Higher cognitive functions such as attention have been difficult to model in genetically tractable organisms. In humans, attentiondistracting stimuli interfere with trace but not delay conditioning, two forms of associative learning. Attention has also been correlated with activation of anterior cingulate cortex (ACC), but its functional significance is unclear. Here we show that a visual distractor interferes selectively with trace but not delay auditory fear conditioning in mice. Trace conditioning is associated with increased neuronal activity in ACC, as assayed by relative levels of c-fos expression, and is selectively impaired by lesions of this structure. The effects of the ACC lesions are unlikely to be caused by indirect impairment of the hippocampus, which is required for mnemonic aspects of trace conditioning. These data suggest that trace conditioning may be useful for studying neural substrates of attention in mice, and implicate the ACC as one such substrate. Selective attention is thought to contribute to conscious awareness, but its neural basis is poorly understood. The search for the neural substrates of attention has been concentrated in the primate visual system (1, 2). Although extremely useful for identifying neural correlates of attention, primates offer limited accessibility for functional perturbation experiments, prompting a search for alternative animal models more amenable to tests of causation. Although some attentional models have been established in rats (3), they depend on operant conditioning paradigms that have proven difficult to extend to mice, and require lengthy training periods.Studies in humans have suggested that attention is required for certain forms of associative learning (4). Associative learning paradigms, such as fear conditioning, have been successfully extended from rats to mice (5). Two commonly used variants of this procedure are delay and trace conditioning. In delay fear conditioning, a conditioned stimulus (CS), such as a tone, is immediately followed by an unconditioned stimulus (US), such as a foot shock. In trace conditioning, a time gap is introduced between the end of the CS and the start of the US. In human eye blink conditioning, another associative learning paradigm, distracting stimuli interfere with trace but not delay conditioning, suggesting that attention is necessary for the former type of learning (4, 6-10). More recent studies have suggested a similar requirement for attention in trace but not delay fear conditioning in humans (11).Potential neural substrates of attention have been identified by functional imaging in humans. For example, attention has been correlated with increased activity in the anterior cingulate cortex (ACC) (12-17). Furthermore, the ACC is preferentially activated during presentation of the conditional stimulus, compared with that of a meaningless stimulus, during aversive trace conditioning (18). The ACC has also been implicated in tasks requiring visual attention in rats (3,(19)(20)(21)(22)(23). Lesion studies have show...

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Three different subtypes of Hϩ -dependent carriers (named VGLUT1-3) concentrate glutamate into synaptic vesicles before its exocytotic release. Neurons using other neurotransmitter than glutamate (such as cholinergic striatal interneurons and 5-HT neurons) express VGLUT3. It was recently reported that VGLUT3 increases acetylcholine vesicular filling, thereby, stimulating cholinergic transmission. This new regulatory mechanism is herein designated as vesicular-filling synergy (or vesicular synergy). In the present report, we found that deletion of VGLUT3 increased several anxiety-related behaviors in adult and in newborn mice as early as 8 d after birth. This precocious involvement of a vesicular glutamate transporter in anxiety led us to examine the underlying functional implications of VGLUT3 in 5-HT neurons. On one hand, VGLUT3 deletion caused a significant decrease of 5-HT 1A -mediated neurotransmission in raphe nuclei. On the other hand, VGLUT3 positively modulated 5-HT transmission of a specific subset of 5-HT terminals from the hippocampus and the cerebral cortex. VGLUT3-and VMAT2-positive serotonergic fibers show little or no 5-HT reuptake transporter. These results unravel the existence of a novel subset of 5-HT terminals in limbic areas that might play a crucial role in anxiety-like behaviors. In summary, VGLUT3 accelerates 5-HT transmission at the level of specific 5-HT terminals and can exert an inhibitory control at the raphe level. Furthermore, our results suggest that the loss of VGLUT3 expression leads to anxiety-associated behaviors and should be considered as a potential new target for the treatment of this disorder.