Past events

A major challenge for biology is to develop new ways of determining how proteins operate in complexes in cells. This requires molecularly focused methods for dynamic interrogation and manipulation. An attractive approach is to use light as both input and output to probe molecular machines in cells. While there has been significant progress in optical detection of protein function, little advance has been made in remote control of any kind, including optical methods. As part of our efforts in the NIH Nanomedicine Development Center for the Optical Control of Biological Function, we are developing methods for rapidly switching on and off with light the function of select proteins in cells. The strategies are broadly applicable across protein classes. Our approach has been to synthesize Photoswitched Tethered Ligands (PTLs), which are attached in a site directed manner to a protein of interest. The site of attachment is designed into the protein to be at a precise distance from a binding site for the ligand. The geometric precision has two important consequences. First, light of two different wavelengths is used to isomerize the linker in such a way that the ligand can only bind in one of the sites, thus making it possible to toggle binding on and off with light. Second, native proteins are not affected by the PTL and remain insensitive to light, since the PTL does not attach. This means that a specific protein in a cell, a tissue and even in an intact freely behaving organism, can have its biochemical signaling turned on and off by remote optical control. The switching is very fast, taking place in ~1 millisecond, i.e. at the rate of the fastest nerve impulse. I will describe how we used our light-gated kaintate-type glutamate receptor, LiGluR, to study vertebrate locomotion. We used intersectional optogenetics in larval zebrafish to identify a new class of neurons that provide an important modulatory drive to swim behavior.

The human ventral stream consists of regions in the lateral and ventral aspects of the occipital and temporal lobes and is involved in visual recognition. One robust characteristic of selectivity in the adult human ventral stream is category selectivity. Category selectivity is manifested by both a regional preference to particular object categories, such as faces, places and bodyparts, as well as in specific (and reproducible) distributed response patterns across the ventral stream for different object categories. However, it is not well understood how experience modifies these representations and how do these representations come about throughout development. Here, I will describe two sets of experiments in which we addressed these important questions. First, I will describe experiments in adults in which we examined the effect of repetition on categorical responses in the ventral stream. Repeating objects decreases responses in the human ventral stream. However, repetition largely does not change the profile of category selectivity in the ventral stream, except for a place-selective region in the collateral sulcus in which long-lagged repetitions sharpened its responses. Second, I will describe experiments in which we examined changes in category selectivity throughout development from middle childhood (7-11 years), through adolescence (12-16) into adulthood. Surprisingly, we find that it takes more than a decade for the development of adult-like face and place-selective regions. In contrast, the lateral occipital object-selective region showed an adult-like profile by age 7. Finally, I will discuss the implications of these results on plasticity in the ventral stream and our theoretical models linking between fMRI measurements and the underlying neural mechanisms.