The Opioid epidemic and the steps towards solving addiction.

In the United States, overdoses have passed car crashes and gun violence to become the leading cause of death. Heroin and other opioids such as pain killers have taken hold of many lives across the nation. Addiction may begin from prescription pain killers or desire to take them, but induce users into a sense of tranquility and cause an abusive cycle. It is known that drugs like Heroin cause a wave of pleasure through the reward pathways in the brain. Users often end up chasing the high that they received the first time they took the drugs and their brain struggling to maintain its own endorphin levels after opioids create an imbalance in the natural equilibrium in the reward pathways in the brain. Opioids produce a surge of dopamine release in the brain which is modulated through the Ventral Tegmental Area. In "Opioid-induced Rewards, Locomotion, and Dopamine Activation: A Proposed Model for Control by Mesopontine and Rostromedial Tegmental Neurons", Dr. Steidl explains the Dopamine pathways that cause drug addiction and conditioned place preference behavior. The VTA has projections from the RMTg, LDTg, and the PPTg in particular that seem to contribute to the addictive behavior that comes from opioids. The New York Times spoke to individuals who had previously struggled with Heroin and other Opioids in the past and when asked to describe their addiction they stated "It’s like a time bomb. You’ve got 24 hours to get heroin, or you’re going to be really sick. You wake up, and your whole life is just based around it."(Sinha). These pathways of addiction are still being understood with research that demonstrates that opioids directly inhibit VTA GABA release, and because GABA is an inhibitory neurotransmitter, its inhibition results in an increase of dopamine release. Dr. Steidl's work demonstrates that Opioids are complex substances because they recruit multiple reward pathways in the brain and thus their euphoric effects can cause extreme withdrawal and dependence. Heroin dependence can cause individuals to act irrationally just to achieve that same level of happiness or reward. Individuals may commit crimes for money, betray family and friends, and have little regard for many of the things that their lives used to be centered around. Currently, the model that has been developed in Dr. Steidl's lab enforces that the RMTg, LDTg, and PPTg all work together in feedback loops promoting one another to send signals to the VTA in order to further release dopamine as a result of the effects of these opioids. These pathways have been studied in Dr. Steidl's work through the use of optogenetics, in which a virally transfected mouse has certain ion channels in the brain that can be inhibited or excited based on the wavelength of light that is shined on them. Dr. Steidl has looked at Acetylcholine and Glutamate channels mainly. Dr. Steidl has most recently found that VTA glutamatergic receptor mechanisms critically contribute to the development of sensitization to cocaine and morphine. Essentially, explaining that glutamate itself makes you more sensitive to the drug. Through experiments regarding drug cocaine, but utilizing similar reward pathways in the brain Dr. Steidl found that LDTg cholinergic inhibition ( turning off the Acetylcholine channels through optogenetics) resulted in less sensitization to the drug cocaine. These are recent results in his lab which have not been published yet but were explained during his presentation. These results mean that if it can be possible to induce this cholinergic inhibition, it would make individuals less likely to relapse and have less sensitization to the drug of abuse overall. Current healthcare solutions for the opioid epidemic can be effective, but with heroin and other drugs of abuse often impacting individuals from more disadvantaged backgrounds it can be difficult to repair the damage done to one's life and improve their outlook for the future. Doctors currently prescribe long-term use of medications, like buprenorphine, methadone and naltrexone. But only about 25 percent of outpatient centers provide them in the nation, so it is clear how there is much more that must be done in terms of discovery and effective treatment as many of these treatments do not work for individuals or take a long time to have an effect. With Dr. Steidl's work, there is a possibility of greater understanding of the pathways towards drug abuse and addiction and through this understanding, it can become easier to find and develop pharmaceuticals and treatment options that can help individuals who have struggled with addiction to fight the urge to relapse as well as those even currently struggling to lessen the rewarding effects and restore balance to the brain's reward pathways. 

Works Cited

Sinha, Shreeya, et al. “Heroin Addiction Explained: How Opioids Hijack the Brain.” The New York Times, The New York Times, 19 Dec. 2018, www.nytimes.com/interactive/2018/us/addiction-heroin-opioids.html?rref=collection%2Fbyline%2Fshreeya-sinha.

Steidl, Stephan, et al. “Opioid-Induced Rewards, Locomotion, and Dopamine Activation: A Proposed Model for Control by Mesopontine and Rostromedial Tegmental Neurons.” Neuroscience & Biobehavioral Reviews, vol. 83, 2017, pp. 72–82., doi:10.1016/j.neubiorev.2017.09.022.

