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.

When stressed, many people eat less, citing lack of time or simple forgetfulness as the reason they skip meals or eat less often when they have looming deadlines. What if, when stressed, people get less enjoyment out of their meals? Recent studies have shown that taste disturbances resulting from anxiety or depression may play a role in lower appetite. When we are anxious, we simply cannot taste food as well as we normally would.

Until the last 20 years or so, taste thresholds were thought to be invariable; genetics determined taste threshold, meaning people could range anywhere from a non-taster to a supertaster. Surprisingly, it has come to light that taste thresholds are far more plastic and variable than previously thought. In the first research studies on taste in depressed patients, it was found that depression resulted in decreased sensitivity to all tastes, but to sweet tastes in particular. Those with panic disorder and average people with induced stress tend to be more sensitive to bitter tastes. These taste disturbances seem to be linked to alterations in serotonin (5-HT) and noradrenaline (NA). 5-HT and NA alter ion channel function, resulting in a change in the excitability of taste cells. As a result of this research, in a 2006 study, Heath et al focused on 5-HT and NA in an attempt to determine the link between these monoamines, mood, and taste.

Heath et al studied taste responses to sweet, bitter, salt, or sour tastes in subjects who had no previous history of depression or anxiety and who were not using psychotrophic medication. Taste perception was measured before and after administration of a 5-HT reuptake inhibitor (SSRI, a common ingredient in antidepressant and anti-anxiety medications), a NA reuptake inhibitor (NARI, which treats depression), or a placebo (lactose). Findings indicated that SSRIs significantly increased bitter and sweet taste sensitivity (i.e. these taste thresholds were reduced), while NARIs increased bitter and sour taste sensitivities. Interestingly, neither drug affected salt taste.

So how exactly can SSRIs and NARIs modulate taste? In an earlier model, part of the mechanism was proposed, with additions by Heath et al. First, receptor cells release ATP (which can function as neurotransmitter) as a result of increased intracellular calcium. Next, ATP activates receptors on presynaptic cells, causing an increase of calcium in presynaptic cells, followed by 5-HT release. Heath et al further suggest that serotonergic feedback from presynaptic cells to receptor cells occurs. The 5-HT released from presynaptic cells binds to receptors on the receptor cells, exerting its effects by volume transmission. SSRI administration blocks 5-HT transporters on both receptor and presynaptic cells and enhances 5-HT signaling, and therefore enhances bitter and sweet tastes. On the other hand, NA can act either as a transmitter released onto gustatory afferent axons or by modulating the action of ATP.

In addition to taste perception due to monoamine manipulation, Heath et al studied the relationship between taste and mood. Although all subjects were in the clinically healthy range for Spielberger State and Trait questionnaire (which represent anxiety levels) and Beck's Depression Inventory, some subjects scored on the high range of the Spielberger Trait questionnaire, meaning that they had higher anxiety levels than the other subjects. The more anxious subjects had lower taste sensitivities to bitter and salt tastes. All patients scored very low on depression, so a relationship between depression and taste perception could not be determined. Since 5-HT or NA manipulations do not alter salt thresholds, this effect would need to be studied further.

The next time you get stressed out, think about whether your food seems to taste different than it normally does.

Main article: http://www.jneurosci.org/content/26/49/12664.full.pdf+html