Cobbers on the Brain

 

The Connection Between Memories and Stress

Memory formation, consolidation, and retrieval are vital functions of a healthy life. When psychologically stressful events occur, memory formation is extra vital. Evolutionarily, the reason for this is to either avoid the stressor in the future or know how to react if the stressor is encountered again at a later time. Psychologically stressful events are difficult to avoid, yet only 10-20% of the population develops a stress related disorder (such as post-traumatic stress disorder, depression, and anxiety) following an extremely stressful event [1]. Maladaptive stress memory formation could be due to overactive signaling pathways. Stress can alter memory formation through changes in gene transcription as a result of these signaling pathways.

Multiple mechanisms and processes can play a role in the expression of stress-related mental disorders. These mechanisms are related to the stress response as well as the formation and retrieval of memories. This is specifically observed within the dentate gyrus, a region of the hippocampal formation within the medial temporal lobe that is associated with autobiographical and episodic memories [2].

Genetic Responses to Stress

Gene transcription changes can be observed in the dentate gyrus neurons in response to stress. These changes are triggered by environmental challenges that stimulate extracellular signals such as glucocorticoid hormones and glutamate. The extracellular signals begin the biochemical process of stress-related memory formation. Stressful events stimulate phosphorylation of S10 and acetylation of K14 in a dual histone mark called H3S10p-K14ac within fos and egr1 gene promoter regions within the dentate gyrus. This suggests that H3S10p-K14ac histone marks are related to promoters of immediate-early genes C-fos and Egr-1 which are stimulated by psychologically stressful events. In rats, a forced swim test is a significant stressor which triggers expression of these dual histone marks in the dentate gyrus [1].

Signaling Pathways Associated with Stress

The NMDA receptor-mediated ERK-MAPK pathway is involved in learning and memory. This pathway is activated by a glutamate ligand binding to the NMDA receptor. This is an excitatory process which stimulates C-fos and Egr-1 gene transcription through H3S10p-K14ac activation within the dentate gyrus. It has been found that NMDA receptor antagonists and MAPK pathway inhibitors strongly inhibited H3S10p-K14ac and the expression of immediate early genes in the dentate gyrus. This demonstrates that a MAPK pathway is related to H3S10p-K14ac and the development of symptoms of high anxiety [1].

Glucocorticoids and glucocorticoid receptors are also active in the immediate-early time domain following a stressor. The GR acts as a scaffold to properly phosphorylate ERK and MSK when faced with psychological stress. This results in the same gene transcription process as the NMDA receptor pathway, as shown in Figure 1.

To provide further evidence for this theory, GABAergic drugs have been shown to block the expected H3S10p-K14ac activation and c-Fos responses to stressful events, leading to decreases in anxiety. This is a logical discovery because GABA plays a modulatory role in the response of dentate neurons to anxiety. This evidence supports the theory that overactive glutamate and glucocorticoid pathways which stimulate H3S10p-K14ac activation and anxiety could be key mechanisms by which stress-related disorders develop following a psychologically stressful event. Anti-anxiolytic effects from changes in GABA signaling can also be shown through a non-pharmacological intervention in the form of exercise. Exercise in rats was shown to decrease anxiety, increase GABA synthesis capacity, and reduce ERK-MAPK signaling and immediate early gene (c-Fos, Egr-1) transcription in the dentate gyrus [1]

Conclusion

There are many factors that contribute to a person’s susceptibility to a stress related disorder such as baseline anxiety levels and neural activity, previous trauma, environment, and genetics. In addition to these factors, the strength of both glucocorticoid receptor signaling and NMDA glutamate receptor signaling in the dentate gyrus could be key areas of modulation that could alter the stress-related memory response. This occurs through the transcription of the specific immediate early genes C-fos and Erk-1 which are promoted by H3S10p-K14ac histone marks. The activity of these pathways can be decreased through increased GABA synthesis and signaling. Both pharmacological and nonpharmacological interventions have been shown to improve symptoms of anxiety by increasing the activity of GABA, thereby decreasing the transcription of C-fos and Erk-1 [1].

