Astrocytes: Shining the Spotlight on the Brain’s Rising Star

Catalyst Volume 10

We have within us the most complex and inspiring stage to ever be set: the human brain. The cellular components of the brain act as players, interacting through chemical and electrical signaling to elicit emotions and convey information. Although most of our attention has in the past been focused on neurons, which were erroneously presumed to act alone in their leading role, scientists are slowly realizing that astrocytes—glial cells in the brain that were previously assumed to only have a supportive role in association with neurons—are so much more than merely supporting characters.

Though neurons are the stars, most of the brain is actually composed of supportive cells like microglia, oligodendrocytes, and, most notably, astrocytes. Astrocytes, whose formal name is a misnomer given that modern imaging technology reveals they actually maintain a branch-like shape rather than a star-like one, exist as one of three mature types in the grey matter, white matter, or retina. Structurally, the grey matter astrocyte variant exhibits bushy, root-like tendrils and a spherical shape. The white matter variant, commonly found in the hippocampus, favors finer extensions called processes. The retinal variant features an elongated structure.¹

Functionally, astrocytes were previously believed to play a solely supportive role, as they constitute a large percentage of the glial cells present in the brain. Glial cells are essentially all of the non-neural cells in the brain that assist in basic functioning; they themselves are not electrically excitable. However, current research suggests that astrocytes play far more than merely a supporting role in the brain. Astrocytes and neurons directly interact to interpret stimuli and store memories⁴, among many other yet undiscovered tasks.

Although astrocytes are not electrically excitable, astrocytes communicate with neurons via calcium signaling and the neurotransmitter glutamate.² Calcium signaling works whereby intracellular calcium in astrocytes is released upon excitation and is propagated in waves that move through neighboring astrocytes and neurons. Neurons experience a responsive increase in intracellular calcium if they are directly touching affected astrocytes, as the signal is communicated via gap junctions rather than synaptically. Such signalling is unidirectional; calcium excitation can move from astrocyte to neuron, but not from neuron to astrocyte.³ The orientation of astrocytes in different regions of the brain and their proximity to neurons allows them to form close communication networks that help information travel throughout the central nervous system.

Astrocytes in the hippocampus play a role in memory development. They act as an intermediary cell in a neural inhibitory circuit that utilizes acetylcholine, glutamate, and Gamma-Aminobutyric Acid (GABA) to solidify experiential learning and memory formation. Disruption of cholinergic signaling, signaling relating to acetylcholine, prohibits the formation of memories in the dentate gyrus of the hippocampal formation. Astrocytes act as mediators that convert cholinergic inputs into glutamatergic activation of neurons.⁴ Without the assistance of astrocytic networks in close association with neurons, memory formation and long-term potentiation would be far less efficient if even still possible.

Astrocytes’ ability to interpret and release chemical neurotransmitters, especially glutamate, allows them to regulate the intensity of synaptic firing in neurons.⁵ Increased glutamate uptake by astrocytes reduces synaptic strength in associated neurons by decreasing neuronal concentration of glutamate.⁶ Regulation of synaptic strength in firing is crucial for healthy brain function. If synapses fire too much or too powerfully, they may overwhelm the brain. Conversely, if synapses fire too infrequently or not strongly enough, messages might not make their way throughout the central nervous system. The ability of astrocytes to modulate synaptic activity through selective glutamate interactions puts them in an integral position to assist in consistent and efficient transmission of information throughout the human body.

Through regulation of neurotransmitters and psychoactive chemicals in the brain, astrocytes are able to maintain homeostasis in the central nervous system. Potassium buffering and balancing of pH are the major ways that astrocytes assist in maintaining optimal conditions for brain function.⁷ Astrocytes are able to compensate for the slow re-uptake of potassium by neurons, thus decluttering the extracellular space of free potassium in response to neuronal activity. Re-uptake of these ions is extremely important to brain function as synaptic transmission by neurons relies on electrically switching membrane potentials along neuronal axons.

