Research
Our aim is to use an innovative and interdisciplinary research approach to study fundamental processes in developmental neuroscience, to gain basic insights into the function of neuronal circuits, and to apply this knowledge to translational research.
Embryonic circuit development
Cortical circuit formation is a highly precise process where neurons wire together to enable complex cortical processing. However, how these circuits form initially and how their development is impacted by specific genes and neuronal activity is not well understood. Cortical circuits start to form during embryonic development and continue into adulthood. Initial circuit formation is dependent on molecular pathways involved in neurogenesis, the formation of cortical layers, and synapse formation . In addition, circuit formation has been shown to be impacted by neuronal activity and some early circuits are transient while others are permanent . The interplay between neuronal activity, changes in gene expression, and circuit formation is not well understood during this early period. To better understand how neuronal circuits are formed during embryonic ages and how activity aids this process, we developed an experimental approach to stabilize a mouse embryo within the dam and perform microscopy and electrophysiology. The resulting stability allows imaging activity and changes of the morphology of neuronal circuits from their inception until birth, in vivo.
Function of neuronal circuits
In addition to circuit development we are also interested in the function and architecture of neuronal circuits once they are fully developed. We are particularly interested in the cortical circuitry – an area of the brain that is thought to be important for sensory perception, cognition, and other high-order functions. Our aim is to understand computations of neuronal circuits in cortex. We are combining in vivo functional imaging, mouse genetics, neural circuit tracing (using viruses), pharmacology (using different anaesthetics), electrophysiological recordings, neuronal activity manipulation (using optogenetics), animal behavior, and others methods to unravel how the cortex makes sense of the environment. Several projects are ongoing. A recent project explored the mechanism by which general anesthetics induce unconsciousness. We identified that, during general anesthesia, one of the major output cell types of cortex showed a striking change in its activity pattern. Instead of the expected reduction of activity, we observed an increase and alignment of activity in layer 5 pyramidal neurons globally across cortex (synchrony). Further, this synchrony was consistent across different anesthetics and specific to layer 5 pyramidal neurons in cortex. Synchrony of layer 5 pyramidal neurons resulted in a decrease in the information output from cortex. Given the functional role of layer 5 pyramidal neurons, this decrease may result in a reduction in communication across the brain thereby disconnecting cortical areas from each other, and cortex from subcortical areas.
Early neuronal circuit development in autism
A large number of genes associated with autism have been shown to converge on embryonic processes that contribute to embryonic brain development. These include neurogenesis, cortical lamination, neuronal activity, and synaptic processes, such as synapse formation. Further, the cortex of autistic children displays patches of disorganisation (focal cortical dysplasias). This makes it important to study circuit formation in a model system that allows for detailed observations during embryonic development in vivo while at the same time being able to manipulate gene expression. Many mouse lines have been developed that have changes in the expression of high risk autism genes. In order to precisely understand which malformations and malfunctions can occur in embryos of these mouse mutants it is crucial to first observe and understand the precise timeline of events during normal development of cortical circuits by imaging embryonic neurons, in vivo. We then compare normal circuit formation in mouse embryos to embryos where gene expression of high risk autism genes is manipulated. This enables a greater understanding how autism gene mutations impact initial wiring of early cortical circuits.
