons using real geometries. The numerical simulations...
The topographic representation of visual space is preserved from retina to thalamus to cortex. We have previously shown that precise mapping of thalamocortical projections requires both molecular cues and structured retinal activity. To probe the interaction between these two mechanisms, we studied mice deficient in both ephrin-As and retinal waves. Functional and anatomical cortical maps in these...
The molecular mechanisms regulating the sensitivity of sensory circuits to environmental stimuli are poorly understood. We demonstrate here a central role for stem cell factor (SCF) and its receptor, c-Kit, in tuning the responsiveness of sensory neurons to natural stimuli. Mice lacking SCF/c-Kit signaling displayed profound thermal hypoalgesia, attributable to a marked elevation in the thermal threshold...
Light is the most potent stimulus for synchronizing endogenous circadian rhythms with external time. Photic clock resetting in mammals involves cAMP-responsive element binding protein (CREB)-mediated transcriptional activation of Period clock genes in the suprachiasmatic nuclei (SCN). Here we provide evidence for an additional photic input pathway to the mammalian circadian clock based on Protein...
Many theories of cerebellar function assume that long-term depression (LTD) of parallel fiber (PF) synapses enables Purkinje cells to learn to recognize PF activity patterns. We have studied the LTD-based recognition of PF patterns in a biophysically realistic Purkinje-cell model. With simple-spike firing as observed in vivo, the presentation of a pattern resulted in a burst of spikes followed by...
Each odorant receptor gene defines a unique type of olfactory receptor neuron (ORN) and a corresponding type of second-order neuron. Because each odor can activate multiple ORN types, information must ultimately be integrated across these processing channels to form a unified percept. Here, we show that, in Drosophila, integration begins at the level of second-order projection neurons (PNs). We genetically...
The neural circuitry that constrains visual acuity in the CNS has not been experimentally identified. We show here that zebrafish blumenkohl (blu) mutants are impaired in resolving rapid movements and fine spatial detail. The blu gene encodes a vesicular glutamate transporter expressed by retinal ganglion cells. Mutant retinotectal synapses release less glutamate, per vesicle and per terminal, and...
Beta amyloid (Aβ), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimer's disease. Recent studies indicate that this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Aβ employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors...
Although radial oblique dendrites are a major synaptic input site in CA1 pyramidal neurons, little is known about their integrative properties. We have used multisite two-photon glutamate uncaging to deliver different spatiotemporal input patterns to single branches while simultaneously recording the uncaging-evoked excitatory postsynaptic potentials and local Ca 2+ signals. Asynchronous input...
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