Due to their role in synaptic regulation and their critical position in the brain network, astrocytes also have the potential to aid in therapies for dealing with neurological disorders. For example, epileptic seizures have been found to be related to an excitatory loop between neurons and astrocytes. Focal ictal discharges, the brain activity responsible for epileptic seizures, are correlated to hyperactivity in neurons as well as an increase in intracellular calcium in nearby astrocytes; the calcium oscillations then spread to neighboring astrocyte networks to perpetuate the ictal discharge and continue the seizure. Astrocytes in epileptic brain tissues exhibit structural changes that may favor such a positive feedback loop. Inhibition of calcium uptake in astrocytes, and consequent decrease in release of glutamate and ATP, is linked to suppression of ictal discharges, and therefore linked to a decrease in the severity and occurrence of epileptic seizures.⁸ Furthermore, it is evident that astrocyte activity also plays a role in memory loss associated with Alzheimer’s Disease. Although astrocytes in the hippocampus contain low levels of the neurotransmitter GABA under normal conditions, hyperactive astrocytes near amyloid plaques in affected individuals exhibit increased levels of GABA that are not evident in other types of glial cells. GABA is the main inhibitory neurotransmitter in the brain, and abnormal increases in GABA are associated with Alzheimer’s Disease; introducing antagonist molecules has been shown to reduce memory impairment, but at the cost of inducing seizures.⁹ Since there is a shift in GABA release by astrocytes between normal and diseased individuals, astrocytes could be as the key to remedying neurodegenerative conditions like Alzheimer’s.

In addition to aiding in treatment of neurological disorders, astrocytes may also help stroke victims. Astrocytes ultimately support damaged neurons by donating their mitochondria to the neurons.¹⁰ Mitochondria produce adenosine triphosphate (ATP) and act as the energy powerhouse in eukaryotic cells; active cells like neurons cannot survive without them. Usually neurons accommodate their exceptionally large energy needs by multiplying their intracellular mitochondria via fission. However, when neurons undergo stress or damage, as in the case of stroke, the neuron is left without its source of energy. New research suggests that astrocytes come to the rescue by releasing their own mitochondria into the extracellular environment in response to high levels of the enzyme CD38, so that damaged neurons can absorb the free mitochondria and survive the damage.¹¹ Astrocytes also help restore neuronal mitochondria and ATP production post-insult by utilizing lactate shuttles, in which astrocytes generate lactate through anaerobic respiration and then pass the lactate to neurons where it can be used as a substrate for oxidative metabolism¹². Such a partnership between astrocytes and neurons presents researchers with the option of using astrocyte-targeted therapies to salvage neuronal systems in stroke victims and others afflicted by ailments associated with mitochondrial deficiencies in the brain.

Essentially, astrocytes are far more than the background supporters they were once thought to be. Before modern technological developments, the capabilities and potential of astrocytes were left woefully unnoticed. Astrocytes interact both directly and indirectly with neurons through chemical signaling to create memories, interpret stimuli, regulate signaling, and, maintain a healthy central nervous system. A greater understanding of the critical role astrocytes play in the human brain could allow scientists to develop astrocyte-targeted therapeutic practices. As astrocytes slowly inch their way into the spotlight of neuroscientific research, there is so much yet to be discovered.

References

1. Kimelberg, H.K.; Nedergaard, M. Neurotherapeutics 2010, 7, 338-353
2. Schummers, J. et al. Science 2008, 320, 1638-1643
3. Nedergaard, M. Science 1994, 263, 1768+
4. Ferrarelli, L. K. Sci. Signal 2016, 9, ec126
5. Gittis, A. H.; Brasier, D. J. Science 2015, 349, 690-691
6. Pannasch, U. et al. Nature Neuroscience 2014, 17, 549+
7. Kimelberg, H.K.; Nedergaard, M. Neurotherapeutics 2010, 7(4), 338-353
8. Gomez-Gonzalo, M. et al. PLoS Biology 2010, 8,
9. Jo, S. et al. Nature Medicine 2014, 20, 886+
10. VanHook, A. M. Sci. Signal 2016, 9, ec174
11. Hayakawa, K. et al. Nature 2016, 535, 551-555
12. Genc, S. et al. BMC Systems Biology 2011, 5, 162

Algae: Pond Scum or Energy of the Future?

Catalyst Volume 10

In many ways, rising fuel demands indicate positive development--a global increase in energy accessibility. But as the threat of climate change from burning fuel begins to manifest, it spurs the question: How can the planet meet global energy needs while sustaining our environment for years to come? While every person deserves access to energy and the comfort it brings, the population cannot afford to stand by as climate change brings about ecosystem loss, natural disaster, and the submersion of coastal communities. Instead, we need a technological solution which will meet global energy needs while promoting ecological sustainability. When people think of renewable energy, they tend to picture solar panels, wind turbines, and corn-based ethanol. But what our society may need to start picturing is that nondescript, green-brown muck that crowds the surface of ponds: algae.