Hands a tool of learning

It is not a secret that math is a hard subject to learn. However, using gestures could be a solution for a fundamental understanding of it. In the article, "Learning from gesture: How our hands change our minds," the authors explained how producing gestures could support learning. They found that when children used their hands, it facilitated the use of new strategies to solve a math problem. Also, it helped them to do well in a paper-pencil test. In comparison to those who did not use their hands, it was challenging to create new strategies to solve the problem. 

Gestures do not only help to learn math but also; help students to learn new words in different languages.  A study done by Shariyta Forrest at the University of Illinois at Urbana-Champaign shows that pair words with gestures help students on learning new words. In this study, students were learning mandarin; no one of the students has previous experience with mandarin. Researchers found that students remember the words best were those who learned them with the aim of gestures when compared with those who learn without gesture. Therefore, they suggest that gesture can facilitate the learning of a new language.

Elizabeth M. Wakefield, Assistant Professor at the University of Loyola at Chicago, has conducted the first study on understanding the neural connections that occurred during learning through gestures. She examined the neural mechanisms of learning math through gesture by using functional magnetic resonance imaging (fMRI). This research taught children to solve mathematical equivalence problems using speech and gesture or speech alone. The researchers chose children who successfully solved the math problems for the neuroimaging study. Children who learn used gestures and speech showed significant activation of motor regions such as frontal premotor region and parietal regions. Also, the same children expressed a dense activation in the angular gyrus, an area that is involved in math problems. These regions were not active as equal magnitude in children who learned by speech alone.  This study demonstrates that learning with gestures leads to lasting neural trace of the motor system, which suggests the beneficial effects of learning through gestures. 

Furthermore,  gestures can improve the learning of challenging subjects such as math and foreign languages. Encouraging professors to incorporate gestures while explaining a complicated topic could support education, and understanding the mechanism could change the way of teaching.

Citation:

Forrest, Sharita. “Study: Gestures Help Students Learn New Words in Different Languages.”ILLINOIS.edu, Illinois News Bureau, 29 Jan. 2019, https://news.illinois.edu/view/6367/745146.  

Novack, Miriam, and Susan Goldin-Meadow. “Learning from Gesture: How Our Hands Change Our Minds.”Educational Psychology Review, U.S. National Library of Medicine, Sept. 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562024/.

Wakefield, Elizabeth M., et al. “Learning Math by Hand: The Neural Effects of Gesture-Based Instruction in 8-Year-Old Children.”SpringerLink, Springer US, 20 May 2019, https://link.springer.com/article/10.3758/s13414-019-01755-y.

 

What do Changes in Tech Mean for Drugs?

The article “As Medicine Evolves, So Too Must Those Who Assure Its Quality” describes how the U.S. Pharmacopeia (USP) has had to evolve their drug testing programs to keep up with modern technology. The pharmaceutical world is rapidly advancing into the world of artificial intelligence, 3D printing, and mobile apps. This new technology is very exciting, since new drugs and treatments are being developed that could dramatically improve healthcare. For example, new pills are being made which can easily dissolve in water or that are reshaped to make swallowing easier. This idea is crucial for disorders like epilepsy, in which patients may struggle to take pills in the traditional manner due to seizures.

So what does this new technology mean for the world of drug quality assurance? Luckily, the USP uses a group of general principles – identity, strength, purity, and performance – which apply to technology in similar ways to drugs. Even though these technological advancements don’t have the same makeup as drugs do, they can still be tested for the same key values to make sure the patient would be treated properly. The USP plans to hire more technological experts to keep up with new developments.

In his lecture on September 17, 2019, Dr. Michael Decker spoke on just how difficult it is to get a drug through the approval process. One drug must go through research, drug discovery, pre-clinical trials, three clinical trials, and FDA review. He gave the example of Alzheimer’s disease specifically, which is a neurodegenerative disorder that affects millions of people nationwide. In addition to being an extremely brutal disease, it costs millions of dollars to treat. However, despite its prevalence and cost, there are very few effective medicines for Alzheimer’s disease.  

For drug developers, it may be time to dive headfirst into the competitive technological market. It is already difficult enough to get a drug passed through clinical trials, and now the addition of new technology could complicate the process. However, technology is also allowing for new ways of thinking about drugs that could put innovative drugs on the market. Perhaps new innovation in technology could assist in the creation of drugs to treat diseases like Alzheimer’s.  The process is competitive, but the payoff in terms of advancement is more than worthwhile. 

