The Relationships Between Obesity, Leptin, and Brain Volumes

Obesity is a widespread issue that impacts many people and may contribute to the severity of symptoms caused by comorbid conditions or even underlying conditions. As obesity’s impact on the human population increases, the need to study obesity, as well as its impacts on long-term health, becomes more and more important and prevalent. One of the biological relationships studied in this condition is the linkage between obesity and leptin concentration in the body. 

 

In the article “A Leptin Analog Locally Produced in the Brain Acts via a conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila”, Beshel and colleagues investigate the role of leptin and analog unpaired 1 (upd1) in Drosophila. Firstly, leptin is a hormone secreted by adipose tissue, and levels of leptin are correlated with body fat. If an organism has excess body fat, more leptin is released into the bloodstream, resulting in satiation, and the organism is not hungry anymore. However, in obesity, this pathway is unbalanced, which leads to high leptin levels in the bloodstream, which eventually leads to hunger signals not turning off properly. According to this study, deletion of upd1 led to increased attraction to eating, which led to that, in addition to genetic factors, obesity may be influenced by the type of food that is available. 

 

In another article titled “Interplay of circulating leptin and obesity in cognition and cerebral volumes in older adults”, Zonneveld and colleagues investigated the independent relationships of leptin and body mass index (BMI) with cognitive decline and brain volume by use of magnetic resonance imaging (MRI) in older subjects that are at risk for cardiovascular disease. According to the results, obese participants with a BMI above 30 had larger volumes of the hippocampus and amygdala than reference individuals, independent of leptin levels in the bloodstream. Individuals with a high BMI level also performed worse on a cognitive function task than the reference subjects. In addition, individuals with high leptin levels also displayed a larger volume of the amygdala, independent of BMI status. However, individuals with high leptin levels performed the same as reference individuals on the cognitive task with no statistically significant differences. Although there is no direct link between leptin and obesity that causes or contributes to cognitive decline, these results indicate that leptin and obesity may both independently have an impact on brain volume levels, which may possibly contribute to other cognitive impairments or conditions that were not measured by the task used in this experiment. 

 

The results of both Beshel et al. and Zonneveld et al. demonstrate the need for research on the relationship between leptin and obesity. Although this biological relationship has been studied in some contexts, there may be further research that needs to be done to be able to show the results of this relationship and how it may impact other parts and functions in the body. According to Zonneveld et al., the link between leptin and obesity may be significant when determining brain volume and according to Beshel et al., external food sources and choice may potentially influence obesity and the eventual release of leptin. Further research is necessary to solidify this relationship to be able to influence it positively to potentially reverse the negative impacts of obesity. With a condition that negatively impacts so many people, any kind of new research finding might be able to help alleviate symptoms.

 

 

CITATIONS: 

 

Beshel, J., Dubnau, J., & Zhong, Y. (2017). “A Leptin Analog Locally Produced in the Brain Acts via a Conserved Neural Circuit to Modulate Obesity-Linked Behaviors in Drosophila”. Cell Metabolism, 25(1), 208-217. https://doi.org/10.1016/j.cmet.2016.12.013

 

Zonneveld, M.H., Noordam, R., van der Grond, J., van Heemst, D., Mooijaart, S.P., Sabayan, B., Jukema, J.W., Trompet, S. (2021). Interplay of circulating leptin and obesity in cognition and cerebral volumes in older adults. Peptides, 135, 170424. https://doi.org/10.1016/j.peptides.2020.170424

 

 

 

  

 

 

Understanding Rett Syndrome: Two possible targets for drug treatments

     Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations on the methyl CpG binding protein 2 (MECP2) gene located on the X chromosome. MECP2 plays a vital role in brain development. Mutations in MECP2 cause severe cognitive, sensory, motor, and emotional impairments in individuals living with Rett syndrome. RTT is the 2nd leading cause of intellectual disability in women. However, there is currently no drug treatment available for RTT, so research into better understanding RTT and its associated mutations in MECP2 is very important. 

