We are interested in the cellular and molecular mechanisms underlying the plasticity of synapses and neural circuits, and the role of neuroplasticity in brain functions and brain disorders.

1. Activity-dependent plasticity of neural circuits

Activity-induced changes in the structure and function of synaptic connections are responsible for experience-dependent development and refinement of neural circuits, as well as learning and memory functions of the brain. Correlated spiking of pre- and postsynaptic neurons is capable of inducing persistent changes in synaptic efficacy, known as long-term potentiation (LTP) and long-term depression (LTD). Moreover, the temporal order of pre- and postsynaptic spiking is critical in determining whether LTP and LTD will be induced at the synapse. This spike timing-dependent plasticity (STDP) may provide a mechanism for the neural circuit to store temporal sequence information.? We are testing the hypothesis that neuronal ensembles in the brain use STDP to store learned sequence of sensory and motor information, and retrieval of stored sequence information could be accomplished by partial activation of a subset of neuronal assembles. We are using multi-electrode array recording, calcium imaging over large populations of neurons over prolonged periods, and optogenetic manipulation of selective neuronal populations in vivo to test this hypothesis.?

2. Synaptic structural mechanisms underlying memory storage

Activity-induced modifications associated with LTP and LTD are known to be accompanied by structural changes at synapses that may serve for long-term storage of memory. While large-scale formation and elimination of new synapses have been observed during early brain development, after injury of adult brain, and in cultures of brain slices and dissociated neurons, the extent of structural rewiring during physiological memory formation and after injury of the adult brain remains unclear. Using long-term two-photon imaging at specific synaptic connections that may be involved in long-term memory, we are searching for the structural changes of synaptic connections that are causally related to the formation and consolidation of long-term memory in the cortical and subcortical structures，as well as the changes in the dynamics of activity-induced synaptic changes associated with aging and brain disorders.

3. Neural circuit basis of higher cognitive functions in primates

Substantial progress has been made in our understanding of neural substrates underlying basic cognitive functions, e.g., sensory perception, multi-sensory integration, learning and memory, decision-making, and attention, using a variety of model organisms.? By contrast, we knew very little about higher cognitive functions that are rather unique in humans, including complex executive functions, empathy, cooperative social behaviors, self-awareness, and language. It is generally agreed that evolutionary changes in the genetic program of humans must account for the emergence of cognitive functions that are uniquely human.? One approach to understanding their neural substrates is to introduce human-specific genes into non-human primates and dissect the corresponding changes in the development of neural circuits and associated cognitive behaviors of these genetically modified non-human primates. With the recent development of efficient methods of genetic manipulation in macaque monkeys and marmosets, this approach is now within the horizon of neurobiological research. In collaboration with other laboratories, we are also taking the initial steps in studying primate-specific cognitive functions, such as self-awareness and complex vocal communication.