GRAD Alumni Research Award 2015 Recipient: William Butler, PBS

Spatial cognition and navigation are evolutionarily critical for a number of tasks that are necessary for survival, including the locating of food, water, and mates. Research in the spatial cognition mechanisms in the human brain has enabled a greater understanding of disorders such as Alzheimer’s disease, in which one of the most common symptoms is spatial disorientation. Rat models have enabled a much more fine-grained understanding of these spatial cognition processes through the recording of single neurons in the brains of freely moving animals. In fact, research in the field of rodent spatial cognition and electrophysiology has recently returned to the forefront of scientific inquiry, thanks to the 2014 Nobel Prize in Physiology or Medicine being jointly awarded to John O’Keefe and May-Britt & Edvard Moser, researchers who have conducted some of the most seminal electrophysiological work in the field. Continuing in that tradition, this research aims to examine one of the outstanding questions about the relationship between these electrophysiological signals and animals’ navigational behavior.

My advisor, Jeffrey Taube, was one of the first researchers to discover a population of neurons in the brain that encode direction, and research in our lab has continued to elaborate on the details of these neurons and the network that forms them. These neurons, known as head direction cells, are thought to serve as an internal compass, helping to guide the rat to its intended goal. Work in our lab, and in others, has provided support for this internal compass hypothesis by showing a correlation between the head direction signal and animals’ behavior on certain navigational tasks. Similarly, lesions of brain areas associated with this signal can cause deficits on spatial behavioral tasks under certain conditions. However, this correlational evidence doesn’t necessarily prove that the head direction signal is used by the animal for navigation, in the same way that knowing where to go to drive yourself home doesn’t prove that you used your GPS to do it.

Recent lesion work we performed has revealed that damage to a very specific vestibular structure in the brain stem, known as the nucleus prepositus, can cause shifts in the head direction signal without destroying the network itself. Therefore, disruption of the cells in nucleus prepositus could theoretically cause a shift in the head direction signal. However, it is important that these structures are intact while the rat is learning to navigate, and that the head direction system isn’t able to compensate for the loss of these structures over time.

With the support of the Graduate Alumni Research Award we were able to carry out a series of experiments in collaboration with Dr. Kyle Smith to demonstrate a functional, causal relationship between the head direction signal and behavior. To disrupt these brain areas selectively during navigation, which would not be possible through an experimental lesion, we used a technique known as optogenetics. Optogenetics refers to using viruses to selectively infect neurons in a specific brain area, and causing those neurons to express a light-sensitive protein.  Through the use of a fiber optic implant connected to an external light source (commonly, a laser), we can then shine light directly onto those neurons and manipulate their firing.

We used this technique to silence neurons in the nucleus prepositus in freely moving animals. In essence, we inactivated neurons in this specific area with the flip of a switch, giving us temporally precise, reversible control of the neurons. In line with our hypotheses, we found that inactivating these neurons caused the head direction signal to drift over time. Importantly, this shift apparently took place outside the animals’ conscious awareness; their overall locomotion and movement patterns did not change. Then, in a second task, we trained animals to return to a home refuge after foraging for food on a round platform. When we performed the same optogenetic manipulation, we found that inactivating these cells during the task caused the animals to shift their homing behavior. Rather than returning directly to the home refuge, there was a significantly greater angular difference between the direction of their homeward path and the direction of the refuge. In other words, the manipulation caused the animals to go the wrong direction when they attempted to navigate back home. Taken together, these experiments demonstrate the behavioral importance of the head direction signal by showing that causing the head direction signal to shift over time, i.e. making the needle on a compass gradually rotate rather than constantly pointing north, also causes a comparable angular shift in behavior.