Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder that is diagnosed based on behavioral symptoms. Given the wide-ranging manifestations of the symptoms of ASD, it would be helpful to be able to find more precise diagnostic criteria to provide more specific diagnoses which could allow for more precise treatments. The symptoms of ASD are broadly described as deficits in social communication and interaction as well as restrictive, repetitive behaviors [1]. Since these symptoms are very broad, it is no wonder that there is not thought to be a single cause of ASD. Alternatively, many assorted mechanisms and genetic variations are thought to be associated with behavioral expressions that can be characterized as ASD [2].
The high heritability of ASD is strong evidence for the genetic influence on the variety of manifestations of the condition. This is also supported by the discovery of many de novosingle nucleotide variants as well as transmitted and de novocopy number variants. Because of the wide range of possible contributions and outcomes related to ASD, it is suggested that ASD diagnoses should be subcategorized based on mechanistic commonalities found within different expressions of ASD. One mechanism that could be used to subcategorize ASD is that of dopamine signaling dysfunction [2].
Dopamine Dysfunction in ASD
Image 1: The caudate nucleus is a major dopamine hub within the brain. In patients with ASD, this region becomes significantly enlarged, which is shown highlighted in red and blue. [5]A strong piece of evidence for this theory is found in MRI studies of the caudate nucleus. The caudate nucleus is a major target of dopamine signaling. Multiple studies have found enlargement of the caudate nucleus (Image 1) in individuals with ASD. This suggests that ASD is associated with alterations in dopamine related structures and the function of these structures. Similarly, increases in connectivity of the fronto-striatal networks has been positively associated with the severity of repetitive behaviors in ASD. This also links ASD symptoms with abnormal dopaminergic connectivity to cortical structures [2].
Figure 1: Representation of the dopamine (DA) signaling pathway and ASD associated variants. Red numbers indicate downregulation, reduction, or inhibition. Green numbers indicate upregulation or potentiation [2].There have been many ASD-associated variants within the dopamine signaling pathway reported from various models (Figure 1). Although the direct application of these variants and the degrees of their effects cannot be completely deduced at this time, the significance in this information is that there appears to be many sites of action within the dopamine pathway that are altered in ASD models. Both upregulation and downregulation at specific points within the pathway emphasize the role of dopamine dysfunction in the behavioral manifestations of ASD [2].
Figure 2: Dopaminergic projection patterns within the brain. Synthesis primarily occurs in the substantia nigra (SN), the ventral tegmental area (VTA), and the hypothalamus. The arrows represent the projections from the sites of synthesis. [2]Given the vast projection patterns of dopamine in the brain (Figure 2), the many variants in dopamine signaling with ASD (Figure 1), as well as the studies linking ASD with changes in dopamine signals and structures, it is difficult to deny the evidence supporting a connection between dysfunction of the dopamine system and ASD behaviors. Dopamine has extensive effects on human behavior including social drive, reward-associated behaviors, allocation of physical energy, attention, and working memory, just to name a few. This broad scope of dopamine related activity could have many implications on the broad scope of ASD manifestations [2].
(2) DiCarlo, G. E.; Wallace, M. T. Modeling Dopamine Dysfunction in Autism Spectrum Disorder: From Invertebrates to Vertebrates. Neuroscience & Biobehavioral Reviews2022, 133, 104494. https://doi.org/10.1016/j.neubiorev.2021.12.017.
(5) Qiu, T.; Chang, C.; Li, Y.; Qian, L.; Xiao, C. Y.; Xiao, T.; Xiao, X.; Xiao, Y. H.; Chu, K. K.; Lewis, M. H.; Ke, X. Two Years Changes in the Development of Caudate Nucleus Are Involved in Restricted Repetitive Behaviors in 2–5-Year-Old Children with Autism Spectrum Disorder. Developmental Cognitive Neuroscience2016, 19, 137–143. https://doi.org/10.1016/j.dcn.2016.02.010.
