A Neuroethological Approach to Understanding Cerebellar Function

Columbia University, New York NY

Investigators

Abstract

Many breakthroughs in neuroscience have come from studies of “champion” animal species. For example, much of what we know about hearing has come from studies of owls and bats, animals whose survival depends on capturing their meals in darkness. Fundamental knowledge about the electrical signals through which neurons communicate with one another came from studies of squid, where electric signals travel through “wires” that are particularly large, enabling fast reactions that help the squid to avoid becoming a meal (and making them easy for neuroscientists to study). Here, the PI will apply this straightforward logic to understand a region of the brain that has long fascinated neuroscientists but whose function remains mysterious. Though relatively small in size, the cerebellum contains ~3/4 of all the neurons in the human brain. Moreover, diseases of the cerebellum cause profound disorders of movement as well as emotion and thought, including autism. Developing treatments requires a better understanding of the normal functioning of the cerebellum. To achieve this, the project proposes to study the cerebellum in the animal in which it the largest and most highly-developed—a group of fish from Africa known as the mormyrids. The cerebellum is so large in mormyrids that their brain is even larger (for their body size) than the human brain. This will help them to build models of how the cerebellum works, down to the details of its microscopic structure. Because this microscopic structure is extremely similar across animals, our work may reveal fundamental principles that apply directly to humans. Though the crystalline circuitry of the cerebellum has long inspired efforts to link neural circuit structure and function, our understanding of its function remains restricted to a few select cases, such as classical reflex conditioning. This projects addresses this challenge by applying integrated experimental and computational approaches to studies of the vertebrate group with the proportionately largest and most highly developed cerebellum--weakly electric mormyrid fish. Preliminary studies of a common mormyrid species, Peter’s elephant-nose fish, have identified a region of the cerebellum, known as C1, dedicated to controlling the finger-like chin appendage, or schnauzenorgan, for which these fish are named. The highly-mobile schnauzenorgan is densely covered with electroreceptors and is vital for the foraging behavior of this species. Remarkably, C1 output neurons project directly to the brainstem motor neurons that innervate schnauzenorgan muscles and control its movement. This concise circuitry contrasts with the complex and highly distributed paths via which the mammalian cerebellum contributes to commonly studied behaviors such as locomotion or reaching. Rapid progress is expected due to the inherent advantages and ecological validity of this system coupled with the tightly integrated experimental and computational modeling approaches. On the experimental side, the PI will leverage new methods for high-resolution behavioral analysis and large-scale neural recordings in freely swimming fish during foraging. Machine learning tools, neural circuit models, and biomechanical models will allow us to identify the computational problems involved in sensorimotor control of the schnauzenorgan and to develop and test hypotheses regarding how they may be solved. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.