Systematic discovery and genetic targeting of neuronal cell types in the neocortex

Understanding cortical circuitry requires comprehensive knowledge of the basic cellular components. In our first round effort, we combined mouse genetic engineering and viral approaches and succeeded in targeting multiple classes of GABAergic neurons. Building on this success, we have extended our effort to target a set of glutamatergic pyramidal neurons and have improved several combinatorial strategies to target increasingly specific cell types. We further use transcriptome analysis to discover the molecular basis that underlie cell type identity and shape anatomical and physiological phenotypes. These studies establish multiple powerful experimental systems that integrate a full range of modern technologies for studying cortical circuitry.

Assembly and function of GABAergic inhibitory circuitry – the chandelier cell module 

How are diverse GABAergic interneurons generated and assembled to regulate the delicate balance and dynamic operation of cortical local circuits? The chandelier cell (ChCs) provides an excellent experimental system to address these questions. ChCs selectively innervate the axon initial segment (the spike initiation site) of pyramidal neurons and represent a distinct local circuit module. Our genetic fate mapping strategy establishes an excellent experimental system that allows tracking the entire developmental trajectory of ChCs, from their progenitor origin to their connectivity and function in cortical circuits. Currently we are studying: 1) the developmental specification of ChC identity and their laminar subtypes, 2) neural activity-dependent integration ChCs into cortical circuits, 3) connectivity pattern and physiological function of ChCs in circuit operations that contribute to behavior.


Cellular basis of cortical processing streams and output channels – the specification and connectivity of pyramidal neuron subtypes 

Diverse pyramidal neurons (e.g. defined by their axon projection pattern) form multiple inter-areal and inter-hemispheric information processing streams and subcortical-projecting output channels that subserve sensorimotor and cognitive functions. Thus distinct pyramidal neuron types likely constitute the basic cellular scaffold of cortical architecture, but their developmental and organizational logic is not well understood. We have generated a set of mouse driver lines that target distinct pyramidal neuron types and their progenitors. We are studying how cell lineage, clonal relationship and birth order contribute to pyramidal neuron identity defined by laminar location and axon projection patterns. We further map the input and output connectivity patterns of different types of pyramidal neurons using anterograde-retrograde tracing and high resolution brain wide imaging. These studies are carried out mainly in the motor cortex in the functional context of controlling movement.

Circuit mechanisms underlying motor cortex control of forelimb movement

Decades of studies (e.g. those in primates and humans) have implicated the motor cortex in volitional control of forelimb movement, a rich set of behavioral skills that allow mammals, including rodents, to interact with and manipulate environment according to sensory inputs and internal goals. However, the underlying cellular and circuitry basis remains largely unknown and unexplored. Systematic genetic access to different types of pyramidal neurons in the mouse provides unprecedented opportunities to dissect motor cortex circuitry.  In addition to anatomical studies of pyramidal neuron connectivity, we are using optogenetic manipulation of different pyramidal neuron populations to define output channels that mediate specific components of movement and upstream processing stations, currently in head-fixed mice. We also train mice to reach and grasp for food using chemical and optogenetic methods to probe the roles of different types of motor cortex pyramidal neurons.