Links

https://www.scientificamerican.com/custom-media/usp-science-of-quality/as-medicine-evolves-so-too-must-those-who-assure-its-quality/?mvt=i&mvn=9461564f99b54129b29ba4089944548a&mvp=NA-SCIEAMERLIVE-11237933&mvl=TagLatest

https://www.dropbox.com/sh/13j3ka06799we8d/AADOyg5ICEL99hAGcGVcLlxla/(09.17.19)%20-%20Michael%20Decker?dl=0&preview=Loyola+Drug+Discovery+Presentation-revised+Decker+2019.pptx&subfolder_nav_tracking=1

References 

“As Medicine Evolves, So Too Must Those Who Ensure Its Quality.” Scientific American, 25 Sept. 2019, https://www.scientificamerican.com/custom-media/usp-science-of-quality/as-medicine-evolves-so-too-must-those-who-assure-its-quality/?mvt=i&mvn=9461564f99b54129b29ba4089944548a&mvp=NA-SCIEAMERLIVE-11237933&mvl=TagLatest

“The Drug Discovery Process: a Brief Introduction from a Biologist’s Perspective.” Neuroscience Seminar. Loyola University Chicago. 17 Sept. 2019.

The Risks of an Obesogenic Environment

Obesity has become the primary health concern across the world, which is evidenced by heart disease’s position as the number one leading cause of death. Fructose, the sweetener commonly found in sugary drinks, may be partially responsible for the massive uptick in obesity. In a study published in the Proceedings of the National Academy of Sciences, researchers found that consuming fructose may increase high-calorie cravings. This research attempts to build off of previous findings indicating that fructose is worse at suppressing appetite compared to glucose. Following consumption of a drink containing either fructose or glucose, participants viewed images of high-calorie foods during fMRI sessions. The neuroimaging results showed that the fructose group had greater activation of the orbital frontal cortex, a brain region involved in attention and reward processing, indicating their hunger was not as satiated as the glucose group. They also rated their hunger levels at various time intervals and got to choose between an immediate food reward or a delayed monetary bonus. The fructose group reported higher levels of hunger and was also more likely to choose the immediate food reward as opposed to the delayed monetary reward. Although there were no differences in leptin and ghrelin levels between the groups, the fructose group did display increases in insulin levels. Upon consumption of glucose, insulin is released and signals to the brain that food has been consumed. Fructose doesn’t stimulate insulin release as well, and therefore your brain isn’t alerted that you’ve been consuming food.

During Dr. Jennifer Beshel’s talk, she highlighted the importance that our current food landscape has on the prevalence of obesity. The rise of fast-food has ensured that we are always surrounded by high-calorie food options, and the few healthy options that do exist tend to be more expensive. You can get a burger from McDonald’s off the dollar menu, but a salad will cost you 5 bucks. In many countries, soft drinks have become cheaper than bottled water. In Dr. Beshel’s study, she examined the effects that an obesogenic environment has on manipulated flies. Beshel and colleagues demonstrated moderate differences in weight gain between normal flies and flies with their upd1 (the leptin analog) manipulated on a standard diet. When only provided a high-fat diet, the upd1-manipulated flies showed a much more significant difference in weight gain compared to the normal flies.

Both of these studies demonstrate the importance and danger of living in an obesogenic environment. For the flies, being genetically predisposed to weight gain only became a serious issue when living off a high-fat diet. For the participants in the fructose/glucose study, consuming an unhealthy sugary drink (like the ones that are widely available) further supported and advanced intake of more high-calorie foods.

Works Cited

Bakalar, Nicholas. “Fructose May Increase Cravings for High-Calorie Foods.” The New York Times, The New York Times, 4 May 2015, https://well.blogs.nytimes.com/2015/05/04/fructose-may-increase-cravings-for-high-calorie-foods/?searchResultPosition=6.

Beshel, Jennifer, et al. “A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila.” Cell Metabolism, vol. 25, no. 1, 10 Jan. 2017, pp. 208–217., doi:10.1016/j.cmet.2016.12.013.

Luo, Shan, et al. “Differential Effects of Fructose versus Glucose on Brain and Appetitive Responses to Food Cues and Decisions for Food Rewards.” PNAS, National Academy of Sciences, 19 May 2015, https://www.pnas.org/content/112/20/6509.