When I chose to come to Concordia for college, I didn’t know the impact it would have on my life. I don’t want to be a clique… but what everyone says is true, “these 4 years have really flown by.” When thinking about life after college, I have been thinking a lot recently about how my experiences at Concordia have helped prepare me for the future.
Concordia has a goal for its liberal arts education called BREW – Becoming Responsibly Engaged in the World. My liberal arts education has prepared me to not only be a curious thinker and the importance of mentor and classmate relationships, but Concordia specifically emphasizes experimental learning that allows students to connect the concepts they are learning outside the classroom as well. This has helped me to build critical thinking skills and to realize the importance of community outreach and gaining multiple perspectives.
When I read about Concordia’s 5 goals for liberal learning, I thought of research. Research is committing to learn for the rest of your life. It’s a love for learning and a drive to follow whatever research questions interest you. Research is continuing to build on your foundation of knowledge and research techniques (i.e. research process, scientific writing, safe laboratory practices, etc.). Research is being able to communicate your findings so that anyone can understand. Wanting to go into a future career in research, I’ll be taking what I have learned at Concordia and applying it to all aspects of my life.
This neurochemistry course has been one of my favorites at Concordia because of its unique structure (it also helps that this is basically the theory behind what I want to do for the rest of my life). During this class, I have learned how to take real-world issues, read current literature, and discuss the complex problems in their mechanisms, treatment, and public perceptions with my classmates. Each week when we read about a new disease, my favorite part is getting to the point where I have learned enough to consider and pose future directions for research on the disrupted signaling pathways and treatments that target them.
If I were to highlight skills or competencies that I improved upon this semester in my resume or an interview, I would be sure to include reading and comprehending complex diseases from recent literature, collaborating with peers, writing blog posts to present findings to the public, and applying critical thinking to understand complex issues involved in diseases. In my future career, I will take what I have learned from this neurochemistry course and use it to understand complex neurological disorders and work to communicate scientific topics effectively with diverse audiences.
I’ve experienced how the lives of children who have ASD as well as their families can be impacted. To research autism from translational approaches in my future career, I am going to need to learn and draw from multiple disciplinary perspectives: Genetics to study the common mutations found and their possible implications in the different pathologies (E/I imbalances, abnormal synapse formations, etc.); Biochemistry to understand the underlying signaling pathways that are disrupted; Psychology to understand the impact on behavior; and Neuroscience to bridge all these disciplines in a translational approach to understanding, diagnosing, and treating ASD.
I know my experiences at Concordia have prepared me for my future, the kernel was planted, and I can’t wait to see how it grows!
Glioblastomas (GBM) are the most common and deadly malignant brain cancer. These brain tumors are aggressive, with their complex genetic makeups and relentless growth patterns. Because of its complexity GBMs are hard to treat, current treatments rely on surgery, chemotherapy, and a single drug – TMZ. GBMs can manifest as primary tumors, emerging rapidly without warning, or as secondary tumors evolving from lower-grade gliomas over several years.
There are four subtypes of GBMs, each with its own molecular fingerprints. The classical subtype is characterized by amplified epidermal growth factor receptor gene (EGFR) and non-mutated TP53 proteins. In contrast, the mesenchymal subtype has common mutations in neurofibromin 1, PTEN, and TP53. These genes are involved in MAPK and PI3K signaling pathways and contribute to tumor cells’ invasiveness and drug resistance. Other subtypes show the heterogeneity challenges of GBM, with pro-neural subtypes classifying younger patients who have multiple genetic mutations and neural subtypes with the worst survival rate and no common genetic pattern.
Figure 1. Gene mutations can lead to the formation and invasiveness of tumor cells (3).
A recent paper looking into the underlying mechanisms of GBMs highlighted the potential to target convergence points and crosstalk of signaling pathways involved in cancer pathogenesis.