In the article “mGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome”, Dr. Rocco G. Gogliotti and colleagues found that mouse models of RTT show deficits in long term potentiation (LTP) at specific synapses in the hippocampus caused by the mutation in MECP2. They were able to show that metabotropic glutamate receptor 7 (mGlu7 ) expression is reduced in the total cortex and the hippocampus in mouse models with a MECP2 mutation and in humans with RTT. The researchers found that metabotropic glutamate receptor 7 (mGlu7) is the predominant receptor expressed presynaptically at these impaired synapses at the hippocampus. mGlu7 activation is necessary for LTP to occur in this area, so the researchers wanted to see if inducing increased potentiation in mGlu7 would treat RTT phenotypes in mouse models. The researchers were also able to show that by using two group III mGlu receptor PAMs, they were able to increase potentiation at mGlu7 mediated synapses in the hippocampus, which effectively rescued these synapses. The effect of these PAMs also rescued RTT phenotypes including learning and memory deficits, social preference and anxiety and apenas. The results of this study show that reactivation of impaired neurons found in RTT is a good target for possible treatment of the disorder. 

Dr. Rocco G. Gogliotti’s study provided a better insight into how mutated MECP2 affects other genes and the neurons and synapses in models of RTT. However, a possible drug that targets these neurons has yet to come around. An article published by Science Daily spoke about a recent study led by Dr. Manel Esteller in which they are looking at another possible drug treatment that targets the neuroinflammation that is seen in Rett syndrome. The researchers were able to show that glycogen synthase kinase-3B (GSK3B), an important neuroinflammatory protein, is over expressed in mouse models of RTT. GSK3B is important for neural and synapse development and neural growth, so the researchers believe it plays a role in the phenotypes of RTT. They decided to test the effects of a drug that acted as an inhibitor of GSK3B on mouse models of RTT. The study used the agent SB216763 (a GSK3B inhibitor), and found that mice with RTT that were treated with this drug lived longer, and it significantly reduced RTT phenotypes such as mobility impairments, apenas and tremors. Inhibition of GSK3B also led to improvement at the molecular level of neurons. As was seen in Dr. Rocco G. Gogliotti’s study, treatment of SB216763 in RTT mice caused increased potentiation in impaired neurons which improved neuronal communication and their synapses and improved their denetric network. The results of this study provide promising evidence for a possible drug treatment for RTT. 

The results of both Dr. Rocco G. Gogliotti and Dr. Manel Esteller studies provide great insight into how the mutation of MECP2 seen in RTT affects other genes and how that translates into various impairments in the brain. However, much is still unknown about the role MECP2 plays in the brain of patients with RTT. It is clear more research is needed to understand this role and explore possible drug treatments further. Future experiments could focus on how the results from these mouse model studies translate into humans living with RTT and how the drugs like the one used in Dr. Manel Esteller’s study would work when looking at a human brain instead of a mouse brain. 

Works Cited:

IDIBELL-Bellvitge Biomedical Research Institute. "A new drug shows preclinical efficacy in Rett syndrome." ScienceDaily. ScienceDaily, 14 May 2018. <www.sciencedaily.com/releases/2018/05/180514122503.htm>. 

Olga C. Jorge-Torres et al. Inhibition of Gsk3b reduces NFk-B signaling and rescues synaptic activity to improve the Rett syndrome phenotype in Mecp2-knockout mice. Cell Reports, 2018 DOI: 10.1016/j.celrep.2018.04.010  

Gestures vs. Learning and Understanding

        Gestures are widely used among individuals throughout the world. A gesture can be defined as a movement of a body part. They are used to express an idea. Gestures are universal because they can be seen as a language that convey the same meaning regardless of an individual’s spoken language or culture. They are widely used because they are simple and easy to remember. It is fascinating how gestures are used to speak to blind people who also use them even though they have never seen gestures. Researchers are inspired to study gestures because of how simple, yet how important they are in our daily lives. 

        Dr. Elizabeth Wakefield presented about how gestures enhance learning. In the article, “Learning math by hand: The neural effects of gesture-based instruction in 8-year-old children”, the researchers examined the neural basis of how gestures promote learning in children. There were two groups that were taught math problems through different conditions. The first group was taught through gesture and speech while the second group was taught through only speech. Next, fMRI was used to observe the neural patterns while the children solved math problems. They found that the children scored better when they learned through both speech and gesture than when they learned through speech alone. They discovered that the motor system is activated when the children solve the problem that was taught using gestures. They found evidence that gestures lead to a lasting neural trace in the motor system which is activated when solving a similar problem. The researchers were able to conclude that gesture engages the motor system in the learning process which helps children learn better. 

