Aim

To characterize the neural circuitry of the entorhinal cortex, an important area involved in memory processes and one of the first brain regions affected by Alzheimer’s disease.
 

Background

When neuroanatomist Menno Witter sets out to learn more about a brain region, such as the entorhinal cortex, his approach is not unlike that of a landscape surveyor. Rather than survey the shape, contour, location and dimensions of a piece of land, however, Witter investigates neural real estate. He surveys the large-scale connections between brain regions and characterizes the features of the small-scale, local neural circuits within each region.

The ultimate goal of a landscape surveyor is to accurately describe the land so that others can begin construction or engineering projects based on that information. Similarly, Witter’s ultimate goal as a neuroanatomist is to accurately describe the connectivity of brain regions so that he and other scientists can plan experiments to explore the functions of these networks and ultimately design tools and therapies to treat diseases that disrupt healthy neural landscapes.
 

Key Research Questions

1. Can functional differences that exist between sub-regions of the entorhinal cortex be explained by underlying differences in neural circuitry?
2. Of the neurons in the entorhinal cortex, which ones are key players in the initiation and development of Alzheimer’s disease?
    

Tools & Methods

Witter’s team uses genetically engineered animals and non-infectious viral tracers to fluorescently visualize specific cell types and connections within the entorhinal cortex.

After identifying cell types and connections, the team can turn specific cells on and off with laser beams (a technique known as optogenetics) and then study the effect of this manipulation on the rest of the circuit.
 

Research

Researchers have previously shown that the sub-regions of the entorhinal cortex (EC) – lateral (LEC) and medial (MEC) – play different functional roles, but no one really knew why. Witter’s research group was interested in seeing if differences in their neural circuitry could provide an explanation.

However, until recently, local circuit analysis revealed striking similarities rather than differences, of the two sub-regions. New data from the lab suggests that rather the larger-scale connections of the LEC and MEC with other parts of the brain explain their functional differences.

The Witter group further discovered an interesting relationship between the large-scale and small-scale connections. Using a complex combination of available techniques, they discovered that connections from different cortical brain areas converged on single neurons in the LEC, and specifically within a small band or layer (named “layer II”) of the LEC. This means that a single neuron in this layer is receiving, and likely integrating, information from many different brain regions. Based on this very recent finding, Witter postulated that the LEC is the main integrator of information about what is happening in our environment and when that is happening, whereas the MEC is involved in keeping track of where things are taking place.

Neurons in layer II of the EC are directly connected to and send information to the hippocampus – a brain area critical for memory. Given that layer II of the EC is one of the first brain areas to be affected in Alzheimer’s disease, a better understanding of this circuitry is essential to understand what is happening in this devastating disease, with the ultimate hope to find treatments that will either slow down the development of, or cure the disease.

Witter has close interactions with his colleague Cliff Kentros, resulting in a recently patented new tool which makes it possible to manipulate the activity of specific neuron cell types. Future work will use this tool to manipulate the activity of layer II neurons in the EC and further clarify the role they play in the healthy and the diseased brain. This integrated research approach will now be extended as part of the newly established K.G. Jebsen Center for Alzheimer’s Disease.