Experimental Systems

While human brain development has evolved into a highly protracted process spanning from the third week of gestation to the third decade of life, neurological development is accelerated in the mouse such that the brain is largely mature by about one month after birth. In addition to the vast number of transgenic and viral tools specialized for studying mice, this accelerated developmental timecourse makes the mouse an ideal model for exploring the biology of the developing brain. 

The visual system of the mouse

The visual circuitry of the mouse has emerged as a highly tractable experimental system for studying neural circuit development and organization. Information about the external world is transformed into precisely patterned neural activity by photoreceptors in the back of the retina, which convey this information to retinal ganglion cells (RGCs), the major output neurons of the eye. RGCs send their axons (which make up the optic tract) to over 50 retinorecipient structures in the brain, with the vast majority of axons terminating in (1) the superior colliculus and (2) the dorsal lateral geniculate nucleus (dLGN) of the thalamus. The superior colliculus is a midbrain structure that is important for essential behaviors including predator evasion. On the other hand, the dLGN is a thalamic nucleus that relays visual information from the retina to the higher order processing structure of the brain, the primary visual cortex (V1). dLGN relay neurons and their postsynaptic targets in the cortex mediate image formation among other complex tasks. 

The well-characterized connectivity of visual circuits and the identification of “critical periods” of development when the system is particularly sensitive to the influence of sensory experience are two major advantages of the visual system as a model of experience-dependent plasticity and refinement. In our laboratory, we exploit these advantages by studying (1) the retinogeniculate circuit (the synaptic connection between RGCs and dLGN relay neurons), (2) the retinocollicular circuit (the connection between RGCs and superior colliculus neurons), and (3) the thalamocortical circuit (the connection between dLGN relay neurons and neurons in layer 4 of primary visual cortex). 

The human brain

While mice provide a robust model for mechanistic interrogation, our interest in disorders of the nervous system has led us to complement our work in mice with studies of primary human brain tissue. Recent advances in genomic and transcriptomic methodologies now enable the analysis of the genome at DNA base-pair resolution in very small amounts of tissue or in single cells, which has opened the door to new possibilities for analyzing the human brain in greater detail than previously achievable. We collaborate with clinicians to obtain freshly resected human brain tissue following electrical stimulation in the course of surgery in vivo, and we compare stimulated to unstimulated tissue to identify the mechanisms that mediate activity-dependent transcription in the full repertoire of neuronal and non-neuronal human brain cells, with an emphasis on microglia. In parallel, we analyze interactions between microglia and synapses in the human brain and contrast features of these functional interactions in the human with our observations in mice.

By combining work in mouse and human brains, we seek to establish a detailed understanding of the neuro-immune mechanisms that sculpt synaptic connectivity and function in both health and disease.