        In the research article, “From hands to minds: Gestures promote understanding”, the researchers studied learning through gestures in native English university students that had no background in technology and engineering. They examined whether the dynamic system with gestures that represent the actions of the system could improve understanding of the dynamic system. The dynamic system is made up of two layers which are structural and dynamic. The structural layer is easier to understand and is made up of the parts. The dynamic layer is made up many types of actions, processes, and consequences. One group of students watched the video about the system with verbal explanations and gestures. Thy found that these students had a better understanding of the system which was seen in their visual and oral explanations. The visual explanation included more details about the stages of the system and the oral explanation included more descriptive words. The researchers were able to conclude that watching an explanation of the system with gestures was more beneficial in understanding than only seeing gestures representing the structures of the system. 

        The two studies are correlated because they both present that gestures are crucial to learning. Whether children learn math problems through gestures or university students learn a technological system through gestures, they both demonstrate a better understanding post training. These studies present compelling data that validate that gestures are helpful in learning and understanding regardless of age. Although gestures are very simple, there are many more different studies that can be conducted to further understand them in various contexts. 

                                                             

                                                               Works Cited

Kang, S., Tversky, B. From hands to minds: Gestures promote understanding. Cogn. 

            Research 1, 4 (2016). https://doi.org/10.1186/s41235-016-0004-9

 

Wakefield, Elizabeth M., et al. “Learning math by hand: The neural effects of gesture-based 

            instruction in 8-year-old children. Attention, Perception, and Psychophysics.The 

            Psychonomic Society, Inc, 2019. https://doi.org/10.3758/s13414-019-01755-y

Two approaches to discovering possible treatments for Rett Syndrome

    This semester, Dr. Rocco Gogliotti from Loyola’s Stritch School of Medicine spoke to us about his research on a mouse model of Rett syndrome, an X-linked disorder which leads to seizures, cognitive impairments, apneas, and other motor deficits. In his presentation, Dr. Gogliotti dissected his paper, “mGLU7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome,” and explained the implications of mGLU7 receptor in the development of Rett syndrome. By investigating brain cells of deceased patients, Dr. Gogliotti found that patients who had Rett syndrome had a mutation in Methyl-CpG binding protein 2 (MECP2) and a subsequent muted mGLU7 expression, suggesting that MECP2 is an activator of mGLU7. The causality of this relationship was confirmed through mice experiments, with results showcasing that a loss of MECP2 impairs the function of the protein mGLU7 at hippocampal synapses. Further results showed that increased mGLU7 may actually lead to long-term potentiation in hippocampal and cortical regions and decrease the phenotypes of RTT syndrome. These results are both fascinating and promising, suggesting that potentiation of mGLU7 may be an effective treatment method for cognitive and respiratory deficits caused by RTT

    At this point of research advancement, it has been established that MECP2 mutations cause the development of Rett syndrome, as Dr. Gogliotti’s research corroborated. However, the approach that researchers have taken to reduce the implications of this mutation has varied. While Dr. Gogliotti focused on the expression of mGLU7 receptor, Dr. In-Hyun Park at Yale University’s Child Study Center and Stem Cell Center examined the relationship between MECP2 mutations and the BRD4 chromatin binding gene. By using a human brain organoid with a MECP2 mutation built from embryonic stem cells, Dr. Park and colleagues found that mutations of MECP2 lead to severe abnormalities, particularly in interneurons. Because interneurons are important in inhibition, regulation, and neuronal communication, the loss of interneuron function leads to the neurological issues presented in patients with Rett syndrome. Furthermore, the researchers found that interneurons with mutated MECP2 had elevated BRD4 binding. This maintained the interneurons in a hyperactive transcription state, which led to dysregulation of neural development genes.

