Astrocytes express neurotransmitter receptors that serve as sensors of synaptic activity and initiate signals leading to activity-dependent local vasodilation and increases in blood flow. We previously showed that arteriolar vasodilation produced by activation of cortical astrocytes is dependent on endothelial nitric oxide synthase (eNOS) and endogenous agonists of N-methyl-D-aspartate (NMDA) receptors. Here, we tested the hypothesis that these effects are mediated by NMDA receptors expressed by brain endothelial cells. Primary endothelial cultures expressed NMDA receptor subunits and produced nitric oxide in response to co-agonists, glutamate and D-serine. In cerebral cortex in situ, immunoelectron microscopy revealed that endothelial cells express the GluN1 NMDA receptor subunit at basolateral membrane surfaces in an orientation suitable for receiving intercellular messengers from brain cells. In cortical slices, activation of astrocytes by two-photon flash photolysis of a caged Ca compound or application of a metabotropic glutamate receptor agonist caused endothelial NO generation and local vasodilation. These effects were mitigated by NMDA receptor antagonists and conditional gene silencing of endothelial GluN1, indicating at least partial dependence on endothelial NMDA receptors. Our observations identify a novel astrocyte-endothelial vasodilatory signaling axis that could contribute to endothelium-dependent vasodilation in brain functional hyperemia.

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In an environment with easy access to highly palatable and energydense food, food-related cues drive food-seeking regardless of satiety, an effect that can lead to obesity. The ventral tegmental area (VTA) and its mesolimbic projections are critical structures involved in the learning of environmental cues used to predict motivationally relevant outcomes. Priming effects of food-related advertising and consumption of palatable food can drive food intake. However, the mechanism by which this effect occurs, and whether these priming effects last days after consumption, is unknown. Here, we demonstrate that short-term consumption of palatable food can prime future food approach behaviors and food intake. This effect is mediated by the strengthening of excitatory synaptic transmission onto dopamine neurons that is initially offset by a transient increase in endocannabinoid tone, but lasts days after an initial 24-h exposure to sweetened high-fat food (SHF). This enhanced synaptic strength is mediated by a long-lasting increase in excitatory synaptic density onto VTA dopamine neurons. Administration of insulin into the VTA, which suppresses excitatory synaptic transmission onto dopamine neurons, can abolish food approach behaviors and food intake observed days after 24-h access to SHF. These results suggest that even a short-term exposure to palatable foods can drive future feeding behavior by "rewiring" mesolimbic dopamine neurons.palatable food | synaptic density | VTA | dopamine | excitatory synaptic transmission P riming effects of food-related advertising (1) and consumption of palatable food (2, 3) can drive sated consumption of food. Overconsumption of food relative to need is an important factor in the development of obesity (4). The priming effects of palatable food on food intake are likely a considerable factor in the obesity epidemic. However, the mechanism by which food-priming effects occur is unknown. The ventral tegmental area (VTA) and its mesolimbic projections are critical for learning about environmental cues used to predict motivationally relevant outcomes (5). Indeed, food-related cues activate the dopaminergic circuit to reinforce food intake (6, 7). VTA dopamine neurons can increase or decrease their synaptic efficacy to modulate their consequent dopaminergic output (8, 9). The strength of excitatory synaptic input onto VTA dopamine neurons plays a central role in rewardrelated behavior with potentiation of synapses formed onto VTA neurons, facilitating the transformation of neutral environmental stimuli into salient reward predictive cues (8). Conversely, depression of excitatory synaptic transmission would likely reduce the intrinsic firing rate and excitability of dopamine neurons, as has been demonstrated for other neurons (10), and would likely reduces the salience of reward predicting cues.The motivation to eat is regulated by a variety of intrinsic and extrinsic factors. Metabolic signals, including neuronal or circulating peptides released in response to internal states such as hunger ...

Amblyopia is the most common cause of monocular visual impairment. Patching, which is modestly effective, is the current treatment of amblyopia in children. There is no clinically approved treatment for adults. The present study is a clinical trial (non-sham controlled and non-randomized) that assessed the efficacy of binocular training for improvement of the visual acuity in children and adults with amblyopia. Twenty-two amblyopic subjects ranging in age from 5 to 73 (mean: 36.2) years for whom patching and/or surgical treatments did not correct their visual impairment completed an average of 14.5 sessions of binocular training over a period of 4 to 6 weeks. Random dot kinematograms were presented dichoptically to the two eyes and the participants' task was to identify the direction of motion of the targets. Mean visual acuity improvement was 0.34 LogMAR (range: 0.1-0.58 LogMAR) and was shown to persist 6 months following the cessation of binocular training. Our study provides results in a large number of patients that confirm the clinical effectiveness of binocular training as a treatment for amblyopia in improving visual acuity in both children and adults. Moreover, this study is the first to demonstrate that the improvements in visual function were maintained for 6 months in the absence of any additional treatment.

Drugs of abuse alter synaptic connections in the ‘reward circuit’ of the brain, which leads to long-lasting behavioral changes that underlie addiction. Here we show that cadherin adhesion molecules play a critical role in mediating synaptic plasticity and behavioral changes driven by cocaine. We demonstrate that cadherin is essential for long-term potentiation (LTP) in the ventral tegmental area (VTA), and is recruited to the synaptic membrane of excitatory inputs onto dopaminergic neurons following cocaine-mediated behavioral conditioning. Furthermore, we show that stabilization of cadherin at the membrane of these synapses blocks cocaine-induced synaptic plasticity, leading to a significant reduction in conditioned place preference induced by cocaine. Our findings identify cadherins and associated molecules as targets of interest for understanding pathological plasticity associated with addiction.