References:

Thinking back on all the classes I have taken so far in my undergraduate education at Concordia, this Neurochemistry course has been one of a kind. It is so satisfying to be able to use the material learned in basic science classes to discuss real world diseases and disorders by looking into all kinds of research. As a student who is on the pre-health profession track, learning about diseases that you hear about everyday was extremely valuable. Not only was the material thoroughly engaging, but it also sparked a new interest in research that I hadn’t had before. I learned to really appreciate the type of learning I was doing even though it wasn’t the typical listen to a lecture, take notes, and then take an exam format most science classes embrace.

The learning I did this semester was not only about mechanisms and biochemical pathways of diseases and disorders, but being able to read research articles and discuss them in such detail provided me with practice in reading and understanding up to date research skills, technologies and techniques, and diagnostic procedures. I learned how to ask and answer questions about highly advanced scientific data and perform my own research about topics to present in an understandable way to my peers.

I really enjoyed the format for the exams as well. I loved being presented with puzzle pieces and figuring out which pieces were needed to form the correct picture. It gave me confidence in what I had learned and that I could apply it to real world problems and provide a correct hypothesis. I think that is a very important skill to practice as someone who aspires to be able to diagnose problems observed in patients.

Being a health professional is not just about being able to diagnose a problem effectively, but to educate patients to encourage proper care and better health outcomes. It is important to be able to relay information to others who do not share a common background in a way that is appropriate and understandable to them. Discussing advanced material with my peers throughout the semester has been a good way to prepare for these types of conversations.

These discussions also raised some ethical questions that need to be considered. Hearing these questions and listening to how others respond based on their own ideas and cultural beliefs was a very beneficial experience and helped to open my eyes and broaden my thoughts about the ways that these types of questions can be addressed. It is important to see different perspectives when dealing with an ethical issue, but it is equally important to provide factual information for the patient to make the best, informed decision for them.

Learning at a liberal institution means that you will not only find success in academics, but will become the best, well-rounded version of yourself that you can be. Concordia’s main goal is to prepare students to become responsibly engaged in the world and by shaping you into the best version of yourself as a whole is just one way that goal becomes a reality.

 

 

Glioblastoma (GBM) is a cancerous brain tumor. GBM is a grade IV cancer with the prediction of a 14-month survival period upon diagnosis for most cases and a 5-year survival prediction in less than 5% of cases [1].  Glioblastoma can be divided into two main categories, primary and secondary GBM. Secondary tumors develop from pre-existing lower grade tumors whereas primary tumors develop on their own. An example of secondary glioblastoma can be from an overgrowth of astrocytes.  Diffuse astrocytoma (grade II) can develop into anaplastic astrocytoma (grade III) which then goes on to develop into glioblastoma (grade IV) over the course of several years [1].

Types of GBM

There are four main types of glioblastomas. Classical GBM is associated with the overexpression of the growth factor receptor gene EGFR and the tumor suppressor protein TP53. Mesenchymal GBM is associated with alterations in specific components of the PI3K and MAPK pathway, NF1, a negative regulator of the MAPK pathway, and PTEN, a negative regulator of the PI3K pathway. Both classical and mesenchymal GBM best respond to aggressive treatment forms. Proneural GBM is most commonly found in younger patients and has to do with an amplification of a platelet growth factor gene, PDGFRA, found on chromosome 4q12. This form of GBM is less responsive to aggressive treatment. Lastly, neural GBM does not have any obvious mechanistic patterns but is associated with the expression of neuronal genes. This form has the shortest survival rate.

Invasiveness of GBM

GBM is a very invasive cancer, causing treatment to be difficult. Complete surgical removal of the tumor is nearly impossible. Matrix-metalloproteinases are thought to allow GBM cells to break down the extracellular matrix and therefore contribute to its invasiveness because of the upregulation of these proteins found in GBM patients. This upregulation is due to dysfunction of several signaling pathways. The dysregulation of signaling pathways is thought to be a promoting factor of this cancer.

Signaling and Crosstalk

The signaling pathways thought to be involved in glioblastoma are the PI3K, MAPK, and cAMP pathways. In the MAPK and PI3K pathways are hyperactivated, whereas the cAMP pathway is hypoactive. Both the MAPK and PI3K pathways have regulation roles for each other along the signaling cascade. When Ras, a molecule that has a role in activating Raf in the MAPK pathway can also activate PI3K. Targeting Ras could potentially be a very beneficial mode of treatment for cancer patients due to the link it has between two different pathways involved in GBM, but the development of this treatment may be difficult due to the molecule’s small size. As mentioned above, the cAMP pathway is hypoactive in GBM patients. Inhibition of PDEs can inhibit tumor growth and promote apoptosis of cancer cells which can also be a potential treatment option after more research is conducted. The CREB transcription factor is a crossing point between all three pathways and could also provide insight into targeting common factors.