Links

https://well.blogs.nytimes.com/2015/05/04/fructose-may-increase-cravings-for-high-calorie-foods/?searchResultPosition=6

https://www.pnas.org/content/112/20/6509

The Link Between Estrogen and The Brain

Dr. Meharvan Singh is the Vice Dean of Research for Stritch School of Medicine and a professor in the Department of Cell and Molecular Physiology at Loyola University Chicago. On September 10th he presented his research on how hormones affect the brain, in particular how they influence aging and neurodegenerative diseases. He discussed how estrogen can enhance cognitive performance, increase neurotrophin, and play a role in protecting cells. While estrogen is very beneficial, women end up spending one third of their life in an estrogen and progesterone deprived state due to menopause. In one of Dr. Meharvan’s many studies his lab removed the ovaries in rats which directly removes the source of estrogen and progesterone. This resulted in a dramatic reduction in BDNF which is an important protein that is important in memory, learning, and survival of nerve cells. Results from Dr. Singh’s study may show evidence for a correlation between a lack of certain hormones, such as estrogen, and the onset of neurodegenerative diseases such as Alzheimer's. 

The Science Daily’s article, “Estrogen Supplements May Protect Against Dementia,” sheds more light on this topic. The Norwegian University of Science and Technology also conducted research on the role of estrogen and neurodegenerative diseases using estrogen supplements before or at the start of menopause. Some findings include, “MRIs of the brains of the women in the study showed that those who had taken estrogen supplements throughout menopause had a larger hippocampus.” The onset of dementia has been correlated with a decrease in the size of the hippocampus. Therefore, taking estrogen supplements increases the volume of the hippocampus which could be associated with slowing the progression of dementia.

While some studies present proof that estrogen therapy can be linked to protecting from some neurodegenerative diseases, others highlight the risks of estrogen therapy. The Science Daily’s article notes on the other hand how a combination of estrogen and progestin has been seen to increase the risk of heart disease and breast cancer. In some studies it has also been seen to lead to “poorer memory and a greater risk for dementia than the control group.” Therefore, estrogen therapy has some risks that should not be ignored. Further research needs to be done to investigate the link between hormones and the brain to be able to fully understand its association.

Works Cited:

The Norwegian University of Science and Technology (NTNU). "Estrogen supplements may protect against dementia." ScienceDaily. ScienceDaily, 22 January 2016. <www.sciencedaily.com/releases/2016/01/160122083802.htm>.

Understanding Obesity's Causes and Effects through Animal Models

          Scientists and news outlets discussed the obesity epidemic frequently over the past thirty years without finding much regarding a solution. Diet fads have come and gone; it feels like every week the food that was supposed to help one lose weight is now the main cause of heart disease. One thing scientists do know is just how dangerous obesity is to one’s health. Obesity can increase one’s risk for many types of cancers—especially colon cancer. The mechanism behind why obesity has such a strong link to cancer, and what puts certain individuals at higher risk for obesity in the first place is still a mystery waiting to be solved.

            Beshel’s lab hopes to discover a neural component to obesity that would eventually lead to a drug therapy solution for individuals who cannot lose weight through dieting alone. She studied the way the Drosophila brain encodes different food odors during varying stages of satiation in the paper she published with Zhong in 2013. Beshel presented hungry and satiated fruit flies with different odors to study how and where in the brain odors derive meaning and value. The researchers found that food odors evoked activity in neurons expressing Drosophila neuropeptide F (dNPF) and the neuropeptide Y homolog, both strongly correlating with food-odor attractiveness. They also discovered that hunger enhances neural and behavioral responses to strictly food odors when compared to non-food odors. Inactivation dNPF-expressing neurons or receptors had the opposite effect: removing food-odor attractiveness. Genetically enhancing dNPF activity increased attraction to food odors and aversive odors. These results demonstrate a possible neural signal that encodes values of odors in the brain that can be varied by hunger state.

            The connection between Beshel’s work and obesity is only in its beginning stages, but appears promising nonetheless. Her research could possibly lead to further studies examining the effects of dNPF neuron inactivation on feeding behavior. If the fruit flies consume less food after inhibiting food odor attraction, these results could set Beshel up nicely for examining dNPF inactivation as a possible therapeutic solution to obesity. Clearly there are many steps that have to fall into place before any of these conclusions can be made, but her work sets her in the right direction. Looking at what neural components can possibly cause obesity may contain the way to treat it or even prevent it in the future.

            Lots of research has been performed looking into not what causes obesity (like Beshel’s work), but instead what obesity can cause. Yilmaz and Sabatini are two researchers who wanted to learn more about the link between cancer in obesity. Their researchers fed mice high-fat and high-calorie food for a year, then tested the effects of this diet on the number and function of stem cells in their intestines. They found that the diet causes mice to overeat and become overweight, and it also activated PPAR-gamma and stimulated proliferation of intestinal stem cells. To test the association between PPAR-gamma activation and intestinal stem cell proliferation, they treated the mice with a drug that activates PPAR-gamma and found similar results. Researchers believe the regeneration of these stem cells are more likely to create tumors than other cells. The exact cause of this change in intestinal stem cell behavior is unclear now. It could be the weight gain or the fatty food. Unfortunately, it is possible that this mechanism may not even exist in humans. The link between diet and cancer is also very difficult to research in humans because of the multitude of possible confounding variables. Nonetheless, Yilmaz’s team hopes to examine the relationship between a fatty diet, obesity, and cancer risk further in follow-up studies.

