Sensations and thoughts result from the coordinated activity of neuronal populations in space and time. I want to understand the mechanisms controlling the spatial and temporal structure of cortical activity.
My work is currently focusing on the dynamics of cortical circuits in the mammalian brain and specifically on the mechanisms that regulate the balance between excitation and inhibition. The work performed in my lab is demonstrating that the main function of inhibitory circuits is to regulate cortical activity in time, while excitatory circuits provide control of cortical activity in space.
The relationship between excitation and inhibition in the brain has received much attention in recent years and understandably so, because a proper balance between excitation and inhibition is fundamental for accurate sensory processing, motor coordination, and higher cognitive functions. Furthermore, any uncontrolled shift in this balance can lead to pathological states, ranging from epilepsy to schizophrenia.
The relationship between excitation and inhibition is highly dynamic. Through this constantly changing ratio, distinct cortical neurons are active at distinct times, either in response to sensory stimuli or during spontaneous activity. In other words, the relationship between excitation and inhibitions shapes the activity of our brain in space and time.
In the cortex, excitation and inhibition work hand in hand. In vivo whole-cell recordings from the cortex of anesthetized animals, for example, show that even the simplest sensory stimulus, like a brief deflection of a whisker, or a simple visual stimulus, leads to an almost simultaneous excitation and inhibition of cortical neurons. Furthermore, even during spontaneous—not stimulus-driven—cortical activity, excitation and inhibition are concomitant, as can be shown through whole-cell recordings of neurons during cortical oscillations.
Understanding the neuronal circuits that coordinate the dynamics between excitation and inhibition is thus fundamental for our understanding of cortical function.
Cortical neurons can be subdivided into two broad categories, namely excitatory glutamatergic neurons and inhibitory, GABAergic neurons. Despite representing only about 20 percent of the neuronal population, inhibitory neurons form a heterogeneous group that can be further subdivided according to morphological, physiological, and immunohistochemical properties.
Excitatory and inhibitory neurons interact through stereotypical connectivity patterns or canonical circuits. These circuits represent basic functional units, or modules, occurring throughout the central nervous system. In the past few years, my lab has focused on two critical circuits mediating interactions between excitatory and inhibitory neurons, namely feed-forward and feedback inhibitory circuits. These two circuits were first recognized by Sir John Eccles as building blocks of cortical architecture nearly four decades ago, yet their function has largely remained elusive. All major cortical excitatory projections known so far provide feed-forward inhibition to their targets by recruiting local inhibitory interneurons. Furthermore, all cortical excitatory neurons provide feedback inhibition to themselves, again by recruiting local inhibitory neurons. Therefore, understanding the mechanism by which these circuits operate is fundamental to uncovering the function and logic of the basic building blocks of the brain.
I have chosen to investigate feed-forward and feedback inhibitory circuits in the somatosensory cortex and in the hippocampus, two cortical areas dealing with very different information, the first being a primary sensory area and the second a multimodal, associational area. The goal is to determine whether these circuits are basic functional modules, with roles that are independent of the cortical structures in which they are embedded.
By using both in vivo and in vitro approaches, my work is thus establishing the relative roles of excitation and inhibition in coordinating the activity of cortical neurons in space and time: Inhibitory circuits play an essential role in precisely timing cortical activity and modulating the gain of pyramidal cells, whereas the spatial parsing of cortical activity into unique ensembles appears to be the specific function of synaptic excitation. Furthermore, I have shown that feed-forward and feedback inhibitory circuits share striking functional similarity, even between disparate brain regions. I am currently developing tools to selectively ablate, silence, or activate these circuits in the living organism. This approach is a natural progression in the study of elementary circuits, from their role in cellular computations in vitro to their function in sensory discrimination in behaving animals. I am convinced that this approach will bring us closer to understanding how these basic modules of cortical organization contribute to the biological nature of our sensations and thoughts.
This work is also supported by grants from the National Institutes of Health.
As of January 22, 2009