Simple cells in the visual cortex respond to the precise position of oriented contours (Hubel and Wiesel, 1962). This sensitivity reflects the structure of the simple receptive field, which exhibits two sorts of antagonism between on and off inputs. First, simple receptive fields are divided into adjacent on and off subregions; second, within each subregion, stimuli of the reverse contrast evoke responses of the opposite sign: push-pull (Hubel and Wiesel, 1962;Palmer and Davis, 1981;Jones and Palmer, 1987;Ferster, 1988). We have made whole-cell patch recordings from cat area 17 during visual stimulation to examine the generation and integration of excitation (push) and suppression (pull) in the simple receptive field. The temporal structure of the push reflected the pattern of thalamic inputs, as judged by comparing the intracellular cortical responses to extracellular recordings made in the lateral geniculate nucleus.Two mechanisms have been advanced to account for the pullwithdrawal of thalamic drive and active, intracortical inhibition (Hubel and Wiesel, 1962;Heggelund, 1986;Ferster, 1988). Our results suggest that intracortical inhibition is the dominant, and perhaps sole, mechanism of suppression. The inhibitory influences operated within a wide dynamic range. When inhibition was strong, the membrane conductance could be doubled or tripled. Furthermore, if a stimulus confined to one subregion was enlarged so that it extended into the next, the sign of response often changed from depolarizing to hyperpolarizing. In other instances, the inhibition modulated neuronal output subtly, by elevating spike threshold or altering firing rate at a given membrane voltage. Key words: visual cortex; patch recording in vivo; simple cell; IPSP; EPSP; spiny stellate cellCortical sensitivity to patterned stimuli has its roots in the arrangement of synaptic inputs to simple cells, whose receptive fields are made of elongated, alternating on and off subregions. Bright signals confined to an on subregion are excitatory, whereas dark ones reduce activity; that is, stimuli of the opposite contrast have a push -pull effect (Hubel and Wiesel, 1962;Movshon et al., 1978;Heggelund, 1981Heggelund, , 1986Palmer and Davis, 1981;Jones and Palmer, 1987;Ferster, 1988;Miller, 1994;Troyer et al., 1998; but see Debanne et al., 1998). Furthermore, when the receptive field is uniformly illuminated or darkened, simple cells respond poorly because their subregions have a mutually antagonistic relationship (Hubel and Wiesel, 1962). Thus, the output of the simple cell relies on the balance of excitation and suppression that various stimuli evoke.We have used the technique of whole-cell recording (Hamill et al., 1981;Edwards et al., 1989;Blanton et al., 1989) in vivo (Pei et al., 1991;Ferster and Jagadeesh, 1992) to analyze the synaptic mechanisms that produce visually evoked responses in the receptive field. First, we examined the origins of excitatory and suppressive components of the responses to stimuli of reverse contrast flashed within a single ...

Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intrahepatic lipid content and stimulates b-oxidation in hepatic cells and liver by an autophagy-lysosomal pathway. Furthermore, caffeine-induced autophagy involved down-regulation of mammalian target of rapamycin signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high-fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: These results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD. (HEPATOLOGY 2014;59:1366-1380 See Editorial on Page 1235 C affeine is one of the most widely consumed drugs in the world. Although its effect on whole-body metabolism and fat oxidation has been well documented in both animals and humans, [1][2][3] little is known about its direct action on the liver.The liver is the major site for fatty acid oxidation (FAO) in mammals. Decreased turnover of hepatic lipid droplets can lead to the development of fatty liver disease in humans. 4 Recently, the rapid rise in the prevalence of obesity and diabetes in the general population has contributed to a parallel increase in nonalcoholic fatty liver disease (NAFLD) in many parts of the world. Currently, it is estimated that up to 46% of the adult U.S. population may have hepatosteatosis. 5 Presently, there are no effective drug therapies for NAFLD, currently considered a risk factor for type II diabetes. 6 Recently, several studies have shown that caffeine intake in humans and animals is inversely correlated with severity of NAFLD and type II diabetes, 7-11 but the mechanism for this action is not known.

In the cat primary visual cortex, neurons are classified into the two main categories of simple cells and complex cells based on their response properties. According to the hierarchical model, complex receptive fields derive from convergent inputs of simple cells with similar orientation preferences. This model received strong support from anatomical studies showing that many complex cells lie within the range of layer IV simple-cell axons but outside the range of most thalamic axons. Physiological evidence for the model, however, has remained elusive. Here we demonstrate that layer IV simple cells and layer II and III complex cells show correlated firing consistent with monosynaptic connections. As expected from the hierarchical model, all connections were in the direction from the simple cell to the complex cell, most frequently between cells with similar orientation preferences.

The pathogenesis and treatment of nonalcoholic steatohepatitis (NASH) are not well established. Feeding a diet deficient in both methionine and choline (MCD) is one of the most common models of NASH, which is characterized by steatosis, mitochondrial dysfunction, hepatocellular injury, oxidative stress, inflammation, and fibrosis. However, the individual contribution of the lack of methionine and choline in liver steatosis, advanced pathology and impact on mitochondrial S-adenosyl-Lmethionine (SAM) and glutathione (GSH), known regulators of disease progression, has not been specifically addressed. Here, we examined the regulation of mitochondrial SAM and GSH and signs of disease in mice fed a MCD, methionine-deficient (MD), or choline-deficient (CD) diet. The MD diet reproduced most of the deleterious effects of MCD feeding, including weight loss, hepatocellular injury, oxidative stress, inflammation, and fibrosis, whereas CD feeding was mainly responsible for steatosis, characterized by triglycerides and free fatty acids accumulation. These findings were preceded by MCD-or MD-mediated SAM and GSH depletion in mitochondria due to decreased mitochondrial membrane fluidity associated with a lower phosphatidylcholine/phosphatidylethanolamine ratio. MCD and MD but not CD feeding resulted in increased ceramide levels by acid sphingomyelinase. Moreover, GSH ethyl ester or SAM therapy restored mitochondrial GSH and ameliorated hepatocellular injury in mice fed a MCD or MD diet. Thus, the depletion of SAM and GSH in mitochondria is an early event in the MCD model of NASH, which is determined by the lack of methionine. Moreover, therapy using permeable GSH prodrugs may be of relevance in NASH.