Signaling Pathways that Promote GBM Carcinogenesis
Hyperactivation of the pathways seen below in Figure 2, often stemming from gene mutations that cause EGFR amplifications or PTEN inactivation, increases tumor growth and GBM progression.
Figure 2. Multiple signaling pathways including MAPK, PI3K, and cAMP contribute to cancer pathogenesis (1).
MAPK Pathway
This pathway regulates cell proliferation (cell survival) and metastasis (how cancer spreads). In cancer, the MAPK pathway is hyperactive because of the mutation-driven higher levels of EGFR growth factors. EGFR activates the MAPK pathway that promotes proto-oncogene transcription factors like Elk1 and CREB to allow tumor cells to multiply. The gene NF1 negatively regulates the MAPK pathway by converting GTP to GDP, inhibiting Ras. This genetic component is seen in 14% of mesenchymal GBM cases, as NF1 is depleted or mutationally inactivated, leading to hyperactive MAPK pathways.
PI3K Pathway
This pathway regulates cell growth and when dysregulated promotes tumor cell invasion. In GBM, PI3K pathways are hyperactive because of genetic mutations that lead to increased levels of EGFR, PIK3CA (the gene that encodes the p110 catalytic subunit of PI3K), and inactivated PTEN genes. Growth factors and Ras activate the PI3K pathway activates the mTOR pathway and transcription factors that promote cell growth. The PTEN gene negatively regulates the PI3K pathway by converting PIP3 to PIP2, leading to the inhibition of Akt, an important role in moderating normal cell growth levels. Disrupted PI3K pathways increase MMP levels, which lead to degraded extracellular matrices and contribute to GBM tumor cell invasiveness.
Tumor Cells and Drug Resistance
GBMs are very resistant to drug treatment because of the multiple signaling pathways that promote tumor growth—MAPK and PI3K pathways. Drug resistance is common in GBMs because targeting one pathway leads to the tumor cells using another pathway to continue its proliferation. This ability to resist is why current drugs that target convergence points of the multiple pathways involved are being researched (the asterisks in Figure 2 above are the possible convergence points).
Potential Drug Targets Focused on Convergence Points Between Pathways
The intricate crosstalk between MAPK and PI3K pathways further complicates therapeutic interventions. While both pathways can be activated by common receptors and Ras proteins, they also exhibit cross-inhibition and cross-activation mechanisms involving their main molecules (GAB1, ERK, TSC1/2, mTORC1, and Akt). Targeted inhibitors against PI3K, MAPK, EGFR, and CREB signaling have shown promise in preclinical studies, yet the challenge of adaptive pathway resistance to single drug targets has highlighted the potential of a combination of drug targets as a future treatment strategy.
Figure 3. Tumor microenvironments are important to consider when considering what to target in drug treatments (4).
Nothing in Glioblastomas makes sense, except in the light of mutationally amplified EGFR genes causing hyperactivation of both the MAPK and PI3K pathways, leading to GBM carcinogenesis.
References
[1] N. H. Fung et al., “Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer,” Cellular Signalling, vol. 57, pp. 2–9, May 2019, doi: 10.1016/j.cellsig.2019.01.011.
[4] J. Hou et al., “Evolution of Molecular Targeted Cancer Therapy: Mechanisms of Drug Resistance and Novel Opportunities Identified by CRISPR-Cas9 Screening,” Front. Oncol., vol. 12, Mar. 2022, doi: 10.3389/fonc.2022.755053.