Conventional fuel sources, such as oil and coal, produce energy when the carbon they contain combusts upon burning. Problematically, these sources have sequestered carbon for millions of years, hence the term fossil fuels. Releasing this carbon now increases atmospheric CO₂ to levels that our planet cannot tolerate without a significant change in climate. Because fossils fuels form directly from the decomposition of plants, live plants also produce the compounds we normally burn to release energy. But, unlike fossil fuels, living biomass photosynthesizes up to the point of harvest, taking CO₂ out of the atmosphere. This coupling between the uptake of CO₂ by photosynthesis and the release of CO₂ by combustion means using biomass for fuel should not add net carbon to the atmosphere.¹ Because biofuel provides the same form of energy through the same processes as fossil fuel, but uses renewable resources and does not increase atmospheric carbon, it can viably support both societal and ecological sustainability.

If biofuel can come from a variety of sources such as corn, soy, and other crops, then why should we consider algae in particular? Algae double every few hours, a high growth rate which will be crucial for meeting current energy demands.² And beyond just their power in numbers, algae provide energy more efficiently than other biomass sources, such as corn.¹ Fat composes up to 50 percent of their body weight, making them the most productive provider of plant oil.^3,2 Compared to traditional vegetable biofuel sources, algae can provide up to 50 times more oil per acre.⁴ Also, unlike other sources of biomass, using algae for fuel will not detract from food production. One of the primary drawbacks of growing biomass for fuel is that it competes with agricultural land and draws from resources that would otherwise be used to feed people.³ Not only does algae avoid this dilemma by either growing on arid, otherwise unusable land or on water, but also it need not compete with overtaxed freshwater resources. Algae proliferates easily on saltwater and even wastewater.⁴ Furthermore, introducing algae biofuel into the energy economy would not require a systemic change in infrastructure because it can be processed in existing oil refineries and sold in existing gas stations.²

However, algae biofuel has yet to make its grand entrance into the energy industry. When oil prices rose in 2007, interest shifted towards alternative energy sources. U.S. energy autonomy and the environmental consequences of carbon emission became key points of discussion. Scientists and policymakers alike were excited by the prospect of algae biofuel, and research on algae drew governmental and industrial support. But as U.S. fossil fuel production increased and oil prices dropped, enthusiasm waned.²

Many technical barriers must be overcome to achieve widespread use of algae, and progress has been slow. For example, algae’s rapid growth rate is both its asset and its Achilles’ heel. Areas colonized by algae can easily become overcrowded, which blocks access to sunlight and causes large amounts of algae to die off. Therefore, in order to farm algae as a fuel source, technology must be developed to regulate its growth.³ Unfortunately, the question of how to sustainably grow algae has proved troublesome to solve. Typically, algae for biofuel use is grown in reactors in order to control growth rate. But the ideal reactor design has yet to be developed, and in fact, some current designs use more energy than the algae yield produces.⁵

Although algae biofuel faces technological obstacles and dwindling government interest, many scientists today still see algae as a viable and crucial solution for future energy sustainability. UC San Diego houses the California Center for Algal Biotechnology, and Dr. Stephen Mayfield, a molecular biologist at the center, has worked with algae for over 30 years. In this time he has helped start four companies, including Sapphire Energy, founded in 2007, which focuses on developing algae biofuels. After receiving $100 million from venture capitalists in 2009, Sapphire Energy built a 70,000-square-foot lab in San Diego and a 220-acre farm in New Mexico. They successfully powered cars and jets with algae biofuel, drawing attention and $600 million in further funding from ExxonMobil. Although diminished interest then stalled production, algal researchers today believe people will come to understand the potential of using algae.² The Mayfield Lab currently works on developing genetic and molecular tools to make algae fuel a viable means of energy production.⁴ They grow algae, extract its lipids, and convert them to gasoline, jet, and diesel fuel. Mayfield believes his lab will reach a low price of 80 or 85 dollars per barrel as they continue researching with large-scale biofuel production.¹

The advantage of growing algae for energy production lies not only in its renewability and carbon neutrality, but also its potential for other uses. In addition to just growing on wastewater, algae can treat the water by removing nitrates.⁵ Algae farms could also provide a means of carbon sequestration. If placed near sources of industrial pollution, they could remove harmful CO₂ emissions from the atmosphere through photosynthesis.⁴ Additionally, algae by-products are high in protein and could serve as fish and animal feed.⁵

At this time of increased energy demand and dwindling fossil fuel reserves, climate change concerns caused by increased atmospheric carbon, and an interest in U.S. energy independence, we need economically viable but also renewable, carbon neutral energy sources.⁴ Algae holds the potential to address these needs. Its rapid growth and photosynthetic ability mean its use as biofuel will be a sustainable process that does not increase net atmospheric carbon. The auxiliary benefits of using algae, such as wastewater treatment and carbon sequestration, increase the economic feasibility of adapting algae biofuel. While technological barriers must be overcome before algae biofuel can be implemented on a large scale, demographic and environmental conditions today indicate that continued research will be a smart investment for future sustainability.

