NRSC 4132 Blog

Energy drinks have taken the general public by storm; in fact, last year marked a $10 billion revenue generated from the energy drink market. Today, nearly every grocery store and gas station is stocked with the likes of Rockstar, Monster, Red Bull, and 5 Hour Energy, to name a few. From the frantic college student cramming in the wee hours of morning for the approaching exam to high-level execs trying to squeeze out a few more hours to complete a business strategy, energy drinks have found their stead among thousands striving to increase productivity. Hence, it comes as much needed news that scientists may have discovered cells responsible for arousal. Interestingly, these cells may also affect depressive states.

A recent study in the Journal of Neuroscience by Ronald McGregor et. al (http://www.jneurosci.org/content/31/43/15455.abstract) analyzes the role of Hypocretin (Hcrt) neurons in arousal and performance of operant tasks in mice. Several research precedents have shown that dysfunction/lesioning of Hcrt neurons produces narcolepsy, while administration of Hcrt results in arousal effects. However, no studies have examined the dependency of Hcrt neuron activity on the nature of the operant task being performed, and the diurnal phase (light or dark) during performance. To address this issue, McGregor et. al examined arousal and Hcrt neuron activity in Hcrt-knockout (KO) and wild-type (WT) mice as they performed operant tasks in both light and dark phases.

A variety of positive and negative reinforcement behavioral tasks were assessed. Positive reinforcement tasks consisted of mice in operant conditioning cages that pressed a lever for the administration of a food pellet. After each reward, the number of lever presses required to issue the food pellet was increased by one to get the successive pellet. A similar regimen was used for the self-administration of water as well. Control experiments were conducted with expected and unexpected food outcomes, whereby mice received a food pellet each time they pushed the lever or were unexpectedly given ample food, respectively. Negative reinforcement tasks consisted of shock avoidance. All of these behavioral tasks were conducted in two phases: light and dark. Arousal was measured using EEG and EMG, and Hcrt/Fos expression was examined in lateral, medial, and perifornical hypothalamic tissues (where Hcrt neurons are located) using immunohistochemistry staining.

Interestingly, the results show that Hcrt neurons only affect performance on positive reinforcement tasks. During positive reinforcement tasks, KO mice exhibited "pauses" whereby they assumed crouched positions that prevented lever pressing. EEG readings show that this state was most similar to non-REM sleep, and likely represents a state of lingering drowsiness. EMG readings reveal partial but not complete muscle atonia, as is characteristic of REM sleep, again supporting the conclusion that KO mice were unable to perform the task due to severe drowsiness as is often seen in narcoleptics. Interestingly, KO mice exhibited dramatically improved performance on operant tasks conducted in the dark relative to those in the light, indicating that Hcrt-depletion is light dependent as well! This is further confirmed by Hcrt/Fos staining, which revealed increased expression in Hcrt neurons during light phases but basal levels during dark phases. Taken together, these results suggest that Hcrt-neurons cause arousal when waking from sleep in the morning (onset of light phase) and motivate performance on positive reinforcement tasks.

The symptoms of the KO mice described closely resemble that of a narcoleptic; severe drowsiness during the day (light phase), and reduced performance on positive reinforcement tasks. The latter has been closely linked to the common occurrence of depression in narcoleptics. A study by Henriques and Davidson (2000) reported that depressed patients worked as hard as controls to avoid losing money, but did not work as hard as control to obtain/gain money. In other words, depressed patients showed unimpaired performance on negative reinforcement tasks, but did not perform well on positive reinforcement tasks. This characterizes McGregor et. al's findings in the Hcrt-KO mice. This explains why narcoleptics (who are often Hcrt-depleted) often develop depressive states.

Perhaps one day, energy drinks will be replaced by Hcrt pills and drinks. They will function to increase Hcrt levels in the hypothalamus, increasing wakefulness and our productive drive during the day, with potential therapeutic benefits against depression.