MIT Reports to the President 1997-98
The Center for Learning and Memory was established in May 1994 as an interdepartmental research center between the Department of Brain and Cognitive Sciences and Department of Biology. The Center's primary research interest is to study the mechanisms underlying learning and memory using multifaceted approaches. Susumu Tonegawa was appointed as the first Director of the Center in May 1994. Matthew A. Wilson joined as an Assistant Professor on July 1, 1994. William G. Quinn who has been a faculty member in Department of Brain and Cognitive Sciences since July 1, 1994 joined the Center on April 1, 1995. Guosong Liu and Earl Miller joined as Assistant Professors on September 1, 1996. Elly Nedivi will join the Center on July 1, 1998.
RESEARCH
Dr. Tonegawa's laboratory continued to characterize the CA1-specific NMDA receptor knockout mice and demonstrated that these mice lack functional NMDA receptors at only one kind of synapse, namely Schaeffer collateral-CA1 pyramidal cell synapses. Combined with the earlier physiological and behavioral studies, the data strengthened substantially the evidence for the causal relationship between synaptic plasticity and explicit memory. Dr. Tonegawa's laboratory also studied the mechanism for the neural activity-dependent development of the visual system. Using the transgenic mouse technology they obtained evidence for the hypothesis that a maturation of inhibitory neural circuitry in the neocortex which is mediated by a neurotrophin, BDNF, is crucially involved in the termination of the plastic period called the "critical period."
Dr. Wilson's laboratory has been studying the pattern of interaction between brain areas during sleep. They have discovered that two areas which are involved in memory and decision-making during the waking state, the hippocampus and prefrontal cortex, communicate during specific windows of activity in slow-wave sleep known as sleep spindles. When combined with earlier results revealing the reactivation of recent memory patterns in the hippocampus during these sleep periods, these results point to what may be a process of memory consolidation involving the coordination of multiple brain regions during slow-wave sleep in which sleep spindles serve as the vehicle for mnemonic information. This is the first demonstration of an interaction between these two regions in the behaving animal.
Dr. Miller's laboratory made an important discovery regarding our ability to integrate the "what" and "where" information of objects. What and where are known to be processed separately in the visual system. Dr. Miller's laboratory identified prefrontal neurons that respond to both types of information of an object. Many can simultaneously represent both an object and its precise visual field location. These neurons may comprise a crucial link that allows actions to be directed toward objects. They can also help synthesize the unified representation of a visual scene that corresponds to our conscious experience. In a second line of investigation, Dr. Miller's laboratory has identified mechanisms in the prefrontal cortex that select the sensory information and stored knowledge that is fully processed and reaches awareness. It is well established that mechanisms that underlie our conscious thoughts and intended actions are severely limited in capacity; we can only think about a few things simultaneously. Thus, these mechanisms may play a major role in regulating the information that gains control of cognitive functions.
Our most exciting results are with the amnesiac gene. The amnesiac mutant in Drosophila was isolated on the basis of its short memory span(1). The gene was transpositionally cloned, sequenced, and found to encode a peptide neuro-transmitter that had significant homology to mammalian PACAP (pituitary-adenylyl-cyclase-activating-peptide (2). More recently, another lab has selected for ethanol-sensitive mutants, and, on the basis of this screen, has isolated new alleles of amnesiac (3). The gene, therefore, is evidently important both for intermediate-term memory storage and for resistance to alcohol intoxication. The crucial questions are: how and where does the amnesiac gene product (a neurotransmitter) act in the fly brain, and are there close mammalian homologues, which might have potential relevance to human memory storage and psychoactive drug metabolism. To this end we have created rabbit antibodies to the inferred amnesiac gene product, we have affinity-purified these antibodies, and we have demonstrated their specificity and functional localization in Drosophila. This sets the stage for an informed screen for mammalian homologues using expression libraries.
In Dr. Liu's laboratory, the overall research objective is to study how synaptic activities regulate the strength of interconnections between neurons in the central nervous system and what role activity plays in the process of synapse formation, elimination, and consolidation. In last year, we focused on uncovering the molecular and cellular events in the process of synaptogenesis. We found that influx of Ca2+ through neural activity plays a critical role in the maturation of presynaptic terminals. Furthermore, proper level of neural activity is essential for postsynaptic receptor clustering, because both increase and removal of neural activity can block clustering of postsynaptic receptors.
Susumu Tonegawa