CB1 receptors are G-protein coupled receptors (GPCRs) that are mostly found in the central nervous system (CNS) but can also be found in peripheral tissues and the peripheral nervous system (PNS). They are found on presynaptic neurons. These receptors play an essential role in learning and memory and synaptic plasticity. When these receptors are coupled with Gi/o proteins, they inhibit adenylyl cyclase, and when they are coupled with Gs proteins, they stimulate adenylyl cyclase. [1]
CB2 Receptors
CB2 receptors can be found in cells and tissues of the immune system and are typically only expressed when there is active inflammation in the body. They are typically localized to microglia which have anti-inflammatory effects. [2]
Figure 1. Graphic differentiating CB1 and CB2 receptors of the endocannabinoid system [3]
Endocannabinoid System
Endocannabinoids are natural agonists for the CB1 and CB2 receptors. They are triggered by the release of calcium at the postsynaptic neuron. The endocannabinoid system controls mood, pain perception, and learning and memory. It can also provide protection against traumatic brain injury (TBI) and can repair neurodegeneration. Learning and memory comes into play with the endocannabinoid system as it plays a key role in modulating synaptic plasticity—the ability of the brain to change connections between neurons. [4]
Figure 2. Cannabis and the brain [5]
THC vs CBD
CBD and THC are both derived from cannabis plants and have very similar molecular structures. The primary difference between the two is that THC is psychoactive and CBD is non-psychoactive. CBD products are federally legal whereas THC is not and is only legal in some states. CBD is also not considered addictive whereas THC can lead to addiction (about 30% of marijuana users become addicted). [6]
Figure 3. Image showing the different molecular structure of THC vs CBD [6]
Cannabis as Treatment for Neurodegenerative Diseases
Multiple Sclerosis
Cannabis, particularly THC, can have positive effects on spasticity and pain in multiple sclerosis (MS). Sativex, a spray that is ingested through the mouth or nose and is composed of both CBD and THC, has been used to treat MS. This treatment acts on both CB1 and CB2 receptors to reduce both pain and inflammation.
Huntington’s Disease
In Huntington’s disease, CB1 receptor expression is reduced which decreases motor performance. To treat Huntington’s disease, CB1 can be activated to reduce symptoms.
Alzheimer’s Disease
Alzheimer’s disease (AD) is partially characterized by dementia and synthetic endocannabinoids may better dementia symptoms in AD. AD is believed to be caused by amyloid-beta plaques and tau protein phosphorylation. Activation of both CB1 and CB2 receptors can provide protection against amyloid-beta toxicity, and CBD can reduce tau protein phosphorylation. [4]
Figure 4. Image of different forms of cannabis used for treatment [7]
Ethical Concerns in Research
Since cannabis is not federally legal and only legal in some states, research participants could be at legal risk if their identity is disclosed. Another issue is impairment of participants and making sure that researchers are getting informed consent. Ensuring that consent is received prior to any ingestion of the drug is imperative for ethics of the study. Individuals’ ability to understand and make sound decisions could be impaired under the influence of cannabis. [8]
Figure 5. Image of cannabis being used for research [9]
References
[1] Howlett, A. C., Blume, L. C., & Dalton, G. D. (2010). CB(1) cannabinoid receptors and their associated proteins. Current medicinal chemistry, 17(14), 1382–1393. https://doi.org/10.2174/092986710790980023
[2] Bie, B., Wu, J., Foss, J. F., & Naguib, M. (2018). An overview of the cannabinoid type 2 receptor system and its therapeutic potential. Current opinion in anaesthesiology, 31(4), 407–414. https://doi.org/10.1097/ACO.0000000000000616
[4] 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(294). doi: 10.3389/fncel.2016.00294
The melanocortin system is located in the hypothalamus. The primary role of the melanocortin system is to maintain glucose homeostasis as well as insulin secretion and glucose production and utilization [1]. The melanocortin system contains neural populations that have high levels of receptors that respond to metabolic cues to control food intake and energy expenditure. One type of neuron in the melanocortin system is POMC neurons which are inhibitory, anorexigenic neurons which inhibit appetite, and the other primary type of neuron is AgRP neurons which are excitatory, orexigenic neurons which stimulate appetite. When the brain is working “normally,” AgRP neuron expression is increased during fasting to induce feeding and suppress energy expenditure. In obesity or metabolic disease, AgRP neurons are activated more than they should be and positively regulates feeding behavior. [2]
