In this section, we’re discussing the circadian rhythm to prepare for sedative medication discussion. We will go over the anatomy and physiology of circadian rhythms.
What are circadian rhythms and their functions?
Many of our physiological processes work according to the daily cycle that moves according to the environmental time cues or “zeitgebers.” For mammals, our zeitgeber is the dark and light cycle. Light and darkness trigger the nucleus in our suprachaismatic nucleus (SCN), the area responsible for our biological clocks, into the neuronal firing of our brain.
Most circadian rhythms are around 24 hours. Below are a few terms that we need to be familiar in this discussion:
- Entrainment: when our body is trained to a certain time stimulus
- Phase shift: when our body has to shift our biological clock, “jet lag”
- Free running: when our body still generates rhythms in the absence of cues, usually 25 hours
- Ultradian: when the cycle is short and happens multiple times in the 24 hours period
- Infradian: when the cycle is long and happens less than once in the 24 hours period.
Our body needs to have a biological clock to allow resources to be used efficiently, and it’s important for health. This biological clock is regulated through a multi-level regulatory network involving cyclical gene transcription, protein turner, feedback pathways, and cells with cyclic outputs.
Almost every biological process in our body is altered according to the biological clock. For example, our cortisol is higher in the morning. Insulin peaks at a certain time in the morning as well. When our biological clock is impaired, it leads to a lot of health issues. Unfortunately, as we age, our biological clock becomes more impaired, which is why elderly patients have a lot of problems with their sleep schedule. Other groups of patients that might have problems with their biological clock are patients with neurodegenerative disorders and chronic or critically ill patients.
Biological Clock Players
There are a lot of players, but the three main ones are:
- The Trigger: Light
- The Coordinator (pacemaker): cells that coordinate the cycle and maintain a consistent cycle –> The cells in SCN.
- The Response: Cells that regulate physiological response to the information sent by the pacemaker.
Let’s get to know the SCN a little bit more. These clusters of neurons are located on both lobes of the brain around the third ventricles. There are roughly 20,000 neurons, and they are connected directly to the retinas. So as light comes in and passes through the retina, the CNS is triggered and fires in a certain rhythmic frequency. This signaling is regulated throughout the body, and the response is synchronized.
There was an experiment that measured the activity of mouse SCN during the day and night time. They discovered that the SCN is actively firing during the day and quiet during the nighttime. So, SCN provides information about the time of day to the rest of the brain and body.
Retinohypothalamic Tract and Melanopsin
Let’s take a closer look at the retina. Inside there is a cluster of cells called the retinal ganglion cells (RGCs). These cells contain a photosensitive pigment called melanopsin.
Melanopsin is a G-protein coupled receptor that is activated through photoisomerization (isomerization caused by light excitation). It sends a signal through the highway connected to SCN, called the retinohypothalamic tract (RHT), and delivers the signals to SCN.
A side note on photoisomerization. When light hits the melanopsin receptor, the 11-cis retinal, which is bound covalently to a melanopsin protein receptor, is isomerized to all-trans, dissociated from the G-protein, and activates the G-protein coupled receptor. Upon activation, the G-protein further activates the PLC-B signaling pathway through a secondary messenger, which sends the signal to SCN.
So, where we’re at right now is the signal from melanopsin is sent through the RHT to SCN. Once the signal arrives at the SCN, it triggers a release of pituitary adenylate cyclase-activating polypeptide (PACAP) and glutamate. These two further move to bind to PAC2 and NMDA, respectively, on the SCN neuron.
Ultimately, both of these signaling pathways’ goal is to enhance NMDA and glutaminergic signaling, leading to an increase in the activity of SCN neurons. We know how glutamate does this, but let’s look and see how PACAP does this. PACAP binds to PAC2 and induces phosphorylation of the NR2B subunit of the NMDA receptor.
The Wonder that is SCN
So now that the SCN is activated, both the PAC2 and NMDA receptors further the signal into the neurons through cAMP –> PKA in the PAC case and Ca –> CaMK in the NMDA case. This leads to the turning on of multiple clock genes and clock proteins that ultimately lead to GABA release from SCN and stop the action of PVN in the hypothalamus.
So what is the action of the PVN of the hypothalamus?
Normally, in the dark, this signaling pathway is turned on because it is not inhibited by the SCN. When there is no GABA from SCN, the PVN of the hypothalamus continues to signal to the ILCC and SCG neurons. This activates the cAMP signaling pathway in a cluster of cells in the pineal gland to convert serotonin into melatonin. Due to the pineal gland’s unique location, melatonin is able to just be released into the capillary and to the rest of the body.
One of the actions of these melatonins is to perform a negative feedback role on the SCN’s receptors, MT1 and MT2, to further inhibit the action of SCN and allow PVN to perform.
MT1 and MT2 are G-protein coupled receptors. MT1 is the G-inhibitory receptor, and MT2 is the Gq receptor. As mentioned before, melatonin binds to these receptors and signals the SCN that it’s currently nighttime. SCN is able to help establish synchronization in the body and help stabilize the circadian rhythm.
What’s the difference between MT1 and MT2? MT1 is responsible more for sleep onset. MT2 is responsible more for the phase-shifting effects of melatonin.
The Clock Gene
The clock gene is activated inside the SCN when the light signal arrives from the retina. Over time, the clock mRNAs translated to proteins in a cyclical manner. There are two transcription factors that play a major role in this: clock and Bmal1 proteins. These two dimerized and clamp onto the promoter region on the gene called the Cry and Per gene.
One thing to note is that the clock gene is not exclusively just in SCN but in other tissues as well. When there is a mutation in the clock gene, it can cause an altered circadian rhythm, psychiatric disorders, addiction, obesity, and cancer.
Pineal Gland
The pineal gland is a very small pine-cone shape gland. Similar to the thymus, it is much larger in children than in adults. The size begins to shrink at the onset of puberty, but unlike the thymus, we still have the pineal gland as an adult!
The pineal gland is located between 2 cerebral hemispheres, right on top of the midbrain, and is hidden by the cerebellum. It is uniquely suspended with CSF, which means that it has no blood-brain barrier. Being suspended with CSF is why it’s also called the circumventricular organ, where it receives oxygen and nutrient through the vascular network still. The primary neurotransmitter that pineal cells utilize is norepinephrine.
The synthesis of melatonin occurs inside the pinealocytes or the neurons of the pineal glands. This begins with a serotonin molecule. An enzyme called 5-HT N-acetyltransferase converts serotonin to N-Acetyl serotonin, which is converted to melatonin by 5-hydroxy-indole-O-methyltransferase. As with serotonin synthesis, the rate-limiting step of this is the tryptophan hydroxylase.
As you can tell, the major function of the pineal gland is melatonin production. Melatonin helps to regulate daily body rhythms, circadian rhythm, and wake/sleep cycle. The activity of the pineal gland depends on the amount of light energy.
There is an abundant level of melatonin in children that further inhibits the secretion of gonadotropin. This is what stop puberty, which prevents the early onset of puberty before the appropriate age.
Melatonin is secreted during the night. It cannot be stored due to its lipophilic nature, so it has to be synthesized as needed. Typically, the onset of secretion is around 8 PM to 2 AM, and the offset is between 7 AM to 9 AM. Over time, melatonin secretion becomes entrained to anticipate the onset of darkness and the approach of daylight. This is called entrainment.
As we age, the amount of melatonin decline. In older people, the production of melatonin is almost negligible, which is why sleep is a big problem in the elderly.
Medications that Disrupt Circadian Rhythms
- Stimulants
- Depressants
- Benzodiazepines
- Barbiturates
- Antihistamine
- Antidepressant