Introduction

Many college students find themselves asking this question. Students wrestle with the thought of whether their exam scores will be better if they stay up all night studying or if they get 8 hours of sleep. Research has found that learning occurs during sleep and is therefore more beneficial to go to sleep than stay up and study. While asleep memory consolidation occurs in the hippocampus by the activation of CRE-mediated transcriptional pathway through REM sleep. Disruption of the circadian oscillations by lack of sleep leads to impaired memory formation.

Sleep stages

While asleep the brain goes through four different stages of sleep each ranging in time and is characterized by different waves and stages of wakefulness. A complete cycle of all stage’s averages about 90 minutes where the cycle repeats all night getting progressively longer through the night. NREM is made up of stages 1-3 and stage 4 is REM sleep.

Stage 1

Stage one is a non-REM stage that makes up 1-7 minutes out of a 90-minute cycle. This stage is characterized by the person falling asleep, slowing brain activity, and relaxing of the body. During this time the brain is experiencing alpha waves. Without any disturbances the quicker an individual can enter stage 2.

Stage 2

Similar to stage 1, stage 2 is also classified as non-REM but can last between 10-25 minutes. Unlike stage 1 that gradually shortens through the night, stage 2 becomes longer and accounts for half the amount of sleep time that night. Brain waves also shift from alpha to theta waves allowing the body to become relaxed, slowing of breathing and heart rate, and a drop of temperature. The brain also starts experiencing bursts of activity, sleep spindles and k complexes, that help the brain block out external stimulation to prevent being awakened.

Stage 3

Stage 3 or slow wave sleep is characterized by delta waves and is still non-REM sleep. At the beginning of the night this stage can last from 20-40 minutes but decreases through the night to allow more time to be spent in REM sleep. During this stage individuals are harder to wake up and are experiencing deep relaxation, a decrease in muscle tone, breathing rate, and pulse. The benefits of slow wave sleep are that it allows the body to grow and recover while strengthening the immune system.

Stage 4

The final stage of a complete sleep cycle is REM sleep. REM sleep occurs 90 minutes into the sleep cycle and time spent in this stage increases throughout the night. While in REM sleep the individual experiences muscle atonia, temporary paralysis, rapid eye movement, fast breathing, and an increased pulse. The brain waves during this stage mimic the brain waves of when the individual is awake, resulting in dreams and memory consolidation.

Memory Consolidation and Learning

The memory consolidation pathway activation has been linked to REM sleep. During REM sleep the brain experiences an influx of calcium ions through NMDA receptor activation. Calcium and cAMP signals activate the MAPK pathway, which activates the Calcium, cAMP, Response Element (CRE) mediate-transcription pathway. The cAMP/MAPK/CRE pathway undergoes a circadian oscillation in REM sleep. When disruption occurs to this oscillation memory persistence is impaired. Therefore, consistent and quality sleep is imperative to allow for memory formation to occur and to solidify concepts while asleep.

Conclusion

To solidify memories and gain a better understanding of a topic it is best to sleep on it. By going to sleep the body enters REM sleep where the cAMP/MAPK/CRE pathway is activated. The continuous activation of this pathway allows for the consolidation of memories. Therefore, instead of studying all night and trying to memorize information it is better to read it over and go to sleep and let your brain consolidate the information for you, allowing you to remember information for the exam and not suffer from sleep deprivation.

References

[1] Saini, R., Jaskolski, M. & Davis, S.J. Circadian oscillator proteins across the kingdoms of life: structural aspects. BMC Biol 17, 13 (2019). https://doi.org/10.1186/s12915-018-0623-3

[2] Suni, Eric. Stages of sleep. Sleep Foundation (2023). https://www.sleepfoundation.org/stages-of-sleep

[3] Xia, Z.; Storm, D. (2017). Role of circadian Rhythm and REM sleep for memory consolidation. Neuroscience Research 118, 13-20. https://doi.org/10.1016/j.neures.2017.04.011

What is the endocannabinoid system?

