Shedding Light On Neuronal Networks

Controlling neurons with light gives neuroscientists a new way to study thought, behaviour and movement.

As we are constantly reminded the human brain is the most complex construct known to man, possibly even in the universe. It contains around 100 billion specialized cells called neurons that each chemically and electrically interact with 1,000 to 10,000 other neurons at junctions called synapses – that’s 1 quadrillion interactions! But it doesn’t end there, as we grow and develop these interactions change based on our experiences and genetic composition, and this is known as plasticity.

It is therefore not hard to believe, that until recently understanding how these interactions within specific regions of the brain translate into movements and thought processes was difficult and extremely limited by the techniques available.

Nevertheless, neuroscientists now have a new tool capable of studying the function of particular groups of neurons through genetic manipulation followed by exposing cells to bursts of a particular wavelength of light.

The technique, called “optogenetics” allows precise manipulation of specific neurons that associate to particular functions through either stimulation or inhibition of electrical signalling within those cells.

Neuronal signalling:

Electrical signals are generated in neurons through the build-up of positively charged ions inside the cell. This generates a noticeable electrical difference between the inside, which becomes positive, and outside of the cell, that is now negative.

neuro picture

This charge is prevented from dissipating by the impermeable membrane and moves along the neuron– this is called a called a nerve impulse or depolarisation.

When this electrical signal reaches 1 of the 1 quadrillion synapses in our brain it triggers release of chemicals into the synapse called neurotransmitters – which induce a similar electrical impulse in the cell it contacts.

The flow of the charged ions into neurons is controlled by tiny pumps buried in the impermeable membrane. These pumps are selective for the type of ion they allow to pass across the membrane and variants exist that can pump negatively charged ions into the cell. Negative ions have an inhibitory effect and prevent nerve impulses firing, while positive ions are stimulatory and cause nerve impulses.

It is this principle that researchers at Stanford University have harnessed to control the activity of neurons at will.

This is through the intrinsic property of an algal protein called channelrhodopsin-2 (ChR2).  A membrane pump found in algae that pumps positively charged calcium ions into cells that are exposed to a specific wavelength of light (460nm) that we see as blue.

Therefore by introducing the gene coding for ChR2 into specific cells using an attenuated form of Lentivirus – a viral particle that inserts its genetic material into host cells – we can stimulate nerve impulses in cells when they are exposed to blue light.

While this is useful, as any geneticist will tell you, the ability to remove a certain gene is the best way to study its function. By looking at what’s gone wrong after its removal, you can accurately hypothesise what that gene did before you removed it. But removing an electrical signal seems a little farfetched…..

This is where the halorhodopsin called NpHR comes in, it too is a membrane pump that can be introduced into neurons in exactly the same way – but instead functions to pump negatively charged chloride ions (Cl) into neurons. Rather luckily NpHR is stimulated to do so when exposed to yellow light of an entirely different wavelength (580nm), therefore giving neuroscientists an effective way to switch “on” or “off” specific neurons within a system. This can be done to such precision that individual nerve impulses can be prevented by exposing neurons to yellow light at the right time. This is a great leap forward from the excitation of neurons with electrodes that can have only stimulatory roles and do so to every cell in the surrounding environment, preventing any real precision.

 Consequences?

While the ability to control brain function in mice might seem a little frightening, it is simply to determine the function of specific circuitry within mammalian brains and will hopefully lead to much greater understanding of how higher level processes are generated.

And for the animal lovers – introduction of ChR2 and NpHR into mouse neurons had no effect on the ability of these brain cells to function normally. This is because both are pumps rather than channels, and so only influence brain signalling when hit by the right wavelength of light.

Image adapted from:

Photo credit: <a href=”http://www.flickr.com/photos/wellcomeimages/5814248573/”>wellcome images</a> via <a href=”http://photopin.com”>photopin</a&gt; <a href=”http://creativecommons.org/licenses/by-nc-nd/2.0/”>cc</a&gt;

Zhang F, Wang LP, Brauner M, Liewald JF, Kay K, Watzke N, Wood PG, Bamberg E, Nagel G, Gottschalk A, & Deisseroth K (2007). Multimodal fast optical interrogation of neural circuitry. Nature, 446 (7136), 633-9 PMID: 17410168

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