Circuits In The Brain Reveal Why Neurological Disorders Occur

Date: Aug-10-2012The human brain contains billions of neurons that are arranged in complex circuits, which enable people to function with regard to controlling movements, perceiving the world and making decisions. In order to understand how the brain works and what malfunctions occur in neurological disorders it is crucial to decipher these brain circuits.

A new study, which is featured in the August 9 edition of Nature reveals that MIT neuroscientists have now come closer towards this goal, by discovering that two major classes of brain cells repress neural activity in specific mathematical ways by which one type subtracting from overall activation, whilst the other type divides it. 



Mriganka Sur, the Paul E. Newton Professor of Neuroscience and senior author of the Nature paper, remarks:

"These are very simple but profound computations. The major challenge for neuroscience is to conceptualize massive amounts of data into a framework that can be put into the language of computation. It had been a mystery how these different cell types achieve that."





The findings could assist in gaining a greater understanding about diseases that scientists believe are caused by imbalances in brain inhibition and excitation, such as autism, schizophrenia and bipolar disorder.

The brain contains hundreds of different types of neurons, although most of the neurons are excitatory, with a smaller percentage being inhibitory. The delicate balance between these two influences is the basis for all sensory processing and cognitive function. Imbalances in neuron excitation and inhibition have been linked to autism and schizophrenia.

Sur, who is also the director of the Simons Center for the Social Brain at MIT says:

"There is growing evidence that alterations in excitation and inhibition are at the core of many subsets of neuropsychiatric disorders. It makes sense, because these are not disorders in the fundamental way in which the brain is built. They're subtle disorders in brain circuitry and they affect very specific brain systems, such as the social brain."



The new study involved examining the two major classes of inhibitory neurons, i.e. the parvalbumin-expressing (PV) interneurons, which target the cell bodies of neurons and somatostatin-expressing (SOM) interneurons, which target dendrites, known as small, branching projections of other neurons. Both PV and SOM cells block pyramidal cells, which are a type of neuron.

To investigate how these neurons exert their influence, the team needed to develop a strategy in which they could activate specifically PV or SOM neurons in the living brain, so they could observe the reactions of the target pyramidal cells.

In a mouse model, the researchers genetically programmed either PV or SOM cells in the animals, so they produce a light-sensitive protein named channelrhodopsin, which when embedded in neurons' cell membranes, controls the in- and out-coming flow of ions from the neurons, changing their electrical activity. By shining a light on the neurons, the researchers were able to stimulate them.

By combining the previous process with calcium imaging inside the target pyramidal cells, the calcium levels reflect a cell's electrical activity and therefore enabled the team to determine the amount of repressed activity by the inhibitory cells.

Runyan explains: 
"Up until maybe three years ago, you could only just blindly record from whatever cell you ran into in the brain, but now we can actually target our recording and our manipulation to well-defined cell classes." 



The team wanted to find out how activation of these inhibitory neurons would affect the visual input of the brain process, and in the case of their study it was either horizontal, vertical or tilted bars. A presentation of such stimulus leads to individual cells in the eye responding to points of light. This information is then conveyed to the thalamus, which in turn relays it to the visual cortex. As the information travels through the brain it remains spatially encoded, so that a horizontal bar activates the corresponding rows of brain cells. 



These cells also receive inhibitory signals, which assist in fine-tuning their response and also ensure that there is no over stimulation. The team discovered that these inhibitory signals have two specifically different effects; Inhibition by SOM neurons subtracts from the total amount of activity in the target cells, whilst inhibition by PV neurons divides the total amount of activity in the target cells. 



Wilson comments: "Now that we finally have the technology to take the circuit apart, we can see what each of the components do, and we found that there may be a profound logic to how these networks are naturally designed."

Both of these inhibition types also have different effects on various cell responses. Every sensory neuron responds only to a specific subset of stimuli like location or a range of brightness. When PV inhibition divides the activity, the target cell still responds to the same range of inputs, but with subtraction by SOM inhibition, the range of inputs to which cells respond narrows down, and therefore makes the cell more selective. 


Unlike inhibition by SOM neurons, elevated inhibition by PV neurons also alters the response gain, which is a measurement of how much cells respond to changes in contrast. The researchers hypothesize that this circuitry is probably repeated throughout the brain and that is also plays a role in other types of sensory perception and higher cognitive functions. 



Sur's lab is planning to examine the function of PV and SOM inhibitory neurons in a mouse model of autism in mice that are missing the gene MeCP2. A lack of MeCP2 causes Rett Syndrome, a rare disease with symptoms similar to autism and other neurological and physical impairments. The team plans to test whether a lack of neuronal inhibition underlies the disease by using their new technology.

Written by Petra Rattue

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