The endocannabinoid system is a neuromodulatory system that is important in the central nervous system for the role it plays in maintaining synaptic plasticity and homeostasis in the brain. This system controls mood, pain, perception, learning and memory, along with other things as well. It also has a neuroprotective role during traumatic brain injuries. An important part of the endocannabinoid system includes the cannabinoid receptors CB1 and CB2 along with a few others. The CB1 receptor has been connected to pathophysiological events ranging from memory deficits to neurodegenerative disorders. The CB1 receptor, therefore, is very important in maintaining well-being. But what is the CB1 receptor exactly that makes it so important for human health? It is one of the most commonly found G protein coupled receptors in the central nervous system, specifically in the neocortex, hippocampus, basal ganglia, cerebellum, and brainstem. A receptor found in such high quantities is bound to play a very impactful role in brain homeostasis. They specifically bind to cannabis sativa, more commonly known as marijuana and THC. On the other hand, CB2 receptors have a more defined pattern of expression and are primarily found in cells and tissues of the immune system. CB2 receptors are associated with inflammation and are localized to microglia.

Cannabis

THC and CBD (cannabidiol) are both cannabinoids that are derived from cannabis plants. While CBD does not produce the high sensation often associated with cannabis, THC absolutely does. THC is a cannabis that has over 60 ligands for CBs, so exposure to it can cause paradoxical effects in humans like relaxation, dysphoria, tolerance, and dependence. However, these effects are blocked with a selective blocker of CB1 receptors. This is because THC must bind with the CB1 receptors to produce a sense of euphoria. Furthermore, THC has positive effects on spasms and pain associated with MS. THC may show improvement in those with multiple sclerosis due to the link between CB1 and CB2 receptors and anti-inflammation effects in CNS. For other common medical purposes, THC has benefits to reduce pain, insomnia, low appetite, nausea, anxiety, etc. However, people might prefer CBD over THC because of the lack of side effects that can occur with THC. CBD has also been shown to help with conditions like seizures, inflammation, pain, mental disorders, migraines, depression, and anxiety.

A long history

Cannabis has been around for quite a long time in different cultures across the world. Cannabis was officially attested to nearly 12,000 years ago near the Altai Mountains in Central Asia. South-East Asia has also been proposed as an alternative region for the primary domestication of cannabis where it was used for fibers for ropes and nets, food, and seeds for oil. However, as for medical purposes, the earliest records point to usage in China. The discovery of the curative
properties of these plants was said to be made by Shén Nóng, a mythical emperor whose name means the Divine Farmer in the 20^th century BC. Later, Europe rediscovered the medicinal and psychoactive properties of cannabis through the translation of Arabic books and manuscripts followed by the scientific observations made by physicians of their time. Eventually, Western medicine became quite popular in the late 19^th and early 20^th century. During this popularization, Queen Victoria took cannabis for cramps, while Empress Elisabeth of Austria took it for cough and appetite stimulation. While it was used often in the past, it is sort of a taboo in our current American society. Today, telling a friend you took cannabis for cramps may raise some eyebrows. Nevertheless, it is still making a comeback for its medical purposes in the healthcare system today.

Conclusion

The endocannabinoid system, composed of two primary receptors CB1 and CB2, is important in brain homeostasis. Cannabis has been around for centuries and while research on it has not been done in depth, there is enough proof of the effects that it can have on human health and well-being. For years, cannabis has been medically used in different regions of the world. Today, it is making a medical use comeback, although it also has negative side effects that make people hesitant on relying on it for medicine.

Citations

1. Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid receptors in the central nervous system: Their signaling and roles in disease. Frontiers in Cellular Neuroscience, 10. https://doi.org/10.3389/fncel.2016.00294
2. Hiding in plain sight: The discovery of the endocannabinoid system // International League Against Epilepsy. (n.d.). Retrieved May 2, 2023, from https://www.ilae.org/journals/epigraph/epigraph-vol-21-issue-1-winter-2019/hiding-in-plain-sight-the-discovery-of-the-endocannabinoid-system
3. The endocannabinoid system: How cannabinoids take effect. (2019, November 15). https://www.encore-labs.com/the-endocannabinoid-system-how-cannabinoids-take-effect
4. Holland, K. (2020, July 20). CBD vs. THC: What’s the difference? Healthline Media. https://www.healthline.com/health/cbd-vs-thc
5. Crocq, M.-A. (2020). History of cannabis and the endocannabinoid system. Dialogues in Clinical Neuroscience, 22(3), 223–228. https://doi.org/10.31887/DCNS.2020.22.3/mcrocq

Nootropics

Nootropics are defined as molecules that aim to improve cognitive functions. You may have heard of them being referred to brain supplements or enhancers. There are several natural and synthetic molecules on the market that claim to have brain enhancing effects. But in order to talk about these nootropics we first need to understand what cognition is, and what it means to have enhanced cognition.

