To tackle our scientific objectives we are using multiple approaches spanning from systems to molecules and back (see pictures below). We integrate this information in computational models to analyze and predict brain function and changes. Besides that we enjoy being puzzled every day.
System neurophysiology in behaving animals
We are probing the brain using in vivo imaging and electrophysiological methods to monitor the activity of single neurons and large neuronal populations. We were one of the first groups to use in vivo 2-photon imaging in auditory cortex (Bandyopadhyay et al 2010). We are combining in vivo 2-photon imaging with in vivo 2-photon holographic stimulation in behaving animals to probe the neural code for sound perception (see holobrain.org).
With in vivo 2-photon imaging we can image the activity of hundreds of neurons over large areas with single cell resolution (see image to right, every round spot is a neuron. This is an older “classic” image from ~2007using synthetic dyes. We now use genetically encoded indicators). We are looking at cortical maps of stimulus features, how they develop and change (i.e. Bandyopadhyay et al 2010., Winkowski & Kanold 2013 , Winkowski et al. 2013, Meng et al. 2017, Liu et al. 2019, Liu et al. 2021) as well how they are modulated during behavior (Francis et al. 2018). We use both commercial and custom 2 (and 3)-photon microscopes.
Ultimately the brain controls behavior and in converse learning changes the brain. We investigate this interaction by training animals and relating their performance and learning to the activity of specific cortical circuits. We develop systems to efficiently and automatically train and test large groups of mice (Francis et al. 2017, Francis et al. 2019).
Imaging in behaving animals can show us which neurons might be important (Francis et al. 2018, Francis et al. 2021). To causally link neuronal activity, we are combining in vivo 2-photon imaging with 2-photon holographic stimulation in behaving animals to probe the neural code for sound perception (see holobrain.org).
We also use single and multi electrode electrophysiological recording techniques to record where we cannot image: deep in the brain or to get information at high time resolution (Petrus et al. 2014, Wess et al. 2017). We are now deploying Neuropixels 2.0.
System neurophysiology and circuit mapping in vitro
We use brain slices to study and dissect mesoscale circuits using patch clamp and imaging techniques coupled with laser-scanning photostimulation (LSPS) (i.e. Zhao et al., Viswanathan et al. Meng et al. 2017, Meng et al. 2021 etc). We utilize brain slices that contain the thalamus and the cortex to study the circuits that connect these structures. With LSPS we activate presynaptic neurons and then observe the responses with whole cell patch clamp recordings. By stimulating many (up to 1000) target sites we can assemble a high resolution map of functional connectivity or functional “wiring diagram”. By comparing these wiring diagrams between animals of different ages to animals that had different experiences we can identify how for example experience shapes brain circuits (e.g. see Meng et al. 2021).
Molecules and pathways
We augment physiological studies by molecular and histological methods (In situ hybridizations, qPCR, immunohistochemistry, anterograde and retrograde tracers) to get a full picture of the developing brain.