    After reaching these conclusions from human brain organoids, Dr. Park and colleagues sought a potential treatment. Testing in vivo, the researchers found that a low dose of JQ1, an experimental cancer drug, corrected the abnormalities in the interneurons of mice with a Rett syndrome model. This is due to JQ1’s function, which reduces the number of dysregulated genes that result from MECP2 mutations and BRD4 augmented binding and subsequent hyperactive transcription. Interestingly, a low dose was helpful, whereas a high dose of JQ1 led to memory impairments. Furthermore, the mice that received the treatment lived about twice as long as those not receiving the drug. Thus, Dr. Park’s findings indicate that the transcription mechanisms of BRD4 are implicated in the development of Rett syndrome phenotypes, which may be reversed by targeting BRD4 using JQ1

    The work of both Dr. Park and Dr. Gogliotti focused on finding a target for treatment of Rett syndrome phenotypes. However, there are notable differences in their approaches and methods. While Dr. Gogliotti target mGLU7 after concluding that MECP2 is an activator of the glutamate receptor, Dr. Park targeted a gene involved in chromatin binding, BRD4. Further, Dr. Gogliotti closely examined hippocampal and cortical synapses, whereas Dr. Park investigated interneurons. Their differences in targets show that there are various pathways to reach a treatment method for Rett syndrome. Additionally, Dr. Park examined the interneurons in a human brain organoid prior to conducting an in vivo experiment on mice, whereas Dr. Gogliotti first looked at brain cells of patients who had Rett syndrome, then utilized mouse models to specify the effect of mGLU7. Although the researchers differ in their approaches, they both advanced basic knowledge of the causality behind a fatal disease and propose targets for intervention. Using this literature and other studies, researchers are continuing to apply findings into developing needed potential treatment for Rett syndrome.

 

Citations:

 

Gogliotti, R.G., Senter, R.K., Fisher, N.M., Adams, J., Zamorano, R., Walker, A., Blobaum, A.L., Engers, D.W., Hopkins, C.R., Danielle, J.S., Jones, C.K., Lindlsey, C.W., Xiang, Z., Conn, P.J., & Niswender, C.M. (2017). mGLU7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome. Science Translational Medicine. 9(403). 

Hathway, B. (2020, July). Yale researchers find potential treatment for Rett Syndrome. Yale News.

Park, I.H., Xiang, Y., Tanaka, Y., Patterson, B., Hwang, S.M., Hysolli, E., Cakir, B., Kim, K.Y., Wang, W., Kang, Y.J., Clement, E.M., Zhong, M., Lee, S.H., Cho, Y.S., Patra, P.,    Sullivan, G.J., & Wessiman, S. (2020, July). Molecular Cell Jounral. 79(1), 84-98.

 

The Role of Gesture Based Learning in Math and Reading

 

Gestures are an important aspect of human communication utilized by individuals of all walks of life. For children, gesture has proved to be an especially useful tool for learning and cognitive development. Studies focusing on gesture based learning in mathematics and reading show promising results that can further be utilized in the classroom setting to promote learning. 

In the article "Learning math by hand: The neural effects of gesture-based instruction in 8-year-old children", researchers utilized functional magnetic resonance imaging to examine the neural basis of how children solve mathematical problems either with the use of gesture and speech strategy or just speech strategy. Children were taught to produce a strategy for solving math equivalence problems either through speech and gesture or just speech alone. After the training period, fMRI was used to compare the neural patterns in each group of children as they solved additional problems during the scan. The results showed that children who learned through speech and gesture were more likely to recruit motor regions when solving problems during the fMRI scan than the children who learned through speech alone. This suggested that gesture can support and promote learning because it is a type of action which engages the motor system. There is also evidence that learning through gesture can leave an impact on the motor system through a neural trace. This neural trace is activated when the children later solve the math problems that they had learned with the gesture strategy. 

Elizabeth Wakefield's work focused on the role of gestures in mathematical reasoning. However, gestures can prove to be beneficial in other subjects as well. Researchers at Pompeu Fabra University in Barcelona have conducted studies investigating the relevance of rhythmic gestures in the development of children's narrative and oral skills. Rhythmic gestures are characterized by rhythmic movements of the hands/arms together with prosody. The participants were shown six stories which were told by two teachers under two different experimental conditions. Under the first condition, no rhythmic gestures were used to stress the keywords in the story. Under the second condition, rhythmic gestures were used. At the end of the experiment, children produced a narrative about the story they had been read to. The results showed that the children who were shown rhythmic gestures produced better stories with a better narrative structure. This study shows that the use of gestures is beneficial in improving story telling skills as well as narrative structure in children. 

Both of these studies have shown that gestures can be a powerful tool to facilitate learning in children in a variety of subjects. With the field of education evolving in the COVID-19 era, the results of these studies can be used to create new teaching methods incorporating gesture based learning. 

