The Brain

The brain was not always recognized as an important organ. Originally, the brain was assumed to bvesaliusbrainbe nothing more than 'head filler' -- perhaps a type of bone marrow. The ancient Egyptians, who so meticulously preserved most organs during mummification, threw away the brain. According to Aristotle, "The brain is an organ of minor importance."

This view did not last. Greek anatomists eventually concluded that the brain -- not the heart -- is the seat of thought and conscious experience. Hippocrates summed things up when he wrote: "Men ought to know that from the brain and from the brain only arise our pleasures, joys, laughter, and jests as well as our sorrows, pains, griefs and tears. ... It is the same thing which makes us mad or delirious, inspires us with dread and fear, whether by night or by day, brings us sleeplessness, inopportune mistakes, aimless anxieties, absent-mindedness and acts that are contrary to habit…"

circuitbrainOver two thousand years later, we take it for granted that the brain defines who we are. But how does it work? How does sensation become experience? What makes us savor and then remember the warmth of a spring day? What tiny switch makes us choose to eat at a certain time, or order a burger and fries instead of salad?

Until the end of the 19th century, scientists generally viewed the brain as some sort of ‘hydraulic calculator’ – a bunch of tiny interconnected tubes and cavities that would trap sensory information and eventually push behavior out.

We now understand that the brain is composed of individual cells, and that information flow within the brain takes the form of electrical and chemical signals. Nonetheless, most people still generally think of the brain as a series of tiny information pathways. They call these tiny pathways ‘neural networks', or 'neural circuits’, because the majority of historical studies have focused on electrical transfer of information, which is generally (but not exclusively) propagated by neurons. The focus on neural circuits ignores many types of brain chemical signaling, and minimizes the importance of glia (a cell type as common as neurons in the brain but about which relatively little is known). So it’s a bit narrow minded. But it’s useful nonetheless, and has driven research in neuroscience for several decades.

 

The importance of glutamatergic synapsessynapse

Circuits and information flow are all about connections. The connections between neurons are specialized cell-cell junctions called ‘synapses’. Their location and function define whether a neuronal circuit exists, and what form it takes. Thus, synapses define circuits. Synapses are not passive connections. They are dynamic information transfer and processing points that can change strength within seconds of experiencing something new, or gradually over hours or years in response to hormones or aging. The results are profound. Many types of memory are formed when synapses get stronger. If a neuron synapses onto two different postsynaptic cells, and the relative strength of these synapses changes, it is like ‘flipping a switch’. Almost all psychoactive drugs work by altering the strength of synapses.

What controls the strength of synapses? There are several types of synapse. The most common type of synapse in your brain is 'glutamatergic'. In this type of synapse, messages from one cell to another take the form of glutamate -- a small amino acid that is secreted by one cell (the 'presynaptic cell') and received via 'glutamate receptors' on another cell (the 'postsynaptic cell'). This is an ancient type of cell-cell signaling that is also found outside the brain. But it is studied most heavily, and therefore best understood, in the brain.

Research by many labs over the last couple decades has shown that glutamatergic synapse strength is controlled, to a large extent, by the number of postsynaptic glutamate receptors. They're like a throttle for information flow. If there are more receptors, the synapse is stronger. If there are fewer receptors, the synapse is weaker. And if there are no receptors, it isn’t a functional synapse at all. Glutamate receptor abundance controls information flow in the brain. Thus, our research is focused primarily on understanding the molecular mechanisms controlling glutamate receptor abundance.

 

fly1The importance of Drosophila (fruit flies)

We are not particularly interested in working on things that we already know about. We want to discover new things. Things we didn't suspect. Things that will surprise us and change the way we think. To do that, we use Drosophila melanogaster (fruit flies). Fruit flies have attributes that make them perfect for discovering new things about glutamatergic synapses. What are some of these attributes?

1) Powerful molecular genetics. By identifying genes, knocking out genes, and modifying gene expression, we can learn -– at a molecular level – how things work. Drosophila have been a premier ‘genetic model organism’ for a century. It is arguably faster and easier to identify and manipulate genes in Drosophila than it is in any other animal. In addition, the functions of many Drosophila genes have been highly conserved through evolution. Thus, the things we learn about genes in flies typically apply to other animals, including humans. For example: 75% of human disease genes, and 87% of human genes associated with mental retardation in particular, have equivalents in flies. Many human genes were named after fly genes, because the genes were first discovered in flies.

2) Experimentally accessible and well-described glutamatergic synapses. Drosophila have glutamatergic synapses and use glutamate receptors the same way we do. Drosophila learning, for example, even depends on the same particular subtype of glutamate receptor found to be critical for human learning. In addition, flies (and other insects) do something particularly convenient with some of their glutamatergic synapses: They use them as neuromuscular junctions (synapses between motor neurons and muscles on the periphery of the animal, outside the dense tangle of brain tissue). This makes glutamatergic synapses in Drosophila uniquely accessible for a variety of powerful experimental techniques, including electrophysiology, immunocytochemistry, laser-scanning confocal fluorescent microscopy, and electron microscopy (all of which we use). We were the first to combine electrophysiology and immunohistochemistry to quantify postsynaptic glutamate receptor abundance in Drosophila, and are still one of only a small handful of labs able to count the number of functional receptors in a postsynaptic density, thanks to our ability measure single receptor currents in Drosophila embryos. Thus, we can say with extraordinary precision whether changes have occurred.

3) Sophisticated behavioral analysis. What good is studying changes in proteins unless these changes mean something? Flies display an extensive behavioral repertoire. Just like us, flies interact extensively with their environment and other animals, relying on several different types of sensory modalities and motor mechanisms. They explore, learn, fight, court, make love, and sleep. Many of the proteins and processes that we study have profound effects on animal viability and behavior. We're not cataloging microscopic trivia.

We want to discover new things. Flies are superb for that.

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Our approach works

We've performed genetic and biochemical screens covering over a quarter of the entire Drosophila genome. This unprecedented exploration has revealed hundreds of proteins that play significant roles in production and clustering of postsynaptic glutamate receptors. We've named and provided initial characterization of several genes. We are now using the knowledge gained from our insights to hone in on what we think are among the most important yet understudied areas of glutamate receptor biology, including entirely new highly conserved protein families and surprising new mechanisms for synapse modulation and learning.

 

 

We're confirming our findings in mice

Drosophila are a wonderful research tool. But we also use mice. We will never be able to manipulate the mouse genome as quickly and easily as we do in flies. Nor will we ever have the same easy access to intact synapses throughout development in mice as we do in flies. For over a century, flies have proven their worth as an unprecedented tool for discovery. But mice are essential too for what we do.

mousednatailStudying flies tells us how flies work. This is interesting, but when we confirm the results in mammals, it becomes very interesting. Why? Because if something is true in two species that diverged hundreds of millions of years ago, then it is almost certainly a fundamental and important biological fact. We are in search of fundamental biological facts. It's therefore important to know whether something holds true in flies and other animals, like mice.

Mouse and rat brains are intensely well-studied. In fact, perhaps surprisingly, we know a lot more about rodent brains than fly brains. Because there is so much we already know about rodent brains, they're a great place to rigorously test our new discoveries and carry the knowledge even further.

Finally, we use mice because if we want to really understand how our own brains work, we need to validate our discoveries in animals whose brains are more similar to ours. Some of our experiments are directed toward specific medical goals. For example: We think some of our work might lead to better treatments for autism, stroke, brain cancer, or amyotrophic lateral sclerosis (ALS).

 

Want to know more? You can find specifics on our Projects and Publications pages.

 

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