For us to interact with the outside world, the brain must plan and dictate our actions and behaviors. In many cases, we learn to reproducibly execute a well-defined series of muscle movements to perform impressive feats of motor skill, such as hitting a golf ball or playing the violin. When injury or disease compromises these processes, we suffer greatly. Despite their centrality to everyday life, however, the neural underpinnings of these learned motor sequences are poorly understood. The Long Lab seeks (1) to identify the relevant processing centers involved in producing specific motor sequences through careful circuit manipulation and (2) to investigate their functional properties during natural behavior.
What computations do individual neural circuits perform? This question is especially difficult to answer when the circuit receives a plethora of inputs from other active brain regions. For example, in the songbird, several motor regions in the brain are necessary for singing behavior (Figure 1). If any one of these regions is lesioned or inactivated, then the bird cannot produce his song. Teasing apart the individual roles played by these interconnected motor circuits is therefore a challenge. One could imagine that different song features are calculated in different regions. Alternately, the motor sequences for song could be determined in a subset of these brain areas with other regions passing signals to the relevant muscles.
Our previous work distinguished between these possibilities, using a miniature thermoelectric device to change the temperature of individual brain regions and to focally alter the speed of neural processes in freely behaving animals. We reasoned that if slowing down an individual premotor region directly affects the temporal pattern of the behavior, then that region plays an important role in generating these premotor sequences. Indeed, this approach has identified pattern-generating, premotor circuits in simpler systems. In the songbird, bilateral cooling of a premotor forebrain region (HVC), but not its direct downstream target (RA), led to a temperature-dependent, monotonic slowing of singing behavior (Figure 2). We are presently investigating the broad use of focal cooling as a tool for determining the functional output of motor circuits across a range of species, including humans.
How are behaviorally relevant computations carried out within identified neural circuits? Because of the technical challenges inherent in recording from behaving animals, researchers often study neural circuit dynamics in the anesthetized brain or in ex vivo tissue. These approaches have been useful in examining a number of brain regions, but an investigation of behaviorally relevant motor regions will be most fruitful in the behaving animal, which necessarily means recording in awake, often freely moving animals. One approach, first introduced for use in rats by Albert Lee and Michael Brecht, allows for intracellular recordings in freely moving animals. We recently built a modified version of the device for chronic recordings in small animals (Figure 3) over the period of several days. This method reveals all the normal synaptic activity impinging on a neuron from the surrounding circuit, and it allows us to inject current into single neurons in order to directly influence their activity and to further characterize their electrophysiological properties. We are presently using our motorized intracellular microdrive to investigate circuit activity within forebrain regions in both the mouse and the songbird.
Our future directions are divided into two broadly defined efforts:
1) To determine the mechanisms by which premotor sequences are generated. What are the large-scale organizing principles of a timing circuit? How do neurons interact within this circuit? How is motor sequence generation affected by the intrinsic cellular properties of the neurons involved?
2) To know the extent to which these findings can be generalized to other neural circuits, including those found in the mammalian forebrain. How do neocortical circuits generate premotor patterns? What roles are played by identified neuronal cell types and their interconnections? How can those roles be changed with experience?