Work Cited:

Universitat Pompeu Fabra - Barcelona. "Telling stories using rhythmic gesture helps children improve their oral skills." ScienceDaily. ScienceDaily, 17 January 2019. <www.sciencedaily.com/releases/2019/01/190117142234.htm>.

Wakefield, E. M., Congdon, E. L., Novack, M. A., Goldin-Meadow, S., & James, K. H. (2019). Learning math by hand: The neural effects of gesture-based instruction in 8-year-old children. Attention, Perception, & Psychophysics, 81(7), 2343–2353. https://doi.org/10.3758/s13414-019-01755-y 

Possible future treatments of spinal cord injuries

 

            Spinal cord injuries occur when there is damage to the spinal cord itself or to its vertebrae, ligaments, or disks. Depending on its severity it can cause permanent loss of strength, sensation, or overall function below the site of injury. Many approaches to the treatment of these injuries have been extensively researched with some producing promising results.

In their paper, “Corticospinal-motor neuronal plasticity promotes exercise-mediated recovery in humans with spinal cord injury”, Dr. Monica A. Perez and Dr. Hang Jin Jo put forth their findings of using non-invasive stimulation of spinal synapses to improve locomotion recovery in humans with varying degrees of spinal cord injuries (SCI). The researchers performed two experiments which both involved studying the effects of paired corticospinal-motor neuronal stimulation (PCMS). During PCMS, transcranial magnetic stimulation (TMS) was used to deliver stimuli over the primary motor cortex to specific corticospinal-motor neurons depending on the injury of the individual. In the first experiment, they randomly placed 25 individuals with different chronic incomplete SCI into two groups: one combined exercise with PCMS, and the other combined exercise with sham-PCMS. Every individual of either group completed 10 sessions over the course of 2-3 weeks. In the second experiment, the effects of PCMS alone, without exercise, were observed in 13 individuals with similar timeframes as the first experiment. Motor evoked potentials (MEPs) and the level of maximal voluntary contractions (MVCs) were measured for each participant before and after each intervention. In addition, a few of the participants from each group in both experiments were asked to complete functional tasks, and some participants returned for a 6 month-follow up session that also examined MEPs and MVCs; though, none of the participants of the second experiment were a part of this 6 month follow up group. One of their findings was that there were increases in corticospinal responses and MVCs of the targeted muscles, but only in participants with PCMS, and not in those with sham-PCMS. In addition, they found that, in the 6-month follow up group, the locomotion improvements were preserved only for those receiving PCMS and not for those receiving the sham-PCMS. Furthermore, the 10 sessions of either PCMS with or without exercise resulted in similar increases in MEPs and MVCs. They hypothesize that the use of PCMS activates mechanisms similar to that of long-term potentiation, which depends on NMDA receptor activity, because an NMDA antagonist can block the effects of PCMS. Overall, the findings obtained by Dr. Perez and her colleague do conclude that PCMS could function as an effective clinical strategy to improve recovery in humans with SCI.

            A separate approach to the treatment of SCI was discussed by Dr. Chizuka Ide and his colleagues in the paper “Cell transplantation for the treatment of spinal cord injury – bone marrow stromal cells and choroid plexus epithelial cells”. The several studies looked at were conducted on rats with SCI and there were several somatic cells mentioned in the article that have been transplanted and have had their effects observed in terms of SCI treatment; however, this particular article focused on bone marrow stromal cells (BMSC) and choroid plexus epithelial cells (CPEC) as well as briefly touched on the main issues with utilizing neural stem/progenitor cells (NSPC) as treatment. The transplants were either done directly into the lesion or injected into the fourth ventricle thereby infusing the cells with cerebrospinal fluid (CSF). They found that in either method of transplantation the cells did not survive past 2-3 weeks after transplant, although, they did result in locomotor improvements, tissue repair, and axonal regeneration. The researchers pointed out that while the short duration of the cells in the body may sound like a drawback, it is in fact a positive characteristic of the cells in that it reduces the possibility of long-term harmful side-effects. Furthermore, because of the short duration of the cells it is hypothesized that the cells secret neurotrophic factors which enhance the spinal cords natural ability to regenerate. As for neural stem cells, the issue, as the article mentioned, is that there is no current way to manipulate or control the cells tendency to proliferate and differentiate. In addition, there is a difficulty in successfully integrating the cells into the host’s spinal cord tissue, and NSPC transplant does not necessarily improve locomotion capabilities in SCI patients which is a parameter that needs to be met for transplants to serve as clinical applications.