            Yilmaz’s research is accompanied by many other studies that attempt to link diet, obesity, and cancer, but Yilmaz’s genetic component sets the work apart. Finding out that PPAR-gamma activation can lead to stem cell proliferation that increases cancer risk is a huge finding. It needs much more research to confirm that this is not the result of some confounding variable, but it is still promising. The obese mice in Yilmaz’s study provide a key piece in the obesity and colon cancer puzzle.

            Both Beshel and Yilmaz’s work demonstrate the significance of biological research prior to the more well-known clinical and translation research done on humans. Their work is crucial because these kinds of experiments would be unethical to perform on humans. It also allows for easier control of confounding variables and ease of implementation. They both provide important information about the progression of obesity in the body. Research like theirs have placed steppingstones on the road to understanding the mechanism behind what causes obesity and how it can affect cancer risk.

Important Links

-          Beshel: https://www.dropbox.com/sh/13j3ka06799we8d/AACBUIsLgo28AhC8IBwmQ7Asa/%2810.01.19%29%20-%20Jen%20Beshel/beshel_jneurosci_2013.pdf?dl=0

-          Yilmaz: https://www.scientificamerican.com/article/fat-mice-provide-clue-to-obesity-colon-cancer-puzzle/

Works Cited

Beshel, J. & Zhong, Y. (2013). Graded Encoding of Food Odor Value in the 

          Drosophila Brain. Journal of Neuroscience, 33(40), 15693-15704.

Yilmaz et al. (2016). High-fat diet enhances stemness and tumorigenicity of 

          intestinal progenitors. Nature, 531, 53-58.

The Lengthy Drug Approval Process

           On September 7, Michael Decker came to discuss Richard Mohs and Nigel Greig’s paper surrounding the lengthy drug development and discovery process. It is shown that the process of finding a new drug and evolving it is arduous, complex, and very expensive. Decker discussed that being presently aware of these processes with eventually lead to measures being put in place that improve efficiency and inevitably increase the opportunity for success surrounding the discovery and development of any new drug. Mohs and Greig outlined six parts of this process and what each part entails. Beginning with “the process” itself, drug discovery originates with a biological target. Taking the time to test this target in ways outside of what is already known can take up to 12 years or longer. Before even reaching the FDA, there has to be basic research, preclinical development, and clinical trials, which take all that time and money. Since it takes so long to do the research into one target, the costs are consistently rising. Developing a new biological or molecular target can cost on average $2.6 billion. The research is this expensive because there are a lot of mistakes made and trials and error which add up. Once reaching the Food and Drug Administration, there are more trials and tests that need to be done to even reach final review.
            For research that needs a shorter timetable, there have steadily been new laws put in place that could alleviate a lot of the empty time taken for the drug approval process. More specifically these laws have been categorized as “the breakthrough approval process” which only take research that qualifies as being outside the “standard” measures of research needs like a change in the size of a tumor or blood test over a trial period. In 2015, the legislation titled “the 21st Century Cures Act” was introduced. This is “a wide-reaching bill aimed at improving medical innovation and reforming the F.D.A.’s approval process for drugs and medical devices” (Margot Sanger-Katz NYT). Having laws like this implemented, make it so that the pathways to combatting and curing life-threatening diseases can be made a priority in order to lessen the length to discovery and saving lives. The clinical trials wouldn’t be rushed to a point that things will be missed, but as Mohs and Greig have stated, with awareness comes efficiency for what is trying to be accomplished. Researchers will be able to garner more precise diagnosis of the molecules that are intended to provide information that will make biological history. Determining how intellectual property and subsequent research is regulated gives rise to a better ability for researchers and the FDA to get medicines to those that need it urgently. 

Works Cited:

Sanger-Katz, M. (2015, May 1). Speedy Drug Approvals Have Become the Rule, Not the Exception . Retrieved from https://www.nytimes.com/2015/05/02/upshot/speedy-drug-approvals-have-become-the-rule-not-the-exception.html?searchResultPosition=3.

Mohs, R. C., & Greig, N. H. (2017). Drug discovery and development: Role of basic biological research. Alzheimer’s & Dementia: Translational Research & Clinical Interventions