References

1. Deaver, Benjamin. Is Algae Our Last Chance to Fuel the World? Inside Science, Sep. 8, 2016.
2. Dineen, Jessica. How Scientists Are Engineering Algae To Fuel Your Car and Cure Cancer. Forbes UCVoice, Mar. 30, 2015.
3. Top 10 Sources for Biofuel. Seeker, Jan. 19, 2015.
4. California Center for Algae Biotechnology. http://algae.ucsd.edu/. (accessed Oct. 16, 2016).
5. Is Algae the Next Sustainable Biofuel? Forbes StatoilVoice, Feb. 27, 2015. (republished from Dec. 2013)

A Fourth Neutrino? Explaining the Anomalies of Particle Physics

Catalyst Volume 10

Abstract

The very first neutrino experiments discovered that neutrinos exist in three flavors and can oscillate between those flavors as they travel through space. However, many recent experiments have collected anomalous data that contradicts a three neutrino flavor hypothesis, suggesting instead that there may exist a fourth neutrino, called the sterile neutrino, that interacts solely through the gravitational force. While there is no conclusive evidence proving the existence of a fourth neutrino flavor, scientists designed the IceCube laboratory at the South Pole to search for this newly hypothesized particle. Due to its immense size and sensitivity, the IceCube laboratory stands as the most capable neutrino laboratory to corroborate the existence of these particles.

Introduction

Neutrinos are subatomic, ubiquitous, elementary particles that are produced in a variety of ways. Some are produced from collisions in the atmosphere between different particles, while others result from the decomposition and decay of larger atoms.^1,3 Neutrinos are thought to play a role in the interactions between matter and antimatter; furthermore, they are thought to have significantly influenced the formation of the universe.³ Thus, neutrinos are of paramount concern in the world of particle physics, with the potential of expanding our understanding of the universe. When they were first posited, neutrinos were thought to have no mass because they have very little impact on the matter around them. However, decades later, it was determined that they have mass but only interact with other matter in the universe through the weak nuclear force and gravity.²

Early neutrino experiments found that measuring the number of neutrinos produced from the sun resulted in a value almost one third of the predicted value. Coupled with other neutrino experiments, these observations gave rise to the notion of neutrino flavors and neutrino flavor oscillations. There are three flavors of the standard neutrino: electron (ve), muon (vμ), and tauon (v𝜏). Each neutrino is a decay product that is produced with its namesake particle; for example, ve is produced alongside an electron during the decay process.⁹ Neutrino oscillations were also proposed after these results, stating that if a given type of neutrino is produced during decay, then at a certain distance from that spot, the chance of observing that neutrino with the properties of a different flavor becomes non-zero.² Essentially, if ve is produced, then at a sufficient distance, the neutrino may become either vμ or v𝜏. This is caused by a discrepancy in the flavor and mass eigenstates of neutrinos.

In addition to these neutrino flavor states, there are also three mass eigenstates, or states in which neutrinos have definite mass. Through experimental evidence, these two different states represent two properties of neutrinos. As a result, neutrinos of the same flavor can be of different masses. For example, two electron neutrinos will have the same definite flavor, but not necessarily the same definite mass state. It is this discrepancy in the masses of these particles that actually leads to their ability to oscillate between flavors with the probability function given by the formula P(ab) = sin2(2q)sin2(1.27Dm2LvEv-1), where a and b are two flavors, q is the mixing angle, Dm is the difference in the mass eigenstate values of the two different neutrino flavors, L is the distance from source to detector, and E is the energy of the neutrino.⁶ Thus, each flavor is a different linear combination of the three states of definite mass.

The equation introduces the important concept of the mixing angle, which defines the difference between flavor and mass states and accounts for neutrino flavor oscillations. Thus, if the mixing angle were zero, this would imply that the mass states and and flavor states were the same and therefore no oscillations could occur. For example, all muon neutrinos produced at a source would still be muon neutrinos when P(mb) = 0. On the other hand, at a mixing angle of π/4, when P(mb) = 1, all muon neutrinos would oscillate to the other flavors in the probability function.⁹

Anomalous Data

Some experimental data has countered the notion of three neutrino flavor oscillations.³ If the experimental interpretation is correct, it would point to the existence of a fourth or even an additional fifth mass state, opening up the possibility of other mass states that can be taken by the hypothesised sterile neutrino. The most conclusive anomalous data arises from the Liquid Scintillator Neutrino Detector (LSND) Collaboration and MiniBooNE. The LSND Collaboration at Los Alamos National Laboratory looked for oscillations between vm neutrinos produced from muon decay and ve neutrinos. The results showed a lower-than-expected probability of oscillation.⁶ These results highly suggest either an oscillation to another neutrino flavor. A subsequent experiment at Fermilab called the mini Booster Neutrino Experiment (MiniBooNE) again saw a discrepancy between predicted and observed values of ve appearance with an excess of ve events.⁷ All of these results have a low probability of fit when compared to the standard model of particle physics, which gives more plausibility to the hypothesis of the existence of more than three neutrino flavors.

