Whole-brain imaging of mice during behavior


In a new study published in Neuron, the team of Botond Roska at the Friedrich Miescher Institute for Biomedical Research in Basel collaborated with Alan Urban (NERF) to demonstrate how functional ultrasound imaging can yield high-resolution, unbiased, brain-wide activity maps of behaving mice. These can lead to a brain-wide understanding of how brain activity relates to specific behavior – in healthy mice and in mouse models of neurologic or psychiatric diseases.

Large numbers of brain regions are active during behaviors and we need high-resolution, brain-wide activity maps, to identify which brain regions are involved in specific behaviors. However, current whole-brain functional imaging technologies, such as functional magnetic resonance imaging, are limited in resolution and difficult to apply to awake and behaving mice.

An international team of scientists led by Emilie Macé and Botond Roska, from the Institute of Molecular and Clinical Ophthalmology Basel, the FMI, and Alan Urban, has developed the emerging technology of high-resolution functional ultrasound imaging to record activity in the whole brain of mice during behavior.

Staring out the train window
We all experience that our eyes reflexively move to follow the passing landscape as we look out of a train window. This innate reflex is called the optokinetic reflex and is well conserved across species, from mice to humans it stabilizes images drifting on the retina both horizontally and vertically by moving the eye in the direction of image drift.

Understanding the neuronal circuitry underlying such sensorimotor integration is challenging because this process requires the recruitment of many brain regions interconnected and distributed across the brain. Both the input of this reflex – a specific type of cells in the retina – and the motor output – eye movements – can be manipulated in mice, which makes this reflex an ideal candidate to study sensorimotor integration in the whole-brain using this new approach.

In the new study, the researchers found out that of the 181 brain regions consistently identified in all animals, 87 regions – distributed across the whole brain – were modulated during the optokinetic reflex. First author Emilie Macé, a postdoctoral fellow in the group of Botond Roska, commented: “We were surprised how precisely we could map activity across the brain and how many brain regions became active during this simple reflex. For example, we discovered that the amygdala – a region usually associated with fear processing – was inhibited during the reflex.”

What happens when things go wrong?
In the next step, the team compared brain activity in healthy mice with mice who lack the optokinetic reflex – either because of a genetic perturbation affecting the retina that makes them incapable of generating the reflex, or because eye motion was mechanically blocked.

The results show that the majority of brain regions active upon eye movement in normal mice become inactive in mice with the genetic perturbation. Some regions in the thalamus were particularly interesting: they still respond in normal mice whose eye movements are blocked, but not in mice with the genetic perturbation, showing that they are independent of the motor output of the reflex.

A window of opportunities
“This work will really open new scientific doors as it is the first of this kind to really demonstrate the power of functional ultrasound imaging technology for circuit mapping, and in identifying important brain areas that are linked to a pathology,” says Urban.

Roska also highlights the value of the technology: “The simplicity, low cost, and ease of use of whole-brain functional ultrasound imaging, together with the ability to precisely identify brain regions, provides a system for obtaining an unbiased view of brain activity in other types of behavior, in wild-type mice as well as in animal models of neurologic or psychiatric diseases.”