            Both labs described possible solutions to, at the very least, mitigate the effects of SCIs. Dr. Monica’s lab incorporated a common treatment of injury, that of rehabilitation exercises, with a relatively safe technique, TMS, which yielded impressive results. Although Dr. Chizuka’s article was conducted on rats and their approach is more invasive than the one proposed by Dr. Monica, it touched on a very intriguing concept which will definitely be around for others to continue studying. They both provided information which could benefit the overall field of study and possibly give patients a greater repertoire of options to give them back their previous lives.

 

 

References

Ide C, Nakano N, Kanekiyo K (2016) Cell transplantation for the treatment of spinal cord injury – bone marrow stromal cells and choroid plexus epithelial cells. Neural Regen Res 11(9):1385-1388

Jo, Perez. “Corticospinal-Motor Neuronal Plasticity Promotes Exercise-Mediated Recovery in Humans with Spinal Cord Injury.” Brain (London, England : 1878), vol. 143, no. 5, May 2020, pp. 1368–82, doi:10.1093/brain/awaa052.

T cell-based delivery of BDNF to modulate Alzheimer's Disease

 

T cell-based delivery of BDNF to modulate Alzheimer's Disease 

Alzheimer's disease is a neurodegenerative progressive disorder that has become more prevalent in society today. Since it has been suggested that the development of Alzheimer’s disease can occur well before the onset of symptoms, researchers need to determine how to locate the origins of the disease early and effectively administer drugs to counteract any degeneration. Some of the hallmark pathological effects of Alzheimer’s Disease (AD) include neurotoxic inflammation, neuronal loss specifically in hippocampal and cortical neurons, an accumulation of amyloid beta-protein plaques, and imbalances in the brain-derived neurotrophic factor (BDNF). In the articles presented below, researchers focus on measuring brain-derived neurotrophic factor (BDNF) biosynthesis and signaling as it relates to Alzheimer’s disease and how BDNF delivery can effectively work to modulate the effects of AD.

In the article titled “Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer’s disease,” researchers Krishna L. Bharani, et al., examined the correlation between BDNF levels in postmortem serum and brain samples and hippocampal pathology in patients who had differing severities of AD. They also observed the relationship between TrkB, BDNF’s receptor, and AD. This is a primitive study, as researchers were able to use and measure BDNF levels in serum, cerebral spinal fluid (CSF), and brain samples from the same patients. In their findings, they discovered that “BDNF in CSF was detected at a lower ratio in the AD group than in the control group…” (Bharani, Ledreux, Gilmore, Carroll, & Granholm, 2020). These findings are supported by previous knowledge that there is an imbalance of BDNF levels in AD patients. In terms of the TrkB BDNF cognate receptor, researchers found that Alzheimer’s patients had a decreased density of these receptors in the hippocampal region. This finding further supports the idea that disruption of BDNF and its receptors are hallmarks of AD. Using these findings, researchers believe that the restoration of BDNF and its receptors in AD may ameliorate AD progression. 

In the article “BDNF-producing, amyloid B-specific CD4 T cells as targeted drug-delivery vehicles in Alzheimer’s disease,” researchers Ekaterina Eremenko, et al., attempt to reduce AD progression by administering BDNF in hopes that it will halt the degeneration of hippocampal brain areas. Since, as shown in the previous study, BDNF and TrkB receptor disruption and imbalance seem to be prevalent in AD, researchers hypothesized that intra-brain delivery of BDNF may decrease some of the effects of AD such as neurotoxic inflammation and amyloid plaque build-up. However, the delivery of BDNF poses a significant challenge, as such treatments of neurodegenerative diseases need to be able to pass through the blood-brain barrier (BBB) to be effective. Using their previous knowledge of the success of CD4 T cells migrating to AB plaques in mice, researchers “...generated AB-specific CD4 T cells, transduced them to express BDNF, and ICV-injected them into the mice to determine whether the targeted delivery of BDNF to sites of amyloid pathology can ameliorate the disease process” (Eremenko et al., 2019).  Notably, they discovered that the mice injected with these CD4 T cells, displayed higher levels of BDNF and TrkB receptors in the hippocampus than their controls. This finding solidifies the use of ICV-injection as a way to deliver drugs to the hippocampal region effectively. They also discovered that their injection increased synaptic and neuronal recovery in the hippocampus and decreased inflammation. Regarding amyloid plaque build-up, it was found that plaques were significantly reduced in the injected mice. Taken together, these findings support AB-specific CD4 T cells as a possible, viable option for the treatment of Alzheimer’s disease. 