GALLEX, an experiment measuring neutrino emissions from the sun and chromium-51 neutrino sources, as well as reactor neutrino experiments gave inconsistent data that did not coincide with the standard model’s predictions for neutrinos. This evidence merely suggests the presence of these new particles, but does not provide conclusive evidence for their existence.^4,5 Thus, scientists designed a new project at the South Pole to search specifically for newly hypothesized sterile neutrinos.

IceCube Studies

IceCube, a particle physics laboratory, was designed specifically for collecting data concerning sterile neutrinos. In order to collect conclusive data about the neutrinos, IceCube’s vast resources and acute precision allow it to detect and register a large number of trials quickly. Neutrinos that come into contact with IceCube’s detectors are upgoing atmospheric neutrinos and thus have already traversed the Earth. This allows a fraction of the neutrinos to pass through the Earth’s core. If sterile neutrinos exist, then the large gravitational force of the Earth’s core should cause some muon neutrinos that traverse it to oscillate into sterile neutrinos, resulting in fewer muon neutrinos detected than expected in a model containing only three standard mass states, and confirming the existence of a fourth flavor.³

For these particles that pass upward through IceCube’s detectors, the Earth filters out the charged subatomic particle background noise, allowing only the detection of muons (the particles of interest) from neutrino interactions. The small fraction of upgoing atmospheric neutrinos that enter the ice surrounding the detector site will undergo reactions with the bedrock and ice to produce muons. These newly created muons then traverse the ice and react again to produce Cherenkov light, a type of electromagnetic radiation, that is finally able to be detected by the Digital Optical Modules (DOMs) of IceCube. This radiation is produced when a particle having mass passes through a substance faster than light can pass through that same substance.⁸

In 2011-2012, a study using data from the full range of DOMs, rather than just a portion, was conducted.⁸ This data, along with other previous data, were examined in order to search for conclusive evidence of sterile neutrino oscillations in samples of atmospheric neutrinos. Experimental data were compared to a Monte Carlo simulation. For each hypothesis of the makeup of the sterile neutrino, the Poissonian log likelihood, a probability function that finds the best correlation of experimental data to a hypothetical model, was calculated. Based on the results shown in Figure 2, no evidence points towards sterile neutrinos.⁸

Conclusion

Other studies have also been conducted at IceCube, and have also found no indication of sterile neutrinos. Although there is strong evidence against the existence of sterile neutrinos, this does not completely rule out their existence. These experiments have focused only on certain mixing angles and may have different results for different mixing angles. Also, if sterile neutrinos are conclusively found to be nonexistent by IceCube, there is still the question of why the anomalous data appeared at LSND and MiniBooNE. Thus, IceCube will continue sterile neutrino experiments at variable mixing angles to search for an explanation to the anomalies observed in the previous neutrino experiments.

References

1. Fukuda, Y. et al. Evidence for Oscillation of Atmospheric Neutrinos. Phys. Rev. Lett. 1998, 81, 1562.
2. Beringer, J. et al. Review of Particle Physics. Phys. Rev. D. 2012, 86, 010001.
3. Schmitz, D. W. Viewpoint: Hunting the Sterile Neutrino. Physics. [Online] 2016, 9, 94. https://physics.aps.org/articles/pdf/10.1103/Physics.9.94
4. Hampel, W. et al. Final Results of the 51Cr Neutrino Source Experiments in GALLEX. Phys. Rev. B. 1998, 420, 114.
5. Mention, G. et al. Reactor Antineutrino Anomaly. Phys. Rev. D. 2011, 83, 073006.
6. Aguilar-Arevalo, A. A. et al. Evidence for Neutrino Oscillations for the Observation of ve Appearance in a vμ Beam. Phys. Rev. D. 2001, 64, 122007.
7. Aguilar-Arevalo, A. A. et al. Phys. Rev. Lett. 2013, 110, 161801.
8. Aartsen, M. G. et al. Searches for Sterile Neutrinos with the IceCube Detector. Phys. Rev. Lett. 2016, 117, 071801.