What Is Cognitive Function?

Cognitive function is a term used to describe someone’s ability to perform a variety of social and intellectual functions. There are 6 neurocognitive domains that the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines (1):

1. Perceptual and Motor Function: one’s ability to coordinate their bodies movements in response to their environment, and ability to interact with the environment.
2. Language: the ability to communicate through writing or speaking, our grasp on grammar and appropriate speech patterns.
3. Learning and Memory: the ability to record and recall information from the past. This involves many subdomains like working memory, and short term and long term memory.

   

4. Social Cognition: the ability to processes, remember, and use information in social contexts to explain our own behavior; or to predict the behavior of others. Recognizing social cues and understanding facial expressions are good examples.
5. Attention: ability to focus on multiple things at once, as well as the ability to prioritize what to pay attention to.
6. Executive Function: higher level functions that allow us to plan and organize tasks, as well as make decisions and respond to our environment.

Many intellectual disabilities are characterized by a reduced ability to perform some or all of these cognitive functions. Research into nootropics to enhance these functions could potentially be used as as a way to combat intellectual disabilities.

Natural Nootropics

L-Theanine

L-theanine is an amino acid that is found in green tea but can also be bought in capsule or pill form as a supplement. L-theanine when taken on its own has been shown to improve self-reported relaxation, and induce a state of calmness with a dosage of 200mg (2).

Caffeine

Caffeine has long been known to decrease drowsiness, due to its ability to bind to adenosine receptors in the body. However it’s also been shown that caffeine can improve performance during long lasting cognitive tasks at doses of 40mg (2).

When taken together L-theanine and caffeine improved performance in attention-switching tasks and in alertness (3). However these are ‘moment of’ improvements, as I like to call them. They will improve function when taking them, but there aren’t any long term effects these compounds have in the body that will improve cognitive function in the long run or permanently.

Synthetic Nootropics

Ampakines

Ampakines are a group of drugs that increase excitatory synaptic responses in the brain. Because of this effect they facilitate long-term potentiation (learning), and induce the production of a family of molecules called neurotrophic factors, which help improve various brain functions and growth (4).

Modafinil

Modafinil is a prescription drug that is often used to treat narcolepsy. Tt has stimulating effects similar to amphetamines, though it has a lower risk of addiction. Modafinil has been shown to improve reaction time, logical reasoning, and short term-memory when compared to a placebo (5). The exact mechanisms of how modafinil enhances these cognitive functions is unknown, however.

References

1. https://altoida.com/blog/defining-the-6-key-domains-of-cognitive-function/#:~:text=Defining%20the%20Six%20Key%20Domains%20of%20Cognitive%20Function,of%20Neurocognitive%20Function%20to%20Improve%20Disease%20Diagnostics%20

2. Effects of Green Tea Phytochemicals on Mood and Cognition, https://pubmed.ncbi.nlm.nih.gov/28056735/

3. https://www.healthline.com/nutrition/nootropics#12.-Modafinil-(Provigil)

4. Ampakines and the Threefold Path to Cognitive Enhancement, https://pubmed.ncbi.nlm.nih.gov/16890999/

5. Modafinil, D-Amphetamine, and Placebo During 48 Hours of Sustained Mental Work, https://pubmed.ncbi.nlm.nih.gov/16890999/

What are Nootropics?

Nootropics are chemicals that are meant to help support the functioning of the brain. These can be either synthetic drugs commonly referred to as “smart drugs” or they can be found in certain foods. These chemicals help activate cognitive functioning and support things such as learning and memory. They also have neuroprotective effects, which means that they help to keep the neurons from dying of either damage or apoptosis. Apoptosis refers to programed cell death that happens when a neuron stops working correctly. These drugs can also help to protect neuronal protein and nucleic acid synthesis, both of which are important for a neuron’s survival (Malik & Tlustos, 2017).