There are specific signaling molecules that could be potential options to target for the treatment of glioblastoma. Because there are multiple pathways involved in the carcinogenesis of glioblastoma, it may be ineffective to target just one pathway, so finding regions of overlap may be more efficient to target when considering different treatment options than the typical chemo and radiation. This can bring up concerns about ensuring specific drug combinations are safe for patients.

Glioblastoma is a very serious cancer that doesn’t give affected patients many options for survival and treatment. Learning more about the intermolecular and intramolecular signaling could assist in providing better treatment options for patients.

The endocannabinoid system (ECS) has a lot to do with homeostatic processes within the brain. It controls mood regulation, pain perception, learning, and memory [1]. Much of the research that has been done to understand the role of the ECS in patients with drug dependencies has been with the use of cannabis.

ECS Receptors and Ligands

There are two main types of receptors of the endocannabinoid system, CB1 and CB2. The CB1 receptors are much more abundant, especially in presynaptic and axonal areas. These receptors are known for binding the active ingredient of Cannabis, delta 9-THC, and is responsible for the effects cannabis has on the central nervous system. CB1 receptors can also bind 2-arachidonylglycerol (2-AG) and arachidonylethanolamine (AEA) which are the two main endocannabinoids. Once these receptors are activated the levels of cAMP drop due to the inhibition of adenylyl cyclase. This inhibition stems from not having an agonist present.

The CB2 receptor is far less abundant, being found mostly in cells and tissues of the immune system. This receptor’s expression is usually involved in inflammation but can also play a role in synaptic plasticity and drug abuse. In a mouse model a CB2 receptor agonist led to inhibition of dopaminergic firing and less cocaine self-administration. The functions of the CB2 receptors have a role in Alzheimer’s disease. They have very selective localization and modulate microglia, which are highly associated with Alzheimer’s disease.

The ligands that bind the CB1 and CB2 receptors are known as endocannabinoids (eCBs). These molecules are produced when there is too high of a Ca2+ concentration within the cell. Endocannabinoids mediate feedback inhibition and modulate synaptic plasticity. The production of eCBs lead to a decrease of neurotransmitter release at either excitatory or inhibitory synapses. AEA and 2-AG act as receptor orthosteric agonists. Other allosteric eCBs are being identified and may have some therapeutic benefits by regulating the ECS.

One hypothesis explaining the process of selecting which signaling cascade is activated or inhibited has to do with phosphorylation by GPCR kinases that create targets for beta-arrestins. These targets are called bar-codes. Beta-arrestin signaling from the CB1 receptors can control the activation of different signaling cascades including the ERK pathways, JNK pathways, and the CREB cycle pathways.

Effects of Cannabis

As mentioned earlier, the active ingredient in cannabis, delta 9-THC, is what binds to the CB1 receptors. When humans are exposed to delta 9-THC they experience feelings of relaxation, auditory or visual illusions, pseudo hallucinations, and dissociation. In mice, exposure to delta 9-THC results in antinociception, hypothermia, hypoactivity, and catalepsy [1]. These psychoactive symptoms are due to the fact that delta 9-THC acts as a partial agonist of the CB1 receptor.

There is still an immense amount of research needed to be done on the affects of cannabis and THC on the human brain. Currently, there is only one university that is allowed to partake in cannabis use for research purposes. Knowing more about the harmful and therapeutic effects of cannabis use will be very beneficial for its possible use for medicinal purposes and even recreational purposes.

CNS Diseases

Disorders localized in the central nervous system, specifically Alzheimer’s disease, Huntington’s disease, and multiple sclerosis, can benefit from some therapeutic qualities of cannabis or delta-9 THC. An oromucosal spray known as Sativex can relieve motor dysfunction and pain symptoms in people with multiple sclerosis and help with neuroprotection for people with Huntington’s disease. Synthetic cannabinoids can reduce inflammation and pain.

References

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