As the first study explored the levels of BDNF in serum, CSF, and brain tissue, the second study built off of those findings to determine a way to ameliorate some of the hallmark pathologies of Alzheimer's disease. The findings presented in the second study provide hope that there may be a way to ameliorate the effects of Alzheimer’s disease on the brain. The results seem promising, as the mice that were treated displayed improvement in terms of reduced plaques and inflammation. However, before such a treatment can be used on humans, additional studies must be conducted to further explore the therapeutic capacity of T cells and what type of administration of the cells would be clinically feasible. Yet, with these studies and many other similar studies working to determine a way to ameliorate Alzheimer's effects, viable treatment options may come within the near future. 

 Citations 

Bharani, Ledreux. “Serum Pro-BDNF Levels Correlate with Phospho-Tau Staining in Alzheimer’s Disease.” Neurobiology of Aging, vol. 87, Elsevier Inc, Mar. 2020, pp. 49–59, doi:10.1016/j.neurobiolaging.2019.11.010.

Eremenko, Mittal. “BDNF-Producing, Amyloid β-Specific CD4 T Cells as Targeted Drug-Delivery Vehicles in Alzheimer’s Disease.” EBioMedicine, vol. 43, Elsevier BV, May 2019, pp. 424–34, doi:10.1016/j.ebiom.2019.04.019. 

Current Applications of Cutting-Edge 3-D Cerebral Organoid Technology

Advances is modern biological science has provided the world with copious amounts of cutting-edge human models and drastic improvements to the level of knowledge in multiple different pathologies. Although, despite the spectacular improvement of modern medicine throughout history, we as a species have still only scraped the surface of potential discoveries and own much more room for improvement. One recent advancement in the field of biological science is the utilization of 3-D cerebral organoid technologies, which despite its novelty, has allowed researchers to make substantial discoveries in many different fields. One current study titled, “Dynamic Characterization of Structural, Molecular, and Electrophysiological Phenotypes of Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids, and Comparison with Fetal and Adult Gene Profiles”, composed by Sarah Logan et al., the researchers propose a novel experiment, where they aim to uncover further understanding of the relatively new 3D cerebral organoid technology, utilizing pluripotent stem cells (iPSCs) (Logan et al., 2020). More generally, an article from Scientific America, authored by Simon Makin, titled “’Organoids’ Reveal How Human Forebrain Develops”, attempts to summarize the methodology and different uses of 3-D cerebral organoid technology, as well as introduce a different use of these organoids, specifically to better understand how the human forebrain develops (Makin, 2020). Together, these studies offer a glimpse into the workings and implications of this novel organoid technology, and how the discovery of one piece of technology can be utilized to study countless questions in the field of neuroscience. 

