Aim

To better understand the neural circuitry underlying learning and memory and to develop powerful tools to precisely investigate questions relevant to brain disease.

Background

In order to understand (1) how neural circuits contribute to normal functioning of complex processes, such as learning and memory and (2) what breaks down in these circuits in pathologies and diseases of learning and memory, neuroscientists need highly precise tools to interrogate these circuits.

The Kentros team has taken a two-fold approach in their investigation by generating state-of-the-art tools with unprecedented precision and by applying these tools to the interrogation of neural circuits, which are important for learning and memory.

Key Research Questions

• How do the different neuron types in a neuronal circuit contribute to the complex process of learning and memory?

• Is it possible to develop highly precise tools and therapies by targeting specific cell types in the brain?

Tools & Methods

The Kentros group is investigating the neural circuitry of learning and memory by applying – and creating – tools based in principles of molecular genetics and electrophysiology (recording from neurons) in awake, behaving animals.

Research

Genetically altered – or transgenic – mouse models are one of the most commonly used tools in a neuroscientist’s toolbox. They are often used to answer questions like: how do these cells contribute to this neural circuit and how does activity in this circuit, in turn, relate to behavior?

However, even within a given neural circuit, there are an astounding number of cell types, distinguished from one another based on the unique combination of proteins and genes they express. Thus, to really understand how the smallest parts of the circuit contribute to something as complex as learning and memory, it is important to have a tool which can identify and ultimately manipulate the circuit on the level of these different cell types.

To address this challenge, Stefan Blankvoort and colleagues from the Kentros group created with a tool known as “Enhancer-Driven Gene Expression” or “EDGE”. Enhancers are the small sequences of DNA which help control which genes are translated into proteins.

It is worth noting that while “promoters” also drive gene expression – and indeed, although most transgenic mouse models that are currently developed are based on different promoter types – enhancers are 1) much more specific to particular cell types than promoters (which can be used to drive many different types of genes) and 2) are smaller than most promoters, making them amenable to drug development.

If we can develop therapies that more precisely target just the diseased parts of a neural circuit, then we increase the chances of more effectively treating diseases and minimizing their undesirable side-effects.

The group has already begun making discoveries using this newly-developed tool. “We have found that stimulating the same neurons in the medial entorhinal cortex leads to the same hippocampal response multiple times, suggesting that there is more “hard-wiring” in the circuitry underlying memory than previously thought,” says Kentros.

Other groups at the KISN already recognize the power of this tool and have been applying it to their own work. For example, a collaboration between Kentros and Witter has led to the application of EDGE to identify and manipulate the cells within layer II of the entorhinal cortex to further clarify the role they play in the onset and pathophysiology of Alzheimer’s Disease (AD).

For more information please visit our lab's external website: kentroslab.com/