Figure 1. Artstract of positive reinforcement of feeding behavior in obesity by Kelly Pudwill
High-Fat Diet
A high-fat diet (HFD) is a diet in which at least 35% of the calories consumed come from either saturated or unsaturated fats [3]. Long-term consumption of a HFD many times results in obesity. Consuming a HFD for a long period of time has various acute effects. Obesity causes activation of cytokines and inflammatory pathways in the hypothalamus. A HFD has been found to reduce insulin sensitivity in the hypothalamus in rats. [2]
Figure 2. Graphic showing the negative effects of a high-fat diet including on cardiovascular health, cognition, and cerebrovascular health [4]
Saturated Fatty Acids
Saturated fatty acids (SFAs) are more problematic than unsaturated fatty acids because they tend to stay solid at room temperature, and therefore are more likely to clog the arteries compared to unsaturated fats which are liquid at room temperature. SFAs can negatively modulate energy homeostasis by inducing hypothalamic inflammation and promote positive energy balance by passing the blood-brain barrier (BBB). SFAs can also trigger the activation of the inflammatory signaling cascade TLR4. [2]
Figure 3. Difference between the molecular structure of a saturated fatty acid and an unsaturated fatty acid [5]
Inflammatory Pathway
SFAs have a big impact on the PI3K pathway (insulin pathway) by inhibiting PI3K, so the FOXO protein does not translocate to the nucleus and does not allow transcription to occur. TNFɑ, an inflammatory cytokine, is activated which then activates JNK which inhibits the insulin pathway by inhibiting PI3K. The Jak/Stat pathway (leptin pathway) is also inhibited in this case as NFB activates SOCS which inhibits the pathway. TLR4 also has an effect on NFB as IKK dissociates from NFB and activating it. This all results in an increase in cytokines and AgRP neurons while simultaneously decreasing POMC neurons. [2]
Figure 4. Graphic outlining the inflammatory pathway including the PI3K, Jak/Stat, NFkB, and TLR4 [2]
Treatment Options
Dietary Changes
One of the best ways to overcome obesity is cutting calories and making healthier eating choices. There is no specific “magical” diet that works for everyone, but generally the best habits for eating changes include: cutting calories, eating foods that have less calories, eating more plant-based foods, and restricting high-carb and high-fat foods.
Exercise and Activity
It is recommended that individuals with obesity get at least 2 and a half hours of exercise every week at a moderate intensity. This will increase as time goes on and fitness improves. Any extra opportunities to move your body are also recommended like taking the stairs rather than the elevator or parking further away from entrances so you have to walk farther.
Behavior Modification
It can be helpful to speak to a counselor to discuss emotional and behavioral issues that are related to eating. This can also help with understanding overeating and recognizing triggers for eating and food cravings.
Medications
There are some medications that are FDA approved to treat obesity, but they are not meant to be a replacement for adopting a healthy lifestyle. These medications are meant to be taken alongside regular exercise and diet changes. [6]
Figure 5. Graphic of various different treatments for obesity [7]
References
[1] Hill, J. W., & Faulkner, L. D. (2017). The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances. Neuroendocrinology, 104(4), 330–346. https://doi.org/10.1159/000450649
[2] Jais, A., & Brüning, J. C. (2017). Hypothalamic inflammation in obesity and metabolic disease. The Journal of Clinical Investigation, 127(1), 24–32. https://doi.org/10.1172/JCI88878
[3] Krisanits, B., Randise, J. F., Burton, C. E., Findlay, V. J., & Turner, D. P. (2020). Chapter Three—Pubertal mammary development as a “susceptibility window” for breast cancer disparity. In M. E. Ford, N. F. Esnaola, & J. D. Salley (Eds.), Cancer Health Equity Research (Vol. 146, pp. 57–82). Academic Press. https://doi.org/10.1016/bs.acr.2020.01.004
