Cobbers on the Brain

Post-traumatic stress disorder (PTSD) is a complicated psychological disorder. While typically associated with army veterans, the disorder is actually common among people who have experienced other horrors, like heinous crimes or natural disasters. What follows is a traumatic reliving of the event. People with PTSD may experience flashbacks, nightmares, unwanted thoughts or memories, and a sense of general anxiety. Symptoms can appear immediately after or may take years to appear. To make things worse, people do not always seek help after the traumatic event, allowing symptoms to worsen.

According to Johannes M.H. Reul, PTSD is really a negative side effect of human’s amazing ability to create strong associations. People associate what would be a neutral stimulus so strongly with a traumatic memory that it impairs daily functioning. However, there is hope to this. PTSD is associated with memory and memory has a biological pathway.

When we experience a stressful event, our bodies release corticosterone. Corticosterone then binds to glucocorticoid receptors (GR). GR then activates extracellular receptor kinase (ERK). Activated ERK can do one of two things: activate mitogen stress kinase 1 (MSK1) or activate Elk-1 by removing a phosphate. Eventually, it will do both.

You might remember from your biology class that our DNA is very long, so long that if all the DNA in your all of your cells was stretched out it would wrap around the solar system, twice![i] To keep our cells to a reasonable size, DNA is wrapped around molecules called histones and condensed into structures called chromatin. MSK1 and Elk-1 unroll DNA (though not all of it at once). This allows for transcription, which makes proteins c-Fos and Egr-1. These proteins work closely with a variety of other mechanism like the NDMA receptor in order to create associations.

[i] How Long is Your DNA? https://www.sciencefocus.com/the-human-body/how-long-is-your-dna/.

While c-Fos and Erg-1 work with NMDA receptors, the NDMA receptor is also part of the memory association process. Glutamate binds to NMDA receptors. This adds a phosphate to MEK, which in turn passes it on to ERK.

Fig. 1. Above is a diagram from the article that outlines the mechanism of memory association.

All of this takes place in specialized neurons within the hippocampus. These neurons are called granule neurons. Unlike neurons in other regions of the brain, these can die off and divide. This is great news for making new memories and associations.

All of this science was discovered very recently, within the last 30 years. Scientists first began to study this mechanism in the 1980s, but it was not until the early 2000s did they finally identify a mechanism. Most of the research was done using mouse models. However, you cannot really give a mouse PTSD. Though, we can identify and induce anxiety in mice. Since anxiety is a symptom of PTSD, we can use anxiety in mice to study PTSD and related disorders.

There are several ways to induce anxiety or stress in mice. One common way is the swim test. A mouse is placed in a pool that has no exit. The mouse frantically searchers for an anxiety, but eventually realizes that there isn’t one. The mouse then goes limp and helpless before being scooped up by a researcher. Mice who undergo this test multiple times eventually spend less time swimming. This retesting is highly dependent on stress hormones. Mice who were given blockers to GR receptors spent more time swimming in the retest[i].

Implications

The article is very technical in its nature and in the descriptions, likely because Johannes M.H. M. Reul were only discovering the pathway, not a connection or implication like other articles discussed on this blog. The authors mention that it took them nearly three decades to find this pathway. This is fairly new science, so it is difficult to pinpoint the exact implications of this study.

Since we know the pathway, it seems plausible to create a drug that acts on an element of this pathway, therefore eliminating or preventing PTSD. However, that is likely not possible. All of this transcription process happens very quickly, less than 15 minutes after the event. People who suffer from PTSD often are not aware of or get treatment for their symptoms until months or years after the event.

Additionally, there is also an ethical side to this. While stress can be bad, it is essential for learning. I’m sure we can all think of a time where we learned something through stress. There is even a common phrase for it in the English language: “learning something the hard way.” Creating a drug that acts on this pathway could have unintended consequences and limit a person’s normal ability to learn. It would be better to have a patient relearn and un-associate everyday things with the traumatic memory.

PTSD is unique among psychological disorders in that it has a direct cause. Disorders like depression and generalized anxiety disorder can affect anyone and be triggered by a number of different things. PTSD is always triggered by some traumatic event. This makes it difficult to study. We cannot expose people to a traumatic event and study them afterwards. This is bad for two reasons: first, we cannot expose anyone to a psychologically harmful event for ethical reasons and second, not everyone who experiences a traumatic event shows signs of PTSD. Exactly why some victims of traumatic events get PTSD and some do not is currently unknown. Women in general are more likely to get PTSD, but this maybe due to the fact that women are more likely to be victims of crimes like rape and assault. We know that there is some genetic basis for anxiety (a common symptom of PTSD and the one symptom that researchers used in testing), so there may very well be some genetic factor with PTSD. However, there is not much that can be done to prevent, except stopping the traumatic events that cause PTSD like rape, war, and assault.

Overall, PTSD is a unique psychological disorder. The disorder is really a side-effect of human’s amazing ability to make associations. However, these associations become so strong that it affects our everyday functioning. It is difficult to study treatments of it because we cannot ethically give a human PTSD. We can induce anxiety in animals, but this is not entirely the same as PTSD, but a mere symptom of it. However, we ought not to shy away from studying disorders like PTSD simply because they are complicated. If anything, their complications show us something about the human condition. We are so good at making associations and learning that sometimes it harms us. But, there is no reason that this amazing ability cannot be used fo

[i] Johanes M. H. M. Reul. Making memories of stressful events: a journey along epigenetic, gene transcription, and signaling pathways. Frontiers in Psychiatry. Vol. 5. Jan. 2014.

Schizophrenia is a neurodegenerative disease which has often been portrayed through various forms of media. However, this depiction is often a misrepresentation of the disease. Movies and tv shows often portray the disease as making an individual very aggressive, delusional, allows them to hear voices, and all around crazy. Although some of these are symptoms of the disorder, this stigma does not nearly encompass the whole disease. Schizophrenia is very complex and still not very well understood by the scientific community. Symptoms span a wide range and often differ dramatically between individuals leading to various treatment options. Current research has shown how each of these treatment options is closely related to the Wnt pathway and Wnt signaling. By better understanding how each of these treatment options affects the Wnt pathway and subsequently schizophrenia, scientists are obtaining a more complete understanding of the disease and breaking down the stigma created by the media.

As previously stated, the symptoms of schizophrenia vary dramatically. According to the Mayo Clinic website symptoms of schizophrenia involve delusions, hallucinations, disorganized thinking and speech, disorganized or abnormal motor behavior or negative symptoms. Negative symptoms are those that reduce the ability to function normally. Examples are lack of personal care and disinterest in everyday activities. These negative symptoms often lead to a misdiagnosis of the disease, as many of these symptoms resemble other neurodegenerative diseases such as depression. Of great importance is the time at which symptoms of schizophrenia begin to manifest as this usually affects how the disease is expressed. For example, symptoms in teenagers are a withdrawal from friends and family, drop in school performance, trouble sleeping, and lack of motivation. These symptoms, which can often be diagnosed as depression, are a far cry from the media’s depiction of the disease. Only by accurately displaying and discussing the disorder can the stigma surrounding the disease finally be torn down. Scientists are also attempting to break this stigma by learning more about this complex disorder. By examining how current treatments affect the disease with respect the Wnt pathway scientists are discovering vital information thus breaking the stigma.

One of the main methods for treating schizophrenia is through the use of psychiatric pharmaceuticals.  Many of these small molecule drugs often directly or indirectly target Wnt signaling. One such molecule is dopamine (DA). DA signaling has been shown to inhibit Akt which inhibits GSK3. If GSK3 is not phosphorylated, then b-catenin cannot enter the nucleus and allow for proper gene transcription. Not having proper gene transcription can lead to the degeneration of neurons thus leading to an increase in neurodegenerative disease such as schizophrenia. However, DA pharmaceuticals are not the only drugs used to repress schizophrenia. Lithium has also been used as a viable treatment option. Lithium directly inhibits GSK3 activity by competing with magnesium as well as indirectly inhibiting it by increasing the inhibitory phosphorylation of GSK3. This leads to an accumulation of b-catenin, which leads to proper gene transcription thus allowing for proper cell growth.

Scientist are not only working on treatments for the disease but also working on identifying potential genes which could lead to the disease. Current research has shown that genes such as DISC 1. DISC 1was first identified in a multi-generation Scottish family that suffered from schizophrenia, bipolar disorder and major depression. Since its discovery DISK 1 has been found to regulate the stability of b-catenin through GSK3, resulting in better gene transcription. Further studies are currently being done to identify other genes which can could lead to the manifestation of this disease.

The stigma surrounding schizophrenia resembles a crazed individual who hallucinates and is plagued by voices in his or her head. However, this is not an accurate representation of the disease. Schizophrenia is very complicated its symptoms manifest itself in a variety of ways. Currently scientists are learning more about the disease in an attempt to break the stigma and help enlighten the public. Only once this misconception is broken can individuals struggling with the disease come forward without fear of humiliation or ridicule.

https://www.mayoclinic.org/diseases-conditions/schizophrenia/symptoms-causes/syc-20354443

https://moodle.cord.edu/pluginfile.php/798923/mod_resource/content/2/2013%20wnt%20GSK%20and%20schizophrenia.pdf

https://www.therecoveryvillage.com/mental-health/schizophrenia/#gref

If any of you were akin to me in your middle childhood, you were probably instructed to NOT do something regularly. The probability that I would listen to such demands was low, sadly very low. However, after feeling the punishment of not listening, either from a natural event or a disgruntled parent, I learned quickly to not engage in such an event again. The formation of memories allows us to grow and learn form painful experiences. What happens however, when such strong memories form from mundane events? This is were anxiety disorders such as PTSD can manifest. There are several neurological factors which are thought to cause these overactive memories and thus lead to a variety of anxiety disorders.

Glucocorticoids

One important factor that can contribute to the overactivation of strong memories are glucocorticoids. These hormones, which are often associated with fear and stress, have been to form a complex for with other enzymes in the brain thus allowing gene transcription leading to the formation of memory. Tests with various animal models show that animals treated with glucocorticoid agonists struggle much longer under various conditions instead of learning quickly from previous events. This leads to the conclusion that these glucocorticoids could be overactive in a variety of anxiety disorders thus producing strong memories from very mundane situations.  The diagram below does a nice job of demonstrating how these glucocorticoids help in gene transcription.

The Role of the ERK/MAPK Pathway

It would be foolish to only discuss the role of glucocorticoids when the figure above also shows how the Erk/MAPK pathway involved in the formation of memory as well. In fact, both of these pathways must happen in tandem for the proper transcription of genes and thus memory formation. Since the Erk/MAPK pathway has already linked to learned behavior it makes sense that it may also play a role in memory. A series of studies found that a NMDA receptor agonist strongly inhibited the learning process during forced swim tests of rodents. In other words, the inhibition of the Erk/MAPK pathway prevents the formation of the glucocorticoid receptor/ERK complex, which in turn cannot phosphorylate MSK-1and Elk-1. It stands that if these two kinases cannot form then there can be no gene transcription which leads to a lack of memory consolidation. However, if the ERK/MAPK pathway is overactive you can have the over activation and phosphorylation of MSK-1 and Elk-1 which leads to the transcription of genes for mundane events.

Conclusion

The formation of memories is vital to not only our learning but also our survival. Memories can be formed through several pathways however, the formation of strong and or painful memories often occurs through the ERK/MAPK pathway along with glucocorticoids. It is thought that the overactivation of this process can lead to a variety of anxiety disorders, including PTSD. There are other aspects to be considered, such as the role of the amygdala and hypothalamus, both of which have been shown to play a role in anxiety. It is imperative that each these factors be more thoroughly examined in order to one day find a cure for those suffering with anxiety disorders.

Sources

https://moodle.cord.edu/pluginfile.php/798920/mod_resource/content/0/anxiety%20making%20memories%20from%20stressful%20events.pdf

Image

http://neurochemistry2019.pbworks.com/w/page/135908691/Making%20memories%20of%20stressful%20events

What is schizophrenia?

Schizophrenia is a chronic disorder of the brain of which no cure is known. There are some treatments that are enhancing patient quality of life but there are a number of comorbid conditions lowering life expectancy like diabetes and heart disease. Some of the symptoms that may occur in adolescence are issues with motivation, poor social relationships and problems with attention. Later, these can manifest into disorganized and impaired thinking along with potential hallucinations. Men usually experience onset at about 20 while females are a few years later. Interestingly, each individual case of schizophrenia is different from others. While some may be strong in positive symptoms, hallucinations, these can range from flashing light apparitions to dangerous people following you on the street. On the other hand, negative symptoms can create a catatonic like state in some. How can this huge range of symptoms be caused be the same areas of dysfunction?

How does schizophrenia develop?

There is a development hypothesis of schizophrenia called the “two hit” approach, meaning there are two key points in development when factors can fall into place to lead to schizophrenia. The first is during the end of the first trimester of fetal development as many individuals diagnosed with schizophrenia have low set ears and highly connected toes- areas that form during this time period. The second important “hit” is during adolescence as this is when some of the early symptomology of schizophrenia begins to appear. Not only are there structural differences between those with and without schizophrenia, some issues with cell signaling has become implicated as well, with the Wnt pathway playing a large roll.

How is the Wnt pathway involved?

When the Wnt ligand binds to the receptor complex, parts from a larger destruction complex are recruited to the membrane (APC and Dvl), effectively destroying the structure that held them together. One specific molecule, GSK3, can no longer phosphorylate beta-catenin when the complex is destroyed, keeping b-catenin levels high in the cytoplasm. When beta-catenin level are high, cell stability is increased and the beta-catenin can enter the nucleus and displace Groucho from transcription factors TCF and LEF so that transcription can occur.

Conversely, when WNT does not bind to the receptor, the destruction complex does not break apart, so beta-catenin continues to be phosphorylated by GSK3 and then is targeted for breakdown. When that happens, there is no beta-catenin that enters the nucleus and Groucho remains lodged to TCF and LEF, preventing cell transcription.

Why does all this matter?

Schizophrenia is a debilitating disorder that can include a number of positive and negative from hallucinations to withdraw from society. The Wnt signaling pathway is highly important in the etiology and development of the disorder as it prominent in the neural development and adult neural circuit function. As discussed above, when the Wnt pathway is off, cell transcription of TCF and LEF can’t occur meaning specific genes are not turned on or off. However, we aren’t exactly sure where to intercept this process for treatment completely because our animal models aren’t exact- animals can not get schizophrenia. This disorder is multifaceted and includes many different factors, both structural and signaling wise, making it difficult to know where to begin for new pharmacological therapies.

https://www.psychiatry.org/patients-families/schizophrenia/what-is-schizophrenia

https://academic-oup-com.turing.library.northwestern.edu/schizophreniabulletin/article/35/3/528/1871490

What should insulin be doing?

You’ve probably heard of insulin before but role does it actual play in our bodies? When functioning normally, insulin helps regulate our blood sugar levels by breaking down carbohydrates into different pieces. One of those pieces is glucose which is our bodies main form of energy. Once this glucose is in our bloodstream, the pancreas starts producing insulin which lets glucose into our body’s cells to give them energy. Your body can also store this insulin in muscles, fat cells and liver to be used later if needed.

What does it do in Alzheimer’s Disease (AD)?

Insulin has also been found to protective of the neurons in our brain making it important for cognition, something we know is implicated in AD! The brain is an insulin sensitive organ and insulin has been found to promote memory functioning within it. So, if there is an issue with insulin, there can be an issue with memory and cognition.

What does it do in Type 2 Diabetes (T2D)?

Insulin is most usually talked about in the context of Type 2 Diabetes. With this condition, glucose levels keep rising because the insulin is not moving the glucose into our cells effectively. It’s not that those with Type 2 Diabetes don’t have insulin, they just usually are not using it effectively or don’t produce enough, insulin resistance and insulin deficiency, respectively.

So… how are they connected??

There appears to be a connection between Type 2 Diabetes and Alzheimer’s as patients who develop one are more likely to develop the other. This means if you get Alzheimer’s, your chances of getting T2D are higher than the rest of the population.

Maybe brain inflammation?

When researchers look at the brains of those with Alzheimer’s they find evidence of issues with insulin signaling. A proposed link between the two is the inflammation that occurs when there is a fat accumulation seen in the body in T2D or the sustained inflammation seen in Alzheimer’s brains. It suggested that this inflammation could be due to a specific inflammatory cytokine called TNF-a that induces insulin resistance.

Maybe gangliosides promote insulin resistance?

   AD is characterized by a plaque build-up on the neuronal level referred to as amyloid beta plaques. When these plaques start to build up, a number of other cells cannot perform their usual functions or jobs, dysregulating a lot of other pathways. A ganglioside called GM3 is important in cell metabolism and it’s possible that when these plaques build up, the GM3 cannot do its job and so the downstream signal is blocked leading to insulin resistance.

Could be mTOR deregulation? The evaluation of mTOR can lead to insulin resistance.

 Could be issues with PTP1B?  Elevated PTP1B is found in T2D and could regulate neuronal inflammation.

 What now?

It’s clear we won’t have all the information about the pathology of either AD or T2D nor do we understand fully the connections between the two. In this short post, I have only scratched the surface of the depth of these potential connections but it’s difficult to determine what causes what. Does inflammation cause a build of plaques, or vice versa? Which comes first? Does the mTOR pathway affect the amyloid beta plaques? We know a number of these things are connected but we don’t know where to start in the pathway. More research on these factors could break open the treatment options for AD and T2D- we just need to figure out where to begin.

https://www.mayoclinic.org/diseases-conditions/diabetes/in-depth/diabetes-treatment/art-20044084

Do you know, or have you ever known, someone with Alzheimer’s in your life? At the moment, your answer to this question may or may not be yes, but as time passes it will become more and more likely for all of us to know someone: It is estimated that approximately 5.5 million Americans currently suffer from dementia caused by Alzheimer’s, but worldwide this number is more likely to be around 36 million people. Experts predict this number to reach 115 million by 2050 if no effective treatments are developed. 

So what exactly is Alzheimer’s Disease (AD)?

In one sentence, it is a progressive neurodegenerative disease that causes dementia. This means it is a disease in which the state of different parts of the brain continuously worsen, ultimately leading to a variety of symptoms, some of which include:

1. Memory loss,
2. A lesser ability to function, and 
3. Worsened judgement. 

The most common symptom listed above is forgetfulness. It is usually less noticeable at first, but throughout the course of the disease becomes increasingly worse until even simple daily chores and activities are impossible to manage without some form of help from a caregiver or family member. What many people do not seem to realize, however, is that Alzheimer’s at its later stages has further characteristics that can affect an individual’s personality: 

1. Agitation, 
2. Withdrawal, 
3. Restlessness, and/ or
4. A loss of language skills. 

Therefore, it is increasingly difficult for affected individuals to be cared for in their home, and often move to nursing homes as the disease progresses.  

For many years, researchers have been trying to describe the etiology of Alzheimer’s and pinpoint its specific cause to develop a treatment, or at least improve therapies to slow the progression. Some of the basic science is described below…

Science Behind the Disease

This TED-Ed video gives a brief overview of the basic molecular science and the disease’s progression throughout the brain, which can be directly related to the visible symptoms we perceive as friends, family members or medical personnel:

While numerous aspects of Alzheimer’s have been researched and described, a treatment or cure is yet to be found. Nevertheless, this research has led to some interesting findings…

Connection to Type 2 Diabetes (T2D) 

Did you know that Type 2 Diabetes doubles the risk of dementia? As we hopefully all do know, insulin plays an incredibly important role in diabetes as it regulates blood sugars. However, insulin is multifaceted because it has many other functions as well. For example, in the central nervous system (CNS, your brain and spinal cord), insulin also:

• Influences the growth and survival of neurons,
• Has neuroprotective roles,
• Modulates synaptic plasticity,
• And regulates different receptors (i.e. GABA- and AMPA-receptors)… 

… among other functions.

These demonstrate that insulin is not only important in the body, but in the brain as well. One of the connections researchers have found between Alzheimer’s and diabetes is that a resistance to insulin exists, which oftentimes is initiated by inflammation in the brain (for AD) or in adipose tissue (for T2D). The amyloid beta oligomers (ABO’s or AB plaques, as mentioned in the video above) could possibly be the cause for secretion of proinflammatory cytokines, leading to said inflammation. These ABO’s could also be a cause for peripheral (not in the CNS) metabolic deregulation, which potentially provides a mechanism for why AD patients often also develop T2D. 

Further connections come from the fact that PTP1B can potentiate the inflammation in both diseases, deregulated mTOR signaling contributes to insulin resistance, and abnormal ganglioside metabolism impairs insulin receptor function. 

For more details linking AD and T2D click here.

Did you know that about 50% of all US adults will experience a traumatic event at some point in their lives? I did not. And while this number is higher than I would have expected, luckily most people do not actually develop post-traumatic stress disorder (PTSD) from their experience(s). But why not? What makes one person more likely to develop PTSD than another?

To answer this question, I will first provide a brief background on the disorder.

As mentioned above, the people who do develop PTSD have experienced some form of traumatic event. While that exact event differs from person to person, there are certain types of events that tend to be the source of trauma more often among one sex compared to another. Among women, experiences more likely to be causing PTSD are… 

• sexual assault, and
• childhood sexual abuse

… whereas men’s trauma will probably originate from:

• an accident, 
• physical assault, 
• combat, 
• a disaster or 
• witnessing death/ injury. 

This demonstrates the wide variety of events that can cause this disorder, which 7-8% of the US population (10% of women, 4% of men) suffer from at some point in their lives.

Symptoms

To diagnose PTSD, a person must exhibit numerous of a long list of possible symptoms. These can include persistent and frightening thoughts, flashbacks to the event, becoming startled more easily, sleep problems, detachment, numbness, etc. They also tend to avoid places, people and objects reminding them of the traumatic event. All the aforementioned symptoms, and others, can be grouped into four categories: intrusive memories, avoidance, negative changes in thinking and mood, and changes in physical and emotional reactions.

These symptoms are strongly linked to various brain regions…

The Hippocampus and Amygdala

In people suffering from PTSD, triggering stimuli can induce processes in the brain, leading to the symptoms of PTSD. One of these processes is hyperactivity in the amygdala, which is important for emotion processing and fear responses. These stimuli can include sounds, words, narratives, visual cues, etc. that resemble the person’s traumatic experience, but in some cases the hyperactivity is increased to such an extent that even unrelated stimuli can initiate symptoms.

Due to the importance of memories in PTSD, the involvement of the hippocampus is vital as well. This is a brain region critical for various memory functions, including encoding and retrieval, but in PTSD its volume is significantly reduced. This furthermore makes it difficult for people to discriminate between past and present events. In healthy humans, the hippocampus is supposed to facilitate input into the amygdala, so behavioral responses to the environment are appropriate. However, with a hypoactive hippocampus the amygdala is more likely to go into a state of distress. 

Risk Factors

Now let’s return to our question: Why are some people more likely to develop PTSD than others? The short answer is that there is no single definitive response because science has not yet figured it out (PTSD is very complex). However, a number of theories do exist. For example, two prevalent risk factors for the development of the disorder are previous traumatic experiences and a generally increased level of anxiety. 

The underlying science starts with glucocorticoids and NMDA receptors. When glutamate activates NMDA receptors, MEK is phosphorylated (a phosphate is added) and thereafter ERK1/2 is phosphorylated as well. Glucocorticoids, necessary for the acquisition and consolidation of stressful memories, then go on to interact with the phosphorylated ERK1/2, which in return phosphorylates MSK1 and Elk-1. This allows the chromatin to be opened by H3S10p-K14ac and for gene transcription to occur, specifically genes c-fos and egr1. This gene transcription is critical for memory consolidation, and possibly occurred at an enhanced level in PTSD patients.

Glutamate receptor antagonists strongly inhibit the increase in dual histone mark H3S10p-K14ac, usually thought to occur after stressful events. This may be an option to moderate a traumatic event’s strong impact.

Treatments

The main types of treatment for PTSD include a number of different psychotherapies or medications, which you can read about here.

More recently, research is also looking into the process of Deep Brain Stimulation (DBS) as a treatment option, especially for cases resistant to currently known treatments. The video below provides a description and specific case.