Project

Discipline

synaptic plasticity; dendritic spines; barrel cortex; experience-dependent plasticity; 2-photon microscopy; long-term potentiation

Lead
Lay summary
When an individual undergoes a novel sensory experience the neurons in the brain that handle this information adapt in order to optimize future processing of the same information and to associate it with other inputs. The functional optimization of neuronal processing has previously been measured using electrodes. This has taught us that, after changes in input, the synaptic connections become stronger between some neurons and weaker between others. Another way to express this is 'that some neurons have changed the loudness with which they talk to other neurons'. It was generally believed that the synaptic changes (also called synaptic plasticity) happen in synapses that have long before been established during development of the brain. However, more recently we and others have found that new synapses are continuously formed and lost even in the adult brain, as if neurons are always looking for ways to optimize their connections. The magnitude of these synapse additions and losses is regulated by sensory experience. In the current project we aim to study how sensory input regulates the size and stability of new and old synaptic connections. To do this we use a microscopic technique with which we can peek into the brain of transgenic mice that express a fluorescent marker in particular synapses. This way we can directly monitor the presence and size of synapses. We do this repeatedly over the time course of a month, keeping track of the stable synapses and the ones that appear and disappear. We perform these measurements in a part of the brain that processes information from the whiskers. The sensory input through the whiskers can easily and painlessly be manipulated, so we can compare 'normal' mice with mice that undergo novel sensory experiences or in which we have repeatedly activated neurons. By comparing all these parameters we hope to gain insight in the mechanisms of synaptic plasticity in the intact mouse brain. This is ultimately important for our understanding of learning and memory. New insights from this work will also help to advance the design of new strategies towards memory enhancement and repair in neurological disorders such as Alzheimer's and stroke.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Number	Title	Start	Funding scheme

Novel sensory experience leads to changes in the functional properties of the adult neocortex. Experience-dependent cortical plasticity is thought to be an important aspect of perceptual learning, and likely depends on activity-dependent strengthening and weakening of pre-established synapses as well as on structural plasticity, including synapse formation and elimination. There is a paucity of information on how structural plasticity relates to functional plasticity in vivo. In vitro studies have shown that synaptic structures such as spines undergo rapid modifications upon strong synaptic stimulation, inhibition or LTP and LTD-like processes. However, in vivo studies so far have mostly focused on spine formation and elimination in relation to long-term sensory map plasticity and motor learning. Detailed information on the structural changes of pre-established synapses in vivo, that putatively relate to early phases of neuronal plasticity is currently lacking. We hypothesize that immediate forms of plasticity in vivo include structural changes of pre-established synaptic connections, analogous to the observations in LTP and LTD paradigms in brain slices. In this research proposal we will use an experimental strategy that combines two-photon laser scanning microscopy (2PLSM) with whole-cell electrophysiological recordings in vivo to study spine structural changes during whisker stimulation induced LTP and LTD. We will also perform a detailed analysis of subcellular structural changes in experience-dependent plasticity paradigms in vivo by measuring sizes and the relocation of dendritic organelles such as the PSD, cytoskeleton, ER and mitochondira. Furthermore, in collaboration with G. Knott at the EPFL in Lausanne we will develop and employ a novel method for high throughput correlative reconstruction of the in vivo-imaged dendrites’ ultrastructure, based on focused ion beam milling combined with serial section scanning EM. Improving our knowledge of how neurons in the cortex modulate the structure of their synaptic connections in response to changes in input and experience is key to understanding how we store information and acquire new skills. In addition, it will help to advance the design of new strategies towards memory enhancement and neuronal repair in neurodegenerative diseases and after traumatic injury.