How do neural circuits give rise to behavior? A fundamental goal of neuroscience research is to explain behavior in terms of neuron function and connectivity. The key steps to achieving this goal are (1) to define neuron populations that contribute to behavior, (2) to develop a wiring diagram of the connections between these neuron populations, and (3) to determine the contribution of the neurons and their connections to behavior. This approach is analogous to a reverse engineering strategy where measurements are made on a complex system as it performs its task; later, components are specifically activated to test ideas about how the system works.
We are exploring neural control of innate mammalian motivated behaviors such as feeding. The hypothalamus, a structure at the base of the brain, has been known for decades to be critical for many of these innate behaviors. However, despite the important role of the hypothalamus, the neurons and the neural circuits that mediate these behaviors are poorly understood.
Manipulating Neural Circuits
To manipulate hypothalamic circuits, we require the ability to perturb the circuit nodes. Our approach is to define small populations of neurons genetically and to use chemical and optical tools to control the activity of these neurons. An advantage of the hypothalamus for circuit analysis is that many circuit nodes can be accessed genetically in mice, using specific promoters. By modulating activity of these genetically defined neuron populations in awake, behaving mice, we can measure directly the contribution of neurons to behavior.
Mapping Neural Circuits
Once genetically defined neuron populations can be assigned a function in regulating behavior, we use a combination of genetic and electrophysiologic techniques to develop a "wiring diagram" for the circuit. We are using channelrhodopsin-assisted mapping (CRACM, with Karel Svoboda at JFRC) to generate circuit diagrams where the synaptic properties of projections between genetically defined pre- and postsynaptic neurons can be measured. Because the nodes of these circuits have genetic entry points, this allows manipulation of the circuitry for studying circuit dynamics.
New Tools for Controlling Neuron Function
We are using a chemical biology strategy to build new tools for perturbing neuron function. Small molecules, which can exert rapid control over biological processes, are being designed to interact with novel receptors and ion channels to activate or inactivate neurons. This approach combines the specificity of genetic targeting with the temporal control of small molecules, and it allows populations of neurons to be switched on or off for in vivo studies of behavior and in vitro analysis of neural circuits. By combining chemical synthesis and protein structure analysis (with Loren Looger at JFRC), we are creating mutant ion channels that are inert to endogenous transmitters but are gated by synthetic ligands. This strategy is aimed at achieving cell-type-specific pharmacology.
In addition to chemical approaches, we are also investigating optical approaches involving channelrhodopsin as a neuronal activator. The advantage of such an approach is the millisecond time resolution of activation. Critical issues being explored by several researchers at JFRC include expression levels and optical properties of channelrhodopsin, as well as light delivery to deep brain structures such as the hypothalamus.
The complexity of the mammalian nervous system creates a tremendous challenge for understanding the neural basis of even fundamental, innate behaviors. By focusing on innate behaviors, it is our hope that we can identify and manipulate hardwired neural circuits. Nevertheless, we require an arsenal of new tools to map neural circuits and to test directly the contribution of neuron population to behaviors. Ultimately, understanding the neural circuits that regulate innate behaviors offers direct insight into how neural activity gives rise to behavior. Furthermore, the circuits may help explain aspects of these behaviors with societal and medical importance, such as obesity and addiction.