Jet lag is a temporary disorder that causes fatigue, insomnia and other symptoms resulting from the disruption of the internal body clock (i.e circadian rhythm) when traveling across multiple time zones. It is considered a circadian rhythm sleep disorder that happens when the internal body clock (circadian rhythm) is out of sync with cues pertaining to a new time zone (i.e. light exposure, dining/sleeping times). As someone who has experienced jet lag firsthand, I can attest to how debilitating and disorienting it can be. For example, after traveling to France earlier this year, I got sick, was unable to sleep for about 1.5 weeks, felt tired at random times and had irregular bowel movements. Unfortunately, there is no cure for jet lag and repeated jet lag exposure increases the risk of lifestyle-related diseases involving the cardiovascular system and metabolism.
In humans and other mammals, internal time is controlled by a master clock in the hypothalamus- the suprachiasmatic nucleus (SCN). The SCN has two interesting properties: it is the only part of the circadian axis receiving unique retinal innervation, thereby enabling it to synchronize light-dark cycles; and, SCN neurons can synchronize their molecular feedback loops to one another. Moreover, the output signal from the SCN synchronizes cell clocks throughout the body and is maintained by arginine vasopressin signaling (AVP).
In order to assess a role for AVP signaling in jet lag related symptoms, Yamaguchi and colleagues used a transgenic (KO) mouse lacking two types of AVP receptors (V1a and V1b) and examined behavioral rhythms under experimental jet lag conditions. KO and wild type (WT) mice were maintained in 12 hour light/12 hour dark cycle (LD) and given food and water ad libitum. After two weeks, the LD cycles were advanced by 8 hours. In WT mice, this advance evoked a gradual shift of locomotor activity rhythms, which took 8 to 10 days for complete adjustment to the new LD schedule. According to the authors, “this slow resetting of locomotor activity rhythm—which is characterized by an activity onset that is not synchronous with “lights off” as normally observed, but is delayed into the night—was expected, as it is the typical sign that mice are experiencing jet lag.”
Following the LD cycle advance, WT started their locomotor activity slightly earlier to finally align to the beginning of the night- which took 8 to 10 days. Surprisingly, the V1a/V1b KO mice showed almost immediate adjustment and only needed 2-4 days for alignment. Thus, preventing AVP signaling allowed these mice to experience substantial changes in their normal day-night phases without exhibiting jet-lag behaviors. Furthermore, this effect was not due to disruptions in SCN function due to lack of AVP signaling, as the authors demonstrate AVP-deficient (KO) mice have perfectly good internal clocks: they show pronounced circadian rhythms of behavior, and body temperature under continuous darkness, suggesting that the behavior of these KO mice is still coupled to the internal clock. And then of course, they assessed causation of V1a and V1b receptor activation in contributing to jet lag-related symptoms via pharmacological blockade of these receptors in the SCN of WT mice, which resulted in an accelerated recovery from jet lag.
Taken together, these findings suggest that although the SCN is a precise regulator of circadian rhythm, it has the ability of making enormous large-phase jumps. Also these results highlight the importance of vasopressin signaling and provide evidence that it may be a potential therapeutic target for management of circadian rhythm misalignment resulting from jet lag.
So far this is my favorite 2013 paper, just so you know…