Neuronal circuits that guide behavior
The Section on Behavioral Neurogenetics studies how neuronal circuits produce behavioral responses that are well suited to environmental context and internal needs. The natural environment presents a continuous stream of sensory stimuli that animals must quickly evaluate to choose an appropriate behavioral response - the laboratory aims to understand the functional development of neuronal connections which mediate these choices To achieve this, the laboratory combines computational analysis of behavior with classical genetic and cell-based circuit manipulations in zebrafish. Larval stage zebrafish larvae have a tractable nervous system and a repertoire of genetically determined behaviors. Zebrafish have the additional advantage of a brain that is structurally similar to that of humans with the likelihood that many neuronal mechanisms are conserved. Capitalizing on the optical clarity of zebrafish at larval stages, the Section uses molecular, genetic and transgenic approaches to visualize and manipulate identified neurons for mapping circuits underlying sensory-guided behavior. Methods currently in use include large-scale calcium imaging, optogenetic manipulations, neuronal tracing, targeted genetic mutations and high throughput analysis of behavior. The laboratory has developed the use of circuit-breaking screens to identifying behaviorally relevant neurons, in which Gal4 enhancer trap lines are used to inactive selected neurons before behavioral testing.
Two important criteria that the nervous system uses to assess stimulus salience are sensory context and motivational state. Natural environments are full of non-salient noise that can mask valuable information. In order to process important signals, the nervous system must avoid being overwhelmed by irrelevant stimuli. Indeed, in humans, breakdowns in filtering mechanisms are thought to contribute to the cognitive flooding that occurs in diseases such as schizophrenia. A clinically relevant paradigm for studying the gating of sensory information is prepulse inhibition. In prepulse inhibition startle responses are suppressed when subjects are exposed to a weak pre-stimulus. Prepulse inhibition and other forms of startle modulation can be robustly induced in fish, where experiments can take advantage of the well described neuronal pathway for startle responses.
Responses to sensory information are also strongly influenced by short-term motivational states such as hunger or fear. Motivational state control in mammals is primarily implemented by neuromodulator systems that project diffusely throughout the brain. The complexity of the mammalian brain and context-specific functions of these systems have made it difficult to rigorously define neuronal pathways that trigger and maintain behavioral states. The Section has demonstrated that larval zebrafish manifest several distinct short-term behavioral states characterized by temporary changes in locomotor activity and responsiveness to sensory stimuli. One such state is light-search behavior, including phototaxis and exploration activity.
Zebrafish neurodevelopmental disease models
Genetic mutations and adverse environmental events during fetal brain development may increase the risk of developing neurological and psychiatric disorders after birth. However, the specific neurodevelopmental abnormalities that predispose the brain to disorders such as autism and schizophrenia remain elusive. These disorders are characterized by breakdowns in sensory filtering and changes in motivational state. A major objective of the laboratory is to therefore use information gained from decoding the circuits that mediate these processes, to revealing how genetic mutations underlying neurodevelopmental disorders disrupt brain development. We aim to identifying the specific neuronal cell types and connections that are adversely effected by genetic and environmental changes leading to neurodevelopmental disorders. The Section also collaborates with other laboratories to help phenotype new zebrafish models of neurological and psychiatric disease.
Tools for neurobiological investigations
To fully harness the power of zebrafish for dissecting neuronal circuits, the laboratory has developed software and transgenic tools to advance neurobiological experiments in zebrafish. These include:
- Transgenic lines for selectively visualizing and manipulating neurons and other cell types
- Software for tracking and analyzing behavioral responses in larval zebrafish
- Robust methods for inactivating and sensitizing neurons during behavioral tasks
- Computational tools for designing transgenes for robust expression
- An atlas of the larval brain based on high-throughput imaging of transgene expression patterns