Hypocretin levels has been shown to correlate with states of attention and arousal,15 with high levels observed during alertness and periods of physical activity.27-29 By inducing ectopic spikes in thalamocortical terminals, prefrontal hypocretin has the potential to affect alertness and attention in vivo. Our results raise questions about the regulation of hypocretin within the prefrontal cortex and in the midline-intralaminar
Figure 12. A schematic showing thalamic inputs to a prefrontal layer V pyramidal neuron can be excited different neurotransmitters: hypocretin excites through hypocretin receptor 2, serotonin through 5-HTM receptors (although unclear whether these receptors are pre- or post-synaptic), norepinephrine through a1 receptors, and acetylcholine through the high-affinity a4p2 nicotinic receptors. This synapse can also be inhibited by enkephalin through mu-opioid receptors, glutamate through group 2/3 metabotropic glutamate (mGlu) receptors, and adenosine through A1 adenosine receptors.
thalamus in healthy subjects. For example, does hypocretin increase in prefrontal cortex during tasks that require attention?
Recently it has been shown that patients with narcolepsy - who lack hypocretin -have selective deficits in the prefrontal or executive attention network.30 While older literature suggests that cognitive deficits in narcolepsy may simply be a result of tiredness, Rieger and colleagues show that the selective deficit in divided attention persists affect controlling for alertness.30 Furthermore, another recent study has showed abnormal frontal cortex physiology in narcoleptics during pre-attentive and attentive tasks.31
Similar to hypocretin, nicotine excites high-affinity nicotinic acetylcholine receptors on thalamocortical terminals and results in a large increase in glutamate release onto prefrontal layer V pyramidal neurons.32 Interestingly, nicotine has repeatedly been shown to enhance attention. While this effect has mainly been demonstrated with systemic administration of nicotine, a recent study showed that direct infusion of nicotine into prefrontal cortex improves performance of rats on a task of divided attention.33 It would be fascinating to study the effect of hypocretin infused into prefrontal cortex in this manner.
Multiple neurotransmitter systems work together at thalamocortical synapses in prefrontal cortex to regulate alertenss and attentional state. In addition to hypocretin, there is evidence to suggest that acetylcholine,32 serotonin,34-36 and norepinephrine35 all can excite thalamocortical synapses. Neurotransmitters that can inhibit this synapse include enkephalin,34 adenosine,37 and glutamate.38 Interestingly, hypocretin neurons project not only to prefrontal cortex but also to the raphe and locus coeruleus,12 the source of serotonin and norepinephrine respectively. The interrelationships among these different neurotransmitter systems under varying physiological states remains to be determined.
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