[4] Zimmerman, B.; Kundu, P.; Rooney, W.D.; Raber, J. The Effect of High Fat Diet on Cerebrovascular Health and Pathology: A Species Comparative Review. Molecules 2021, 26, 3406. https://doi.org/10.3390/molecules26113406
Post traumatic stress disorder (PTSD) is a psychological disorder that develops in some people after they have experienced some sort of trauma or been through a traumatic event. Some common traumas include war, natural disasters, sexual assault, terrorist attacks, domestic violence, and others. Symptoms include repeated intrusive thoughts and memories and flashbacks from the event, avoiding reminders of the traumatic event, distorted thoughts and negative thoughts and feelings, and being irritable and having angry outbursts. [1]
Figure 1. Artstract of anxiety by Kelly Pudwill
Glucocorticoid Receptor
The glucocorticoid receptor is an intracellular receptor that is located in the cytoplasm and moves to the nucleus when glucocorticoid hormones bind to the receptor. This receptor modulates transcription. Glucocorticoid hormones are steroid hormones that are released from the adrenal glands and are important for maintaining stress-related homeostasis. [2]
Figure 2. Glucocorticoid receptor signaling pathway from ligand binding to transcription in the nucleus to translation to make enzymes and proteins [3]
ERK/MAPK Pathway
Extracellular signal-regulated kinase 1/2 (ERK) is part of the mitogen-activated protein kinase (MAPK) family which is important for transmitting extracellular signals to intracellular components. MAPK cascades regulate various cell processes including proliferation, apoptosis, and stress responses. The MAPK cascade transmits signals through sequential activation of protein kinase layers: MAPKKK, MAPKK, and MAPK. The ERK pathway includes specific kinases of Ras, Raf, MEK, and ERK. [4]
Figure 3. Outline of MAPK signaling pathway on the left and specific ERK signaling pathway on the right [4]
How Do You Develop PTSD?
Glucocorticoid receptors are essential in the development of PTSD as stress induces the release of glucocorticoid hormones which are ligands for glucocorticoid receptors. Following a stressful event or trauma, a dual histone mark H3s10p-K14A appears in granule cells in the dentate gyrus which is part of the hippocampus. This histone mark is important for opening up DNA strands to express immediate-early genes (IEGs), in this case, c-Fos and EGR1. After the appearance of this dual histone mark, PTSD symptoms develop. The ERK/MAPK pathway is essential for creation of emotional memories and the behavioral response associated with them. Glucocorticoid hormones act as a scaffold for phosphorylation in the ERK pathway. Without this, the dual histone mark does not appear, and histone marks are important for the consolidation of memory formation. When this chain of events happens too often, PTSD occurs. [5]
Figure 4. Image locating the dentate gyrus where the dual histone mark appears in granule cells [6]
How Can PTSD be Treated?
Cognitive Behavioral Therapy (CBT)
Therapy that focuses on problematic and/or dysfunctional patterns of thinking and how they affect behavior patterns. Key of therapy is to change current ways of thinking and make them more functional so that, in turn, behaviors change to be more productive. In relation to PTSD, the therapist works with the client to see if what the client is describing about their trauma and about themselves is accurate.
Exposure Therapy
Type of CBT that teaches the client to gradually expose themselves to situations that are related to their trauma. This could also be gradually approaching trauma-related memories and feelings. These previously avoided memories, feelings, and situations are faced which conditions the client to understand that these are not dangerous and do not need to be avoided.
Eye Movement Desensitization and Reprocessing (EMDR)
This therapy encourages the client to think about a traumatic memory while also experiencing bilateral stimulation through eye movements. This has been found to reduce vividness and emotion associated with those traumatic memories. [7]
Figure 5. Graphic outlining the benefits of Eye Movement Desensitization and Reprocessing (EMDR) therapy [8]
[4] Guo, Y. J., Pan, W. W., Liu, S. B., Shen, Z. F., Xu, Y., & Hu, L. L. (2020). ERK/MAPK signalling pathway and tumorigenesis. Experimental and therapeutic medicine, 19(3), 1997–2007. https://doi.org/10.3892/etm.2020.8454
[5] Reul, J. M.H.M. (2014). Making Memories of Stressful Events: A Journey Along Epigenetic, Gene Transcription, and Signaling Pathways. Frontiers in Psychiatry, 5(5). https://doi.org/10.3389/fpsyt.2014.00005.
