Activation of the Akt/protein kinase B (PKB) kinase pathway can be neuroprotective after stroke. Akt is activated by growth factors via a phosphorylation-dependent pathway involving the kinases phosphoinositide 3 (PI3) kinase and phosphoinositide-dependent protein kinase-1 (PDK1) and is negatively regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Akt kinase blocks apoptosis by phosphorylating the substrates forkhead transcription factor (FKHR) and glycogen synthase kinase 3␤ (GSK3␤). We found that intra-ischemic hypothermia (30°C) reduced infarct size and improved functional outcomes up to 2 months. Changes in phosphorylation levels of Akt, as measured by Western blots and immunostaining, differed from levels of Akt activity measured in an in vitro assay in normothermic animals. Hypothermia blocked most of these changes and maintained Akt activity. Inhibition of PI3/Akt enlarged infarct size in hypothermic animals. Hypothermia improved phosphorylation of PDK1, PTEN, and FKHR. Hypothermia did not improve GSK3␤ (Ser9) phosphorylation but blocked the nuclear translocation of phosphorylated ␤-catenin (Ser33/37/Thr41) downstream of GSK3␤. Phosphorylation levels of PTEN, Akt, and Akt substrate decreased before apoptotic cytochrome c release and degradation of microtubule-associated protein-2, a marker of neuronal survival. Hypothermia may protect from ischemic damage in part by preserving Akt activity and attenuating the apoptotic effects of PTEN, PDK1, and FKHR.

In Experiment 1, three pigeons' key pecking was maintained under a variable-interval 60-s schedule of food reinforcement. A 1-s unsignaled nonresetting delay to reinforcement was then added. Rates decreased and stabilized at values below those observed under immediate-reinforcement conditions. A brief stimulus change (key lit red for 0.5 s) was then arranged to follow immediately the peck that began the delay. Response rates quickly returned to baseline levels. Subsequently, rates near baseline levels were maintained with briefly signaled delays of 3 and 9 s. When a 27-s briefly signaled delay was instituted, response rates decreased to low levels. In Experiment 2, four pigeons' responding was first maintained under a multiple variable-interval 60-s (green key) variable-interval 60-s (red key) schedule. Response rates in both components fell to low levels when a 3-s unsignaled delay was added. In the first component delays were then briefly signaled in the same manner as Experiment 1, and in the second component they were signaled with a change in key color that remained until food was delivered. Response rates increased to near baseline levels in both components, and remained near baseline when the delays in both components were lengthened to 9 s. When delays were lengthened to 27 s, response rates fell to low levels in the briefly signaled delay component for three of four pigeons while remaining at or near baseline in the completely signaled delay component. In Experiment 3, low response rates under a 9-s unsignaled delay to reinforcement (tandem variable-interval 60 s fixedtime 9 s) increased when the delay was briefly signaled. The role of the brief stimulus as conditioned reinforcement may be a function of its temporal relation to food, and thus may be related to the eliciting function of the stimulus.

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The current study demonstrates the ability of neuropeptide Y (NPY) to increase break points under a progressive ratio 1 (PR1) reinforcement schedule. An initial response resulted in delivery of a food reinforcer (45 mg pellet) under the PR1, and an additional response was required for each successive reinforcer. The break point, the number of responses emitted to obtain the last reinforcer, is considered a measure of reinforcing efficacy or motivational strength of the food reinforcer. NPY (0.3-10 micrograms) significantly increased break point to levels comparable to those produced by 36-48 h of food deprivation. Although insulin (3-8 U/kg) and 2-deoxyglucose (150-250 mg/kg) also increased food intake, neither increased break points to levels produced by NPY or food deprivation. These data suggest that NPY may change the value of food in ways that cannot be accounted for by changes in insulin, glucose levels or intracellular glucoprivation. These results emphasize that simply measuring the amount of freely available food eaten is not a fully adequate measure of the strength of the feeding behavior.

Two experiments evaluated rate dependency and a neuropharmacological model of timing as explanations of the effects of amphetamine on behavior under discriminative control by time. Four pigeons pecked keys during 60-trial sessions. On each trial, the houselight was lit for a particular duration (5 to 30 s), and then the key was lit for 30 s. In Experiment 1, the key could be lit either green or blue. If the key was lit green and the sample was 30 s, or if the key was lit blue and the sample was 5 s, pecks produced food on a variable-interval 20-s schedule. The rate of key pecking increased as a function of sample duration when the key was green and decreased as a function of sample duration when the key was blue. Acute d-amphetamine (0.1 to 3.0 mg/kg) decreased higher rates of key pecking and increased lower rates of key pecking as predicted by rate dependency, but did not shift the timing functions leftward (toward overestimation) as predicted by the neuropharmacological model. These results were replicated in Experiment 2, in which the key was lit only one color during sessions, indicating that the effects were not likely due to disruption of discriminative control by key color. These results are thus consistent with rate dependency but not with the predictions of the neuropharmacological model.