Memory retrieval 

Since patient H.M., researchers have known that the hippocampus is essential for memory.  This discovery was confirmed by animal studies showing that dysfunction in this area produces profound amnesia for spatial and contextual information.  Despite these facts, it has remained unknown why the hippocampus is so fundamental for memory.  The dominant idea, based on the work of Marr, is that memory is retrieved when the hippocampus reinstates patterns of cortical activity that were observed during learning.  To examine this idea, we use fos-tTA mice to tag active CA1 neurons with a long-lasting fluorescent protein and the light activated proton pump archaerhodopsin (ArchT).  These proteins allow us to identify encoding neurons several days after learning and inactivate them with laser stimulation.  When tagged CA1 neurons were silenced, we find that memory retrieval is impaired and representations in the cortex cannot be reactivated.  These results provide the first direct evidence that the hippocampus is fundamental for memory because it reinstates patterns of activity that were originally present during learning.

Memory consolidation

Systems consolidation is the process by which memory becomes independent of the hippocampus and stored in the cortex.  This concept is based on the finding that hippocampus damage impairs recently acquired episodic memories but does not affect those formed in the distant past.  For example, patient E.P. could remember the city where he was raised fifty years prior, but was unable to recall a new neighborhood where he had lived for six years.  To explain findings like these it was proposed that memory retrieval initially requires the hippocampus because this structure can reactivate cortical regions that were engaged during learning.  Over time, continued reactivation strengthens the connections between cortical regions until memory can eventually be retrieved without input from the hippocampus.  This influential theory is referred to as the Standard Model of Consolidation (SMC).

SMC assumes that hippocampal reactivation after learning drives memory storage in the cortex.  Consistent with this idea, place cells are reactivated after learning during periods of inactivity and sleep.  This phenomenon (called replay) is thought to be the primary mechanism by which systems consolidation occurs.  We are testing this fundamental idea by identifying and controlling the activity of specific hippocampal neurons after learning.  In one line of research, we are tagging hippocampal neurons that are active during learning and selectively silencing them during consolidation.  This manipulation should prevent reactivation and, according to SMC, block long-term memory storage in the cortex.  In other experiments we are determining if stimulation of hippocampal neurons induces systems consolidation by reactivating cortical circuits that were engaged during learning.

Addiction and memory

Addiction to opiate drugs is a major problem in the United States, costing an estimated $78 billion dollars and 27,000 lives lost per year.  This problem is exacerbated by the fact that tolerance to opiates develops rapidly, leading to dose-escalation and an increased liability for dangerous side effects like dependence and overdose.  Consequently, a major goal in neuroscience is to understand the mechanisms that give rise to tolerance so that it can be prevented.  The current application will examine the contribution of learning to opiate tolerance and characterize the neural circuits by which these processes interact.  Since the 1970s, it has been known that environmental cues paired with opiates can dramatically influence tolerance.  Specifically, animals that receive morphine in a particular context exhibit associative tolerance that can be eliminated by simply administering the drug in a new environment.  These data suggest that contextual cues paired with morphine elicit a compensatory (or modulatory) response that reduces the analgesic effects of the drug.

The context specificity of opiate tolerance suggests that the hippocampus may be involved.  Place cells in this structure have been shown to fire in specific locations and are thought to form the basis of spatial maps in both humans and animals.  Consistent with this idea, when the hippocampus is silenced or damaged, subjects show dense amnesia for recently acquired spatial information.  One possibility is that spatial representations in the hippocampus that are paired with opiate drugs come to control associative tolerance.  If an animal finds itself in a drug paired environment, the place cells encoding this location fire and activate target structures that produce a compensatory response.  We are currently testing this idea by manipulating context-specific activity in the hippocampus and examining the effects on associative tolerance in mice.