In the initial study, the researchers were curious on certain properties of these organoids, attempting to understand the molecular and cellular electrophysiology, as few studies have been done in this area. The authors analyzed the possibility of comparison between the lab organoid and human organoids, by utilizing gene expression profiles of cerebral organoids, being either from fetus or adult brains (Logan et al., 2020). This is significant, as comparison between in-vivo models and human models has been historically difficult to dissertate, though the human-induced pluripotent stem cell-derived cerebral organoid has been sufficient in its tasks to model the human brain. After their experimentation was completed, the data was thoroughly analyzed and the researchers concluded that these cerebral organoids held the ability to produce and increase heterogeneous expression of genes of many different types of neuronal cells, (astrocyte, glial, etc.) (Logan et al., 2020). This substantial finding suggests the 3-D cerebral organoid technology may mimic the process of neurogenesis, meaning the production of new functional neurons from adult neuronal precursors (Ming & Song, 2011). In addition, the neuronal cells produced by the cerebral organoids were dosed in the anesthetic agent propofol and showed the expected electrophysiological responses, as well as the evidence of action potentials and activity in various channels, and through bioinformatical analysis, the researchers discovered the gene profiles in the cerebral organoids showed close to an equidistance length apart from each other in all the brain tissues sampled (Logan et al., 2020). Also, in the analysis, the Ingenuity Pathway Analysis (IPA) performed by the researchers suggested that synaptogenesis signaling, glutamate receptor binding, cyclic adenosine monophosphate (cAMP) binding protein CREB signaling, and calcium signaling exclusively were downregulated in the fetal samples, whereas all the phenotypic pathways were suggested to be shown in the adult samples (Logan et al., 2020). This analysis suggests that the pluripotent stem cells (iPSCs) were in-fact performing in the expected fashion, where the neurochemical molecules the researchers were observing were affected by the 3-D cerebral organoid. Overall, the researchers found that electrophysiological drug response closely resembles what occurs in-vivo, specifically the neuronal attributes of the cerebral organoid are closely related to human function, which is beneficial to possible application of these organoids in future models of disease and overall health in the human brain (Logan et al., 2020). This study serves as a glimpse into the many potential implications of this 3-D cerebral organoid technology, where the authors effectively paved a path for future researchers to continue improvement on their human model, hopefully allowing for a better understanding of the human brain overall. 

The second study further illustrates the implications of 3-D cerebral organoids, where author Simon Makin explores the work of psychiatrist Sergiu Paca of Stanford University, and his use of 3-D cerebral organoids to develop a more accurate understanding of how human forebrain develops (Makin, 2020). Furthermore, the researchers utilized the same human induced pluripotent stem cells used in the study by Logan, though in the current study they are utilized to mimic the development of the earliest two sections of the forebrain (Makin, 2020). In doing so, the authors utilize a technique known as ATAC-seq, which is a genetic sequencing tool that determined which genes were available for generating proteins, if they are active, current stage of the cell cycle, and what type of neuronal cell it will make (Makin, 2020). Following this, the authors implemented the 3-D cerebral organoids for approximately twenty months, where they observed both the prenatal and postnatal stages of development (Makin, 2020). Most excitedly, once the researchers compared their findings to previous literature, they suggested that the changes they were observing during this twenty month process actually closely mimicked the development of a human brain (Makin, 2020), which effectively adds to the power of this technology, given the first study also happened to make this claim. Following the results of this study, the researchers utilized their findings on this 3-D cerebral organoid technology and found that they can utilize it to find when genes that are linked to autism and schizophrenia (Makin, 2020). Overall, this study provides future researchers with a functional resource when determining if a certain genetic disease may be playing a role in its development, effectively allowing researchers to know what stage to observe when genetic manipulation takes place (Makin, 2020). The study provides sufficient evidence to the use of 3-D cerebral organoid technology, as well as providing resource to future researchers that aim at decoding the mechanisms that develop the human brain.  

Thus, these two studies, both equally important, shed light into the vast potential applications and uses of this cutting-edge 3-D cerebral organoid technology. Whether 3-D cerebral organoid technology is aiding researchers in understanding the molecular and cellular electrophysiology, or functionally allowing researchers to better understand the development process of the human forebrain, the development of this technology has been shown to greatly aid researchers in developing more accurate models of disease and function. Despite this technology’s great benefits, both studies discussed here have noted the requirement for more research into 3-D cerebral organoids. As more research is conducted, the potential discovery of different medicines and therapeutics to combat these pathologies is important and crucial to society. 

 

 

 

 

 

 

 

 

 

 

 

 

 

References 

 

Makin, S. (2020, January 24). “Organoids” Reveal How Human Forebrain Develops. Scientific American.https://www.scientificamerican.com/article/organoids-reveal-how-human-forebrain-develops/

Ming, G. L., & Song, H. (2011). Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron, 70(4), 687–702. https://doi.org/10.1016/j.neuron.2011.05.001

Logan, S., Arzua, T., Yan, Y., Jiang, C., Liu, X., Yu, L. K., Liu, Q. S., & Bai, X. (2020). Dynamic Characterization of Structural, Molecular, and Electrophysiological Phenotypes of Human-Induced Pluripotent Stem Cell-Derived Cerebral Organoids, and Comparison with Fetal and Adult Gene Profiles. Cells, 9(5), 1301. https://doi.org/10.3390/cells9051301