How should we approach solving the most fundamental questions in neuroscience? Some would say that our current endeavors into mapping the complement of neuronal connections (the connectome) within the human brain will bring us the most fruitful gains; and they could be right. This is the main focus of several (expensive) big data initiatives such as the BRAIN Initiative, the Human Connectome Project and the Human Brain Project.

However, a major shortcoming of these projects is the lack of goals slated to mapping the other half of the brain; a complement of cells known as glia, of which there are three predominant populations. These cells make up fifty percent of the total brain volume and are integral to normal brain function. A complete understanding of the brain’s “support cells”, as they are also called, along with mapping the neuronal wiring, will be paramount for a global theory of how the brain works to bring about consciousness and our plethora of behaviors.

Microglia

Neuroglia consist mainly of astrocytes, oligodendrocytes and microglia, the last of which do not actually originate in the brain. Instead, microglia (my current field of research), originate in the fetal yolk sac (a structure involved in primitive hematopoesis, or blood formation) where many other primitive and tissue resident macrophages are born. Contrary to original theories, microglia migrate into the brain early in embryonic life and reside there as a stable, self-sustaining population of cells, which are never replaced by bone marrow-derived cells from the periphery.

In essence, unlike other glia, our microglia grow old with us. As a pool of tissue-specific macrophages, microglia constitute the immune cells of the central nervous system. They are capable of mounting an immune response against foreign invaders (e.g. blood cells or proteins and bacteria) as well as clear neuronal debris after injury. As such, they have, somewhat insultingly, been dubbed the “garbage men of the brain.”

It has become clear that this is short-sighted. For example, microglia mediate the elimination of supernumerary synapses from the developing brain through a mechanism known as phagocytosis. Essentially, they gobble up the unnecessary synapses that the brain generates during development, a process without which many developmental and behavioral abnormalities can occur. Understanding this process is thus essential for determining how the brain’s connections are wired.

Extending their services into postnatal life, microglia also maintain the status quo within the brain. For example, when microglia are completely depleted from the central nervous system, adult mice show deficits in learning. In other words, your microglia can make you smarter through learning-induced synaptic remodeling; they act to balance removal of unused or inappropriate synapses allowing neuronal energy expenditure to be allocated to forming efficient synapses.

What important programs do these little “electricians” employ to bring about an appropriately wired brain? How can we manipulate them to prevent or curb neurological and mental illnesses? These are important questions that the neuroscientific community is currently asking, but must be put into the wider framework of mapping the human brain.

Astrocytes

Astrocytes (or astroglia) perform the most diverse set of functions of the glial cells, including sharing with microglia the role of synaptic maintenance. How could they not? A single astrocyte can contact up to one million synapses. At the microstructure level this is known as the “tri-partate synapse”.

It is at this juncture of the pre- and post-synaptic clefts (where the electrical signal of one neuron is coupled via a chemical signal – a neurotransmitter – to the next neuron) and the astroglial process, that astrocytes do most of their work. Here, they can regulate the rate and strength of synaptic transmission across neurons by releasing or sequestering neurotransmitters and modifying extracellular ion concentrations. Not only do they “listen” and “talk” to neurons, but they also provide metabolic support of endothelial cells, which line the brain vasculature, making up the blood brain barrier. At this site, they are also well positioned to regulate the amount of blood flow to a local brain region.

Recently, astrocytes have made public headlines with the discovery of their involvement in bulk clearance of brain metabolic waste during sleep, the importance of which is not lost on us after staying up too late the night before an exam.

Oligodendrocytes

Oligodendrocytes (oligos for short), the central nervous system equivalent of the Schwann cell in the peripheral nervous system, wraps a fatty sheath around the axons of neurons. This sheath known as myelin provides insulation to the axon and allows for much faster propagation of the electrical signal and thus faster communication and transmission of information. Think of it as the insulation around electrical wires on your favorite appliance.

Oligos seem to only function in this capacity, but we do not actually know that – a rough search on PubMed shows about 25 times more papers are published on neurons than oligodendrocytes. For example, a study published this week in the journal Science found that oligos are much more diverse than previously known. The study authors found that this cell type alone could be sub-divided into six classes based on their molecular signatures. We do not yet know the function of each or how each type may play a role in brain cytoarchitecture to facilitate faster, more efficient neuronal signaling, but it should become a priority.

Each of the glial functions listed above (and we have left out other types of glia, such as Bergmann glia, NG2 glia and ependymal cells, but we know even less about them) are essential to global brain plasticity and learning. Because of their intimate relationship with neurons, glial cells hold a central position in influencing cognitive processes. Author of The Other Brain, R. Douglas Fields suggested in a Nature Comment:

“[That] these include processes requiring the integration of information from spatially distinct parts of the brain, such as learning or the experiencing of emotions, which take place over hours, days and weeks, not in milliseconds or seconds.”

In other words, because glia work on the slower chemical level, not via electrical signals, they may facilitate paradigms such as learning, which do not happen instantaneously like say, visual perception. I could not agree more. But at this time, we can only speculate as to how glia might impart their “magical elixir” on neurons, facilitating the workings of the most complex biological entity in the known universe.

Over a century after the start of glial research, we still lack fundamental knowledge of glial numbers, diversity, distribution throughout the brain and function in the context of neurons and between themselves. The “neurotechnologies” that arise from the neurocentric initiatives should additionally be allocated to studying these questions.

If our minds, which emerge from the tangled wet mass of neurons, make us who we are, then paraphrasing my mentor’s mantra sums it up best: What have your glia done for you today?

References

Araque A, Parpura V, Sanzgiri RP, & Haydon PG (1999). Tripartite synapses: glia, the unacknowledged partner. Trends in neurosciences, 22 (5), 208-15 PMID: 10322493

Kettenmann, H. & Ransom, B. R. (eds) Neuroglia 3rd edn (Oxford Univ. Press, 2013).

Paolicelli RC, Bisht K, & Tremblay MÈ (2014). Fractalkine regulation of microglial physiology and consequences on the brain and behavior. Frontiers in cellular neuroscience, 8 PMID: 24860431

Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, Hempstead BL, Littman DR, & Gan WB (2013). Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell, 155 (7), 1596-609 PMID: 24360280

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, & Nedergaard M (2013). Sleep drives metabolite clearance from the adult brain. Science (New York, N.Y.), 342 (6156), 373-7 PMID: 24136970

Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, La Manno G, Juréus A, Marques S, Munguba H, He L, Betsholtz C, Rolny C, Castelo-Branco G, Hjerling-Leffler J, & Linnarsson S (2015). Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science (New York, N.Y.), 347 (6226), 1138-42 PMID: 25700174

Image via Jose Luis Calvo / Shutterstock.