These drugs can be used to enhance the cognitive functioning of healthy individuals and possibly could delay the onset of neurodegenerative disorders. Though more research is still needed to confirm their usefulness in delaying the onset of neurodegenerative diseases. But these drugs could also possibly be used to treat memory and learning disorders. Though the gains that can be achieved via the use of these drugs seems to be dependent on the severity of the disorder (More, Lauterborn,  Papaleo, & Brambilla, 2020).

How are Nootropics Studied?

Nootropics are an important thing to be studied as they have the possibility to help a lot of people. But they can’t be studied on human participants until their safety and efficacy as been established in animal models. Animal models are animal subjects that share certain characteristics with humans that allow them to act as stand ins for humans. For instance mice and rats have several neuronal similarities with humans that make them a good model for neuroscience research. But when studying nootropics it is important to establish how measure their cognition in comparisons for humans.

There are six neurocognitive domains that are used to examine cognition in humans: 1) perceptual and motor function, 2) language, 3) learning and memory, 4) social cognition, 5) attention, and 6) executive function. There are certain tests used in rodent models to determine their ability in each of these domains. Here I will go over three of these tests (More, Lauterborn,  Papaleo, & Brambilla, 2020).

The first test is called the Digging Task and this is used to measure their discrimination skills requires adequate perceptual and motor function. For this task the rodents are conditioned to associate a certain sent with a treat. They are then put in a box with two separate cups of sand, with each cup being a different sent. The subject must decide which cup to dig in to get the treat. It was found that subjects with bilateral frontal cortex damage had more difficulty with this task than the control subjects (Dig Task, 2023).

(Dig Task, 2023)

The next task is called the Continuous Performance Test which is used to measure attention. This test was originally designed for humans and then was modified for rodents for preclinical trials. For this task rodents are put in a box with a screen and are shown five black and white stimuli. Before the trials begin the subjects are conditioned to associate one of the pictures with a reward. They have to watch the pictures as they cycle through until they see the one associated with a reward. They then need to interact with that stimulus in order to get their reward. Subjects who struggle with reacting to the appropriate stimulus have deficits in attention (Rodent continuous…).

(Rodent continuous…)

Finally there is the Three Chamber Social Approach Task, which is used to determine if the rodent has any deficits in social functioning. This task involves putting the subject in a three chamber box where it can move freely between all the chambers. In the two side chambers there are wire cages. First there is a stranger rodent put in one of the wire cages. If the subject in socially functional it will spend most of its time interacting with this first stranger rodent. Then a second stranger rodent is put in the cage on the other side. Again if the subject is socially functional it will want to investigate this new rodent and spend most of its time interacting with the new rodent (Maze Engineers, 2018).

(Neural Circuits and behavior core) 

References

Dig task. Maze Engineers. (2023, February 10). Retrieved May 2, 2023, from https://conductscience.com/maze/portfolio/dig-task/

Malik, M., & Tlustos , P. (2017). Home – PMC – NCBI. National Center for Biotechnology Information. Retrieved May 2, 2023, from https://www.ncbi.nlm.nih.gov/pmc/

Maze Engineers. (2018). The Sociability Chamber: A Test of Social Approach. Retrieved May 2, 2023, from https://www.google.com/search?q=the%2Bthree%2Bchamber%2Btask&rlz=1C5CHFA_enUS926US931&sxsrf=APwXEdeWCW9JDhzNhRtr60NdnGcoM1VX7w%3A1682473366665&source=lnms&tbm=vid&sa=X&ved=2ahUKEwiAqvTatcb-AhUtjYkEHTtUCqgQ_AUoAnoECAEQBA&biw=1438&bih=690&dpr=2#fpstate=ive&vld=cid:d298c613,vid:HJjanD_Mk9c.

More, L., Lauterborn, J. C., Papaleo, F., & Brambilla, R. (2020). Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders. Neuroscience and Biobehavioral Reviews 110. 28-45. https://doi.org/10.1016/j.neubiorev.2019.02.003.

Neural Circuits and behavior core. Social Behavior | Neural Circuits and Behavior Core. (n.d.). Retrieved May 2, 2023, from https://ncbc.medicine.uiowa.edu/equipment-fees/equipment/behavior/social-behavior

Rodent continuous performance task: Image (rCPT) for mice. Neuroscience by Lafayette Instrument Company. (n.d.). Retrieved May 2, 2023, from https://lafayetteneuroscience.com/products/image-cpt-mice/