Research Overview

In the brains of mammals, birds and invertebrates, the sensory world is organized into regular neuronal arrays or maps. Common examples are the map of body surface in somatosensory cortex (the so called “homunculus”) and the representation of oriented bars or edges in visual cortex. We are interested in understanding how genes (‘nature’) and the environment (‘nurture’) interact to guide the development of neuronal maps.

Our research focuses on development of the visual and somatosensory systems. We employ a broad range of experimental techniques, including neuroanatomy, molecular biology and biochemistry, in vitro and in vivo electrophysiology as well as optical imaging. This array of approaches allows us to examine neural circuit development from many perspectives, and provides synergistic impetus to our exploration of the cellular and molecular mechanisms for sensory map development.

Below you will find more detailed information about the research we do in our lab.

HERE IS AN EXAMPLE

In the brains of mammals, birds and invertebrates, the sensory world is organized into regular neuronal arrays or maps. Common examples are the map of body surface in somatosensory cortex (the so called “homunculus”) and the representation of oriented bars or edges in visual cortex. In these maps, neighboring cells respond to similar features of stimuli in the sensory periphery, and there is usually an orderly progression of the optimal stimulus across the array of neurons. We are interested in understanding how genes (‘nature’) interact with the environment (‘nurture’) to guide the development of these neuronal maps.

For example, it is well established in the vertebrate that molecular/genetic mechanisms guide sensory afferents to their appropriate target brain structure. Neuronal activity, shaped by sensory experience, is then thought to refine the arrangement of afferent synapses in order to ac! curately reflect the pattern of sensory input from the periphery. Research in my laboratory is currently focused on the development of the sensory pathways in rodents, particularly the visual and somatosensory system, because they allow for the relatively easy and rapid investigation of developmental mechanisms, but they are similar in many respects to analogous neuronal circuits in the human.

We specifically use the retinotopic map of the visual world in the superior colliculus of the mouse to investigate mechanisms of visual map development, and the ‘barrel’ map of facial whiskers in the somatosensory cortex of the rodent to investigate mechanisms responsible for the development of cortical maps. We employ a broad range of experimental techniques, including neuroanatomy, molecular biology and biochemistry, in vitro brain slice electrophysiology, single and multi-unit in vivo electrophysiology as well as optical imaging techniques in vivo. This array of approaches allows us to examine! neural circuit development from many different perspectives, and provides synergistic impetus to our exploration of the cellular and molecular mechanisms responsible for sensory map development.

Past experiments that colleagues and I conducted on the visual system of the cat revealed the importance of intrinsic mechanisms for the initial patterning of visual maps in the cortex, as well as the powerful influence of sensory experience in maintaining and refining these maps (Crair, Gillespie and Stryker, 1998; Crair et al., 2001). These experiments convinced me that we could examine the rules responsible for neural circuit formation using the mammalian sensory cortex as a model system, but they also lessened my enthusiasm for using the cat as an experimental model because of the paucity of genetic tools in the cat and the consequent difficulty manipulating cellular signaling pathways that mediate synapse formation in the large mammal (Gillespie , Crair and Stryker, 2000).

More recently, I have focused on using the mouse, where we can harness the power of modern molecular biology to examine the cellular and molecular mechanisms responsible for synapse and neural circuit formation in the mammalian CNS. In the somatosensory cortex, for instance, we have used transgenic mice with targeted mutations in the cAMP/PKA signaling pathway to show that the development and plasticity of ‘barrel’ columns in the cortex likely involves cellular processes at thalamocortical synapses that are akin to long-term potentiation and depression (LTP and LTD), cellular processes at hippocampal synapses that are thought to mediate learning and memory in the adult (Crair and Malenka, 1995; Lu et al., 2001; Lu et al., 2003; Inan et al., 2006; Lu et al., 2006). These experiments demonstrate how neuronal activity regulates the expression of glutamate receptors at developing thalamocortical synapses, and thereby ‘instructs’ the formation or elimination of connections between particular synaptic partners that are appropriate given their mutual activity pattern. These synapse-specific ‘learning’ rules for activity dependent synapse formation and elimination generate global patterns of synaptic connections, such as ‘barrel’ columns, that are functionally appropriate for that sensory pathway.

In the mouse visual system, we demonstrated that similar cellular signaling pathways are also involved in retinotopic map formation (Plas et al., 2004). In the visual system, as in the somatosensory system, development of the initial pattern of sensory maps likely depends on intrinsic molecular mechanisms that guide axon growth and branching (Plas et al., 2005; Plas et al., 2008, Mehta et al., 2005), and then retinotopic map refinement relies on synaptic learning rules that make use of spontaneous and sensory driven neural activity to guide neural circuit formation (Chandrasekaran et al., 2005; Shah and Crair, 2008). Interfering with either molecular targeting mechanisms for ganglion cell axon path finding or intrinsic spontaneous neural activity in the retina perturbs map development in the superior colliculus. Interfering with both in the same animal has a dramatic cumulative effect (Chandrasekaran et al., 2005). These experiments demonstrate explicitly how ‘nature’ and ‘nurture’ interact to guide neural circuit formation in the developing vertebrate CNS.

We propose to address fundamental questions regarding the development, plasticity and function of sensory maps using a combination of in vivo and in vitro approaches. With an in vivo preparation, we would like to understand how innate and experiential factors interact to guide the initial development and plasticity of retinotopc maps in the superior colliculus of the mouse. With in vitro methods, we propose to study the underlying cellular and molecular processes responsible for sensory map formation and plasticity, concentrating on the development of thalamocortical synapses in the somatosensory cortex and retinocollicular synapses in the superior colliculus. These approaches are synergistic in nature, with insights gained from in vitro experiments about the cellular and molecular mechanisms involved in synapse formation and plasticity guiding subsequent in vivo studies, and vice-versa.

A large gulf still remains between our current rather superficial knowledge of sensory map development and a deeper understanding of the rules and underlying mechanisms responsible for map development. We hope to bridge this gap, and make headway in addressing the essential underlying issue, which is one of the fundamental open questions in Neuroscience today: How does the brain wire itself up during development?