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].
Image 1: lateral left view of the dentate gyrus [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.
Figure 1: Psychological stress can induce extracellular signals of glucocorticoids (corticosterone) and glutamate within neurons of the dentate gyrus. Both of these signaling pathways lead to gene transcription of immediate early genes c-Fos and Egr-1 which are associated with memory formation. [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:
(1) Reul, J. M. H. M. Making Memories of Stressful Events: A Journey Along Epigenetic, Gene Transcription, and Signaling Pathways. Front. Psychiatry2014, 5. https://doi.org/10.3389/fpsyt.2014.00005.
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.
AI generated image by Olivia Tuhy using Canva Magic Media.
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.
This figure from Fung et al. shows each signaling pathway involved in GBM and how they intersect in certain areas [1].
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.
Humans obviously experience stress, so obviously scientists have studied how being stressed impacts our brains. They have found that stress results in hormone release in the brain; these hormones are known as glucocorticoids with the most important one being cortisol.
In an article by Reul from 2014, they followed these hormonal signals and deduced how they are able to result in memories. Why is it important to connect stress to memories? Because, while many people can bounce back from stressful situations, many also suffer from those memories and end up with severe anxiety disorders like Post Traumatic Stress Disorder (PTSD). Therefore, if we know how the stress to memory formation path works, we can utilize that knowledge to develop effective treatments for PTSD and similar anxiety disorders.
Reul found that when glucocorticoids are expressed, 30-60 minutes shortly afterwards a set of immediate early genes (IEGs) are transcribed and expressed. IEGs can be thought of as the ‘First responders’ of all the genes. Many genes need proteins or other small molecules in order to go from DNA to a functional protein. IEGs code for (will end up making) these helper proteins. Most commonly, IEG proteins will be transcription factors which aid the transcription from DNA to RNA and eventually to a fully functioning protein.
Interestingly, these IEGs do not arise directly from the glucocorticoid hormones. Reul deduced this by looking at this time frame of 30-60 minutes; additionally, they tried to inhibit glucocorticoids receptors and the IEG activation inhibition was not reflected as it should have been if it were a direct glucocorticoid to IEG interaction. Well it turns out that an additional cell signaling pathway comes in between the hormone and the IEGs. That is the MAPK pathway. The MAPK pathway is a cellular signaling pathway that involves many proteins that will eventually end up affecting the proteins around DNA whether that be activating transcription factors, unwinding DNA for transcription, or activating RNA polymerase.
How do we connect this hormone to MAPK to IEGs pathway to memory formation? We can connect it because of where this takes place in the brain. Mainly, this pathway, especially the activation of IEGs, happens in the hippocampus region of the brain. The hippocampus is most well known as the memory center of the brain. Here is a short 2 minute video explaining the basics of the hippocampus structure and function. It was highlighted that a structure within the hippocampus, the dentate gyrus, is where the highest concentration of the IEG activation happens in memory formation. So as you experience a stressful event, the hormones are activating the MAPK pathway which then will activate the transcript of IEGs, and this is all happening in the dentate gyrus inside of the hippocampus.
This pathway is one piece in the larger puzzle of memory formation. Unfortunately, it is still unclear how exactly our brain forms and stores memories, but unlocking it piece by piece, like was done with this pathway, is how humans will eventually find all the puzzle pieces to put together into one big picture.
Reul, J. M. H. M. (2014). Making Memories of Stressful Events: A Journey Along Epigenetic, Gene Transcription, and Signaling Pathways. Frontiers in Psychiatry, 5.https://doi.org/10.3389/fpsyt.2014.00005
