The brain is composed of a wide array of interconnected neurons, including both excitatory principal cells and a diverse assortment of regulatory interneurons. As neurons communicate through electrochemical mechanisms, characterizing the electrical signatures of both control and experimentally perturbed neurons provides great insight into the properties of the fundamental components that compose brain circuits.

With whole cell electrophysiology, we use finely pointed glass electrodes to precisely record the electrical signal from within individual neurons. Thus, we can examine both the functional electrical properties intrinsic to that particular cell and monitor the synaptic inputs that neuron receives. While recordings are often made from the neuronal cell body, the Soltesz lab has experience recording specifically from smaller structures, including hippocampal dendrites or even axonal terminals.

We also utilize several variants on the whole cell electrophysiology approach to interrogate other features of neuronal networks. We can apply compounds to manipulate neuronal activity either through bath application onto the entire brain slice, or through more targeted application via a microinjection system. Through paired patch-clamp recordings, we explore how two simultaneously recorded neurons (whether of the same or different cell types) are interconnected and how they influence the electrical properties of each other. We also employ optogenetic techniques to alter the activity of genetically targeted neuronal populations in response to light stimulation, both to examine their downstream connectivity and how they influence the electrical properties of other neurons. Furthermore, we have the capacity to combine whole cell electrophysiology with simultaneous high-speed imaging of optical probes (e.g. calcium and voltage indicators), enabling us to incorporate the high single cell precision of electrophysiology with broader population level readouts of activity within a brain slice.

Neurons recorded with whole cell electrophysiology can be filled with intracellular tracers, allowing enabling later morphological reconstruction of the cell. Subsequently, the labelled cell can be further stained for neurochemical markers with immunohistochemistry.

Below is an example of data from paired recordings of hippocampal interneuron (CB­₁BC) signaling to pyramidal cells (PC), where CB₁BC stimulation evoked inhibitory currents in the PC (panel A). The impact of a manipulation on CB₁BC to PC signaling, in this case following proton irradiation (0.5 cGy) was then quantified (panel B). The morphology of the recorded neurons was then reconstructed (panel C). For further information, see Lee S-H et al., 2017, Brain Structure and Function.

Lab Members

The optical transparency and small brain sizes of larval zebrafish have enabled unprecedented access to single-cell neural dynamics across the whole brain.  With this, we seek to discover novel principles of cellular resolution communication networks that are integral for generating pathological seizure dynamics. Just recently, we have incorporated the chronically epileptic mouse into our analysis. Which is to say, we can now draw insights across evolutionary time, and which will be directly relevant towards translation. Our key advances so far:

• Built biologically constrained single-cell whole brain effective connectivity models optimized from experimentally acquired calcium dynamics as a platform for hypothesis testing.
• With the help of novel clustering algorithms, we discovered a new ‘type’ of neuron – the higher-order hub neuron – which is responsible for destabilizing epileptic networks by facilitating unrestrained excitation downstream.
• Things are surprisingly similar in chronically epileptic mice! This means we have characterized a previously unrecognized organization of epileptic networks that leads us to predict a new target for seizure control.

Moving forward, we will use our lab’s full-scale data-driven models of hippocampal dentate gyrus and CA1 to dig deeper into the underlying circuit mechanisms responsible for the emergence of higher-order hubs in epileptic networks.

Lab Members