SummaryCholinergic neurotransmission throughout the neocortex and hippocampus regulates arousal, learning, and attention. However, owing to the poorly characterized timing and location of acetylcholine release, its detailed behavioral functions remain unclear. Using electrochemical biosensors chronically implanted in mice, we made continuous measurements of the spatiotemporal dynamics of acetylcholine release across multiple behavioral states. We found that tonic levels of acetylcholine release were coordinated between the prefrontal cortex and hippocampus and maximal during training on a rewarded working memory task. Tonic release also increased during REM sleep but was contingent on subsequent wakefulness. In contrast, coordinated phasic acetylcholine release occurred only during the memory task and was strongly localized to reward delivery areas without being contingent on trial outcome. These results show that coordinated acetylcholine release between the prefrontal cortex and hippocampus is associated with reward and arousal on distinct timescales, providing dual mechanisms to support learned behavior acquisition during cognitive task performance.

Despite nominally common mechanisms of action and often presumed biological equivalence, the NMDA antagonists tested produced very diverse effects on the expression of instrumental action. Other aspects of responding were left intact, including switching and matching behaviours, and the ability to respond to conditional stimuli. The implications of such findings with regard to animal modelling of schizophrenic psychotic symptoms are manifold.

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a b s t r a c t a r t i c l e i n f oReal-time in vivo oxygen amperometry, a technique that allows measurement of regional brain tissue oxygen (O 2 ) has been previously shown to bear relationship to the BOLD signal measured with functional magnetic resonance imaging (fMRI) protocols. In the present study, O 2 amperometry was applied to the study of reward processing in the rat nucleus accumbens to validate the technique with a behavioural process known to cause robust signals in human neuroimaging studies. After acquisition of a cued-lever pressing task a robust increase in O 2 tissue levels was observed in the nucleus accumbens specifically following a correct lever press to the rewarded cue. This O 2 signal was modulated by cue reversal but not lever reversal, by differences in reward magnitudes and by the motivational state of the animal consistent with previous reports of the role of the nucleus accumbens in both the anticipation and representation of reward value. Moreover, this modulation by reward value was related more to the expected incentive value rather than the hedonic value of reward, also consistent with previous reports of accumbens coding of "wanting" of reward. Altogether, these results show striking similarities to those obtained in human fMRI studies suggesting the use of oxygen amperometry as a valid surrogate for fMRI in animals performing cognitive tasks, and a powerful approach to bridge between different techniques of measurement of brain function.

The purpose of this study was to further examine the effect of activation of 5-HT WAY100635 (0.1-0.5 mg/kg) reversed the effect of 8-OH-DPAT over a dose range that did not alter swimming when given alone. The effect of anpirtoline (1.25 mg/ kg) was reversed by GR127935 (1.25 mg/kg) and isamoltane (2.5-5 mg/kg) but not by WAY100635 (0.1-0.5 mg/kg). The effect of the mixed agonist RU24969 (0.6 mg/kg) was also reversed by GR127935 (1.25-2.5 mg/kg) and isamoltane (1-5 mg/kg), but not by WAY100635 (0.1-0.5 mg/kg).The effect of imipramine (5 mg/kg) was significantly reversed by GR127935 (1.25 mg/kg) and isamoltane (5 mg/kg) while WAY100635 (0.1-0.5 mg/kg) was without effect.These results confirm previous findings that direct stimulation of either 5-HT 1A or 5-HT 1B receptors induces antidepressant-like effects in the FST. This study further suggests that the effects of RU24969 and imipramine in the forced swim test are mediated by 5-HT 1B rather than 5-HT 1A receptors. These findings confirm previous findings that blockade of 5-HT 1B receptors attenuates the anti-immobility effects of imipramine in "behavioral despair"-type tests suggesting that activity at these receptors may be an important mediator of its behavioral effects in this test.

Using environmental cues for the prediction of future events is essential for survival. Such cue-outcome associations are thought to depend on mesolimbic circuitry involving the nucleus accumbens (NAc) and prefrontal cortex (PFC). Several studies have identified roles for both NAc and PFC in the expression of stable goal-directed behaviors, but much remains unknown about their roles during learning of such behaviors. To further address this question, we used in vivo oxygen amperometry, a proxy for blood oxygen level-dependent (BOLD) signal measurement in human functional magnetic resonance imaging, in rats performing a cued lever-pressing task requiring discrimination between a rewarded and nonrewarded cue. Simultaneous oxygen recordings were obtained from infralimbic PFC (IFC) and NAc throughout both acquisition and extinction of this task. Activation of NAc was specifically observed following rewarded cue onset during the entire acquisition phase and also during the first days of extinction. In contrast, IFC activated only during the earliest periods of acquisition and extinction, more specifically to the nonrewarded cue. Thus, in vivo oxygen amperometry permits a novel, stable form of longitudinal analysis of brain activity in behaving animals, allowing dissociation of the roles of different brain regions over time during learning of reward-driven instrumental action. The present results offer a unique temporal perspective on how NAc may promote actions directed toward anticipated positive outcome throughout learning, while IFC might suppress actions that no longer result in reward, but only during critical periods of learning.

Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely-moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS−) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS− trials during training and early extinction. In contrast, they were lower during CS+ than CS− trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS− trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging.