Cobbers on the Brain

A stressful world

Every day the average person goes through a plethora of stressful events. We go to work, school, or take part in other tasks that demand a lot from our brains. We never have the chance to “get away” from our stressors with the invention of email and smartphones. They continuously remind us of things we have to get done and interrupts our downtime. It seems like many of us, especially college students, have never ending lists of things to do before we get any time to relax. Stress has become such integral component of our daily lives that we are beginning to see more and more cases of anxiety disorders. Research has shown that physical changes occur in our brains as they respond to stress suggesting semi-permanent effects. Our DNA is modified is response to prolonged anxiety causing changes in neural connections. These changes can cause problems with memory and can even lead to heightened anxiety. The topic of stress and anxiety is an important one as it is a common feeling felt in most people and is a prevalent issue in mental health.

What’s going on in our heads?

Anxiety is the brain is a difficult mechanism to piece to together even for top anxiety scientists. Nevertheless, there are some concrete pathways that we for sure know are involved in stress and anxiety. The stress response begins in the brain. The hypothalamus or pituitary gland release hormones into the blood to induce a change in body physiology. Ultimately, these hormones change how we feel and are an integral component of our fight or flight response. However, an imbalance in these signaling hormones can lead to anxiety disorders.

The hippocampus is a structure in the brain utilized in memory consolidation. This structure includes a lot of cells containing receptors for the hormones described previously. It is believed that these hormones are essential for proper memory formation and that too much or too little of them will cause problems with anxiety. In cases of PTSD, it is believed that there are too many of these hormones in the hippocampus leading to a strong association to be made. This results in the formation of a memory that could trigger feelings of anxiety or stress in unnecessary circumstances. The excess hormone in the hippocampus pairs with action of a neurotransmitter called glutamate. Together, these two molecules cause a cascade of signaling to occur resulting in modification of our DNA. This change in DNA causes new genes to be turned on that improve our ability to learn. In many cases this is a good thing, but in cases of PTSD, this means that traumatic events are remembered very vividly and can cause excessive feelings of anxiety. Today, scientists are working to find out how to alleviate the memories of traumatic events while preserving normal functioning in learning and memory.

So what’s the deal? Is anxiety good or bad?

Generally, anxiety is a good mechanism to help keep us safe. If a specific situation causes anxiety, we are generally going to avoid contact with that situation. Perhaps you get anxiety being around snakes so you never touch them or get near them. From an evolutionary prospective, this is very beneficial. Snakes can be dangerous and avoiding them through prevention of an anxious feeling would be beneficial overall. The problem arises when anxiety occurs in situations where it shouldn’t. Social interactions with people you know to be good should not cause a severely heightened sense of anxiety. There is no danger to be anxious about in this situation so there is no reason for us to try to avoid it. Yet many people do get this feeling at seemingly random times. Some people don’t even have to be in a stressful situation to feel stress, they just have to be reminded of one. Perhaps an image vaguely relating to a traumatic event brings on these feelings of anxiety. This is the case for many people with PTSD who experience trauma and are unable to weaken the association of their anxiety to the memory of the event. In these cases, anxiety is a very negative response and holds no survival value. We should remember to avoid dangerous things but these memories should not lurk into safe situations. Further research is necessary to help treat individuals with anxiety disorders because they can have profoundly negative impacts on the person’s quality of life.

The importance of regular exercise for our physical health is drilled into us starting in elementary school gym class. However, there are also mental health benefits that result from exercise. In multiple studies it has been found that exercise has been shown to reduce anxiety levels.

How does this work?

When one experiences a psychological stressor, the pathway in the brain that responds to this is the NDMAR-ERK-MAPK pathway. This process involves multiple steps of phosphorylation and acetylation, eventually resulting in the opening of the chromatin and the alteration of gene transcription. When this pathway is over-activated, it leads to the formation of strong, long-term memories  which are often times associated with anxiety and post-traumatic stress disorder (PTSD).

It is thought that the decreased anxiety levels seen from exercise is due to changes in the GABAergic system. GABA is an inhibitory neurotransmitter; therefore, the increased gene transcription of a GABA synthesizing enzyme allows for more GABA to be created and excreted. With increased levels of this inhibitory neurotransmitter, it is less likely that this anxiety-related pathway will be over-activated leading to decreased levels of anxiety and better response to stress.

These conclusions were determined through experiments with mice and rats, but there was a similar experiment conducted with humans at UC Davis. Participants who exercised showed higher levels of GABA but they were not put through a stress tests like the experiments with mice and rats were. The similar increase in GABA indicates the similar conclusions of the two studies.

Maintaining a Balance

It is crucial that this GABAergic system maintains the correct balance of GABA. As previously discussed, not enough GABA can lead to anxiety and PTSD-related symptoms, because there is not enough inhibitory signaling going on in the brain. On the contrary, too much GABA can be dangerous as well. This excess of inhibitory signals can promote carelessness and cause an individual not to be as aware of danger.

Current Treatments

Medications– used to treat symptoms of anxiety and PTSD but do not target the cause. These are the most commonly used classes of medications.

• SSRIs (Serotonin Reuptake Inhibitors) which are also antidepressants: Fluoxetine, sertraline and paroxetine all work to decrease anxiety, depression and the panic associated with PTSD
• Atypical antipsychotics– risperidone, olanzapine and quetiapine are mostly used to treat PTSD to help with agitation and paranoia
• Mood  stabilizers – sleeping tablets or anti-anxiety medications

Psychotherapy- also referred to as ‘talk therapy’ is very effective for treating PTSD. The patient meets once a week with the therapist for 3-6 months. These therapies include teaching the patient how to reframe their thoughts surrounding the traumatic event and learning how to be in control of one’s feelings

Usually a combination of medication and psychotherapy is used in the treatment of PTSD. However, with the recent research regarding the benefit exercise can have on mental health, that may become part of the treatment plans for this disorder. It would be a more natural way of using the body’s natural functions to try heal the pathways that have been impaired in the brain.

Memories make up who we are as individuals. When memories are interrupted, degraded, or inhibited, we see cases of dementia such as Alzheimer’s Disease–what we discussed last week. There are many different types of memory that people may form (Fig. 1). Explicit memory refers to memories that individuals can consciously discuss whereas implicit memories cannot be distinctly defined or stated. A type of implicit memory is procedural memory. This type of memory exists for skills and actions–like remembering how to ride a bike or play a sport. Procedural memories may also be referred to as “muscle memory” in popular language. Episodic memory is a type of explicit memory that refers to memories regarding autobiographical events–the who, what, when, where, and why. Semantic memories tend to involve facts and concepts.

This week in class, we discussed traumatic memory in regards to PTSD, Anxiety, Depression, and other psychiatric illnesses. Traumatic memory, also called somatic memory, are strong, resilient memories formed following traumatic, psychologically damaging events. In order for an individual to form a traumatic memory, that same individual has to personally experience the trauma. If a societally traumatic event happens around an individual, a memory formed for that event would be considered a flashbulb memory. As defined in 1977 by Brown and Kulik, flashbulb memories refer to emotionally charged memories formed upon learning about a public emotionally charged or traumatic event. These memories are not autobiographical in nature–they did not occur to the person, but around the person. The name, “flashbulb memories,” stems from their nature of allowing the individual to visualize themselves as they were when the event happened, as if they had taken a picture of themselves during that moment.

Although the nature of the memories may differ, flashbulb memories may be similar to trauma or stress induced memories. Originally, Brown and Kulik, 1977, hypothesized that due to their emotional strength, flashbulb memories might be formed using a unique pathway. The researchers also believed that flashbulb memories were not subject to change–that they were stronger than normal memories and not susceptible to the inevitable forgetting and reforming that other memories experience. More recent research has shown the opposite of Brown and Kulik’s claim regarding the resilience of flashbulb memories. A study by Talarico and Rubin, 2003, used a test-retest methodology to find substantial inconsistencies in flashbulb memory recall–from the initial to the latter recall of the memory.

When it comes to traumatic memories, the study of flashbulb memories has helped researchers understand memories that stem from psychological stress. Specifically, one study looked at the memories made by individuals who were not directly impacted, but lived in New York City during the events occurred on September 11th, 2001. The study assumes that the individuals created flashbulb memories of 9/11 and found, using brain imaging, that their amygdalae still showed increased activity levels three years following the events. These individuals were not at Ground Zero, but lived or worked near the epicenter of the attacks. This finding is important for the distinction between flashbulb memories and traumatic memories. Due to their similar nature, it remains unclear if molecular differences exist between the two types of memory.

When discussing these two types of memory, their similarities seem to outweigh their differences. The major difference between the two seems to be whether the individual themselves experienced the traumatic event or if the individual witnessed the traumatic event as an outside observer. Regardless of this characteristic difference between traumatic memories and flashbulb memories, they likely utilize the same formation pathway (Fig 2). Research understands that once formed, both types of memory may lead to the onset of PTSD, Anxiety, Depression, or other psychiatric illnesses if not properly treated soon after the traumatic event. Although different treatment options exist such as pharmaceuticals like SSRIs, atypical antipsychotics, or mood stabilizers, treatment that utilizes psychotherapy tends to be more successful. Common psychotherapy treatment options include Cognitive Processing Therapy (CPT), Prolonged Exposure (PE), and Eye-Movement Desensitization and Reprocessing (EMDR). Each therapy aims to address and process the negative thoughts one possesses due to the traumatic event. Regardless of the treatment process, it remains important to address negative thoughts–as a result of the trauma–as soon as they appear. The earlier the intervention, the less likely an individual is to develop psychiatric illness following a traumatic event.

The Relationship:

When considering an individual suffering from Alzheimer’s Disease (AD), one doesn’t often associate Type II Diabetes (T2D), or vice versa. However, this may become the new norm as studies are now showing a link between these two diseases. When you take a closer look, many similarities exist, turning this relationship toxic.

What is Alzheimer’s:

Alzheimer’s is a neurodegenerative disorder characterized by progressive mental deterioration due in part to the buildup of amyloid plaques and neurofibrillary tangles in the brain. This type of dementia is the most common worldwide, causing problems with memory, thinking, and behavior. There is no treatment currently capable of reversing, stopping, or significantly slowing down the progression of this disease, making the study of its origination crucial to future treatment.

http://az616578.vo.msecmd.net/files/2016/04/10/635958482997470921934663329_alzheimers1.jpg

What is Type II Diabetes:

Type II Diabetes, or noninsulin-dependent diabetes, is a disease that affects the way that the body metabolizes sugar. This disease is characterized by high blood sugar, insulin resistance, and relative lack of insulin. T2D primarily occurs as a result of obesity and lack of exercise and is seen to be becoming far more prevalent in recent years, likely due the poor diet and lifestyle exhibited by the American society.

The Connection:

Insulin, as we know, plays a large role in the body as a regulator of blood glucose. However, it also has an important role in brain function. Insulin is now understood to play a large part in neuroplasticity, neuromodulation, as well as memory and cognition. Lack of insulin function, as characterized by T2D, can disrupt these pathways, leading to common symptoms seen in Alzheimer’s disease.

Insulin function has been found to be disrupted by prolonged inflammation in the brain as seen in both T2D and AD. In individuals experiencing T2D, the accumulation of fat causes the accumulation of inflammatory molecules. It is likely that obesity associated systemic inflammation causes excesses circulating free fatty acids. These circulating cytokines, free fatty acids, and immune cells reach the brain and initiate local inflammation, including microglial proliferation. This chronic inflammation not only disrupts the insulin pathway in the brain, but also causes synaptic remodeling and degeneration through the overactivation of microglia.

In Alzheimer’s, prolonged inflammation of the brain is a characterizing factor of the disease. This chronic inflammation is largely due to the overactivation of microglia, as seen in T2D. Microglia work to degenerate the buildup of amyloid plaques commonly found in the brain of individuals suffering from Alzheimer’s. When these macrophage-like molecules can’t keep up, they continue to release pro-inflammatory cytokines in response, often damaging neurons and synapses in close proximity. This leads to neurodegeneration. Inflammation itself, such as from T2D, can also trigger the activation of microglia as they both respond to, and cause, neuroinflammation.

Importance:

Though there is no cure for Alzheimer’s, we have found that due to its strong link to T2D, diet may play a role in in alleviating the onset and progression of this neurodegenerative disease. It is important for not only your physical heath, but also future neurological heath, to be cautious of the food you put into your body as it may have a long-term effect.

For those of us who have experienced the terrors of watching a loved one suffer through the horrors of AD, we know the impacts that this knowledge could have. Alzheimer’s is not only detrimental for the individual, but also significantly traumatic for the family as well. Though it is easy to say, “that won’t happen to me” or “I’ll deal with that when I get there”, it may be vastly beneficial to both you and your loved ones to be aware and proactive as it could affect your future and quality of life.

Bibliography:

https://www.sciencedirect.com/science/article/pii/S0889159114000889

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4237995/

https://en.wikipedia.org/wiki/Diabetes_mellitus_type_2

https://moodle.cord.edu/pluginfile.php/723477/mod_resource/content/0/2018%20AD%20and%20insulin%20signaling.pdf

Alzheimer‘s disease or AD is a degenerative disease that leads to memory loss, and decline of cognitive functions. Type 2 diabetes (T2D) is caused by problems due to insulin resistance. How are these two different diseases related? Is glucose regulation related to neurons dying? Research has shown that having type 2 diabetes is a major risk factor for AD, and vice verses. These two diseases are more alike than they appear. The inflammation and insulin pathway are two molecular mechanisms that explain the correlation between the two diseases.

 The Insulin Pathway

In order to understand the insulin pathway we must first talk about insulin resistance. This resistance takes place in both AD and type two diabetes.

Type 2 Diabetes: In order to breakdown glucose the body needs insulin. In T2D insulin does not work properly. This leads to high levels of glucose in the body, which causes high blood sugar. Having problems with insulin production can lead to other problems in the body, like in the brain for example.

 Alzheimer’s: Insulin resistance can be shown in postmortem brains of people who suffered from AD. This impaired insulin signaling can be seen clearly in the hippocampus region of the brain. It is thought that insulin resistance in an AD brain may be caused by the build up of amyloid beta plaques. However, this is one hypothesis. There are many more hypotheses being developed surrounding the topic of insulin resistance in the brain.

Inflammation

Insulin resistance plays a large role in the inflammation found in type 2 diabetes, and AD.

Type 2 Diabetes: Obesity, due to poor diet is often linked to the development of insulin resistance, and ultimately T2D. When fat cells accumulate, inflammatory cells follow. One of the main inflammatory cells involved in T2D is the cytokine TNF-α. 

Alzheimer’s: Chronic inflammation is one of the characteristics of AD. The inflammation seen in AD is caused by the immune cell called microglia. The microglia are responsible for the protection and remodeling of synapses in the brain, and help contribute to neuroplasticity. Microglia often produce inflammatory cells in response to increased accumulation of amyloid beta plaques. Research has shown that in order for amyloid beta to cause insulin resistance, and therefore inflammation the cytokine TNF-α must be present.

What does this have to do with my diet?

Our society values convenience, so when given the choice between fast food and taking the extra time to pack food it is not surprising that many of us would choose the fast food option. These poor dietary choices combined with spending your free time watching Netflix can lead to serious problems. Nearly 40% of Americans are obese, and 30% of those who are overweight or obese have type 2 diabetes. While maybe these statistics alone aren’t enough to change your mind maybe this next statistic will make you question whether that extra piece of cake is truly worth it. Having T2D doubles your chances of developing Alzheimer’s Disease. Now I am not saying to ditch fast food entirely, I enjoy treating myself too, but the next time I am given the option of packing my lunch or get fast food, I’ll be packing my own.

 Why should you care?

There is no cure for Alzheimer’s Disease, so it is important to take preventative steps now. Remember, little changes can make all the difference.

• Pack a meal for on the go instead of getting fast food
• Watch TV or Netflix while you work out
• Find health snacks that you enjoy
• Take time for yourself!! Whether it by cooking dinner, or working out try to find healthy practices to implement now. Trust me, your future self will thank you.

Image 1  https://www.psychologytoday.com/us/blog/diagnosis-diet/201609/avoiding-alzheimer-s-disease-could-be-easier-you-think