Past events

The cortico-basal ganglia pathway is involved in normal motor control and implicated in multiple movement disorders. We used focal microinjections of the GABA-A antagonist bicuculline to the sensorimotor putamen of behaving primates to induce stereotyped tics similar to those observed in human Tourette syndrome. The tics were accompanied by synchronized phasic changes in the local field potential and single cell activity of neurons throughout the cortico-basal ganglia loop. We also used focal injection of bicuculline to different functional domains of the globus pallidus external segment (GPe) to induce a variety of hyper-behavioral symptoms. These, symptoms varied between dyskinesia, stereotypy and attention deficit depending on injection site within the motor, limbic and associative domains respectively. The injections led to distributed uncorrelated changes in firing pattern throughout the cortico-basal ganglia loop. The neurophysiological findings and their implication on models of information processing in the basal ganglia will be discussed in the lecture.

Neurogenesis (birth of new neurons) occurs in many vertebrates, including humans. Most of the new neurons die before reaching destination. Those which survive migrate to various brain regions, replace older ones and connect to existing circuits. Evidence suggests that this replacement is related to acquisition of new information. Therefore, neuronal replacement is seen as a form of brain plasticity that enables organisms to adjust to environmental changes. However, direct evidence of a causal link between replacement and learning remains elusive. I will review a few of our studies which tried to uncover conditions that influence new neuronal recruitment and survival, and how these phenomena relate to the life of birds. We hypothesize that an increase in new neuron recruitment is associated with expected or actual increase in memory load, particularly in brain regions that process and perhaps store this new information. Moreover, since new neuronal recruitment is part of a turnover process, we assume that the same conditions that favor the survival of some neurons induce the death of others. I will offer a frame and rational for comparing neuronal replacement in the adult avian brain, and try to uncover the pressures, rules, and mechanisms that govern its constant rejuvenation. I will discuss a variety of behaviors and environmental conditions (food-hoarding, social change, parent-offspring recognition, migration) and their effect on new neuronal recruitment in relevant brain regions. I will describe various approaches and techniques which we used in those studies (behavioral, anatomical, cellular and hormonal), and will emphasize the significance of studying behavior and brain function under natural or naturalistic conditions.

The neural representation of value is a matter of great debate. In particular, it is not clear whether multiple valuation systems exist, each representing value under different conditions, or whether a single system that uses a “common currency” for the representation of value under many different conditions can be identified. I will present two studies in which we combined experimental methods from behavioral economics with functional MRI to study the representation of value in the human brain. The first study compared choices under two terms of uncertainty: risk, when probabilities of different outcomes are known, and ambiguity, when such probabilities are not known. Our results show that although subjects exhibit markedly different choice behaviors under these two conditions, a single system, consisting of the striatum and the medial prefrontal cortex (MPFC) encodes choice values in both cases. In the second study we used MPFC activation elicited by passive viewing of goods in the scanner to predict subsequent choices between these goods made outside of the scanner. Our predictions were significantly above chance, suggesting that the same valuation system is engaged whether or not choice is required. Based on these results together with previous studies we suggest that the striatum and the MPFC are the final common pathway for valuation – other areas may be differentially involved in encoding value under different conditions, but all of these areas should transfer their output to the final system to guide choice behavior.

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.