Mechanisms of long-range retrograde signal propogation - Deinhardt - BBSRC

The aim of this work is to understand how long-range growth factor signalling shapes neurons of the brain. Throughout life we encounter new experiences, meet new people, learn and forget. All this information is encoded within neuronal networks of the brain, and the ability of the brain to remodel and adapt these networks to store new information is termed plasticity. To restructure neuronal networks, components of the network, i.e. individual neurons change their shape. They extend processes where new synaptic connections are built, and retract other processes where old ones are abolished. This is a strictly controlled and tightly balanced procedure important in normal brain development, and its deregulation contributes to cognitive dysfunction. Neurons are specialised cells that extend axons and dendrites over very large distances. Particularly the axon, the delivering end of the neuron, can reach up to several centimeters in the human brain, and up to over a meter in motor and sensory neurons, from the spinal cord to the toes. This poses multiple logistical challenges, for example with regards to information processing within the neuron. Neurons communicate with their environment via electrical signal propagation and neurotransmitter release, or via a slower mode of communication, involving growth factors. These molecules are detected by receptors that sit on the neuronal surface and can prompt signalling cascades inside the cell. As their names suggest, growth factors are key to the structural organisation of the cell. In contrast to electrical signals, growth factor signalling is not by default unidirectional, and therefore allows the cell body to gather information about events happening at the axon terminal. This direction of information flow is termed retrograde. Each growth factor detected near the axon terminal (distally) may initiate signals that are processed locally, to be translated into e.g. start building a new synapse at this place. Alternatively, it can be sent back to the cell body, to instruct the entire neuron to start growing. This retrograde long-distance communication from the terminal back to the cell body is crucial for neuronal health, and defects in this process have been found associated with a large number of diseases, including motor neuron degeneration and dementia. However, surprisingly little is know about retrograde signalling within neurons of the brain. Brain-derived neurotrophic factor (BDNF) is a major growth factor of the brain that is first detected early postnatally and is expressed throughout life, and is known to promote network plasticity. The work proposed here will address how signals activated by BDNF at the distal axon are processed within the neuron, and how this relates to changes in cell shape and thus neuronal plasticity. We are particularly keen to understand what information is sent back to the cell body, where it can alter gene expression and affect the makeup of the entire neuron, and how this process of sending back information works on a mechanistic level. We will address this question by growing hippocampal neurons in specialised devices that allow isolation and controlled perfusion of the axon with BDNF. We chose the hippocampus as it is a highly plastic area of the brain, crucial for learning and remembering. We will identify the intracellular mechanisms that are activated locally and those relayed back to the soma using this approach, and monitor how interfering with select information impacts on changes in the shape of individual neurons. This will help understand how all signals, supportive or adverse, are communicated over distances in neurons of the brain, and why this process is so crucial for the proper function of individual nerve cells. A broader knowledge of mechanisms required for normal maintenance and plasticity of individual neurons will also provide information about processes that are failing in cognitive dysfunction.