Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
095—Learning and Memory: Physiology I
Saturday, November 09, 2013, 1:00 pm - 5:00 pm
95.09: Manipulating a cocaine-cue memory in mice
Location: Halls B-H
">*H.-L. HSIANG1,2, C. YEN1,2, A. RASHID1,2,3,4, M. VAN DEN OEVER1,2,4,5, S. PATEL1,2,3,4, P. W. FRANKLAND1,2,3,4, S. A. JOSSELYN1,2,3,4; 1Hosp. for Sick Children, Hosp. for Sick Children, Toronto, ON, Canada; 2Inst. of Med. Sci., 3Psychology, 4Physiol., Univ. of Toronto, Toronto, ON, Canada; 5Mol & Cell Neurobio, VU Univ., Amsterdam, Netherlands
Abstract Body: One significant obstacle for the treatment of drug addiction is the high incidence of relapse to drug-taking following months, or even years, of abstinence. Exposure to stimuli that were associated with prior drug use can awaken powerful memories that may trigger drug craving and provoke relapse. Understanding how animals learn and remember the association between a cue and a drug of abuse (such as cocaine) is a crucial step to develop more effective treatment strategies for preventing and treating relapse in humans. CREB (cAMP/Ca2+ responsive element binding protein) is a transcription factor that has a well‐documented role in neuronal plasticity and long-term memory formation. Previously we found that increasing levels of CREB in a subset of lateral amygdala (LA) neurons enhanced the formation of a fear memory and that selectively ablating these neurons essentially “erased” the fear memory (Han et al., Science, 2007, 2009). We took advantage of this approach to investigate whether LA neurons are also critically involved in a cocaine-cue associated memory. To assess cocaine-cue memory, we used the conditioned place preference (CPP) paradigm. We microinjected HSV vectors encoding CREB or GFP (control) into the LA of mice to increase CREB in a small proportion (~15%) of LA neurons. Increasing CREB in a small subset of LA neurons during (but not after) conditioning enhanced cocaine-CPP memory. Moreover, by using fluorescent in situ hybridization (catFISH), We found that these LA neurons with relatively increased CREB levels (with CREB vector) were 3X more likely to be incorporated into cocaine-cue memory trace. Post-conditioning deletion or temporary silencing of LA neurons with increased CREB function (but not a similar proportion of random neurons) blocked subsequent cocaine-CPP memory. Our results indicate, similar to a conditioned fear memory, a small population of LA neurons comprise a crucial component of the cocaine memory-trace.
Lay Language Summary: Our research shows that it is possible to specifically “erase” a cocaine memory in mice by targeting a handful of cells in the brain such that mice behave as if they have never received the drug. Some people say that drugs of abuse (such as cocaine) are so “good, one shouldn’t even try them even once”, suggesting that taking these sorts of drugs creates powerful rewarding memories that may continue to influence behavior even during abstinence (when drug use has actually stopped). This powerful long-lasting “memory” created by taking a drug of abuse might explain one of the most significant obstacles for the treatment of drug addiction; the high incidence of relapse to drug-taking following days, months, or even years, of abstinence. One way this drug-related memory may be triggered is by exposure to people, places or things previously associated with drug-taking. Even in people who have not taken a drug for years, exposure to stimuli that were associated with prior drug use can awaken dormant, but robust, drug-related memories that may then trigger drug craving and provoke a relapse to drug-taking. Therefore, understanding how animals learn and remember the initial association between a stimulus or cue (such as a person, environment or object which was previously linked to drug-taking) and a drug of abuse (such as cocaine) is a crucial step to develop more effective treatment strategies for preventing and treating relapse in humans. Our work shows how (and where) this powerful drug-reward memory is formed in the mouse brain, and, more importantly, that once acquired, this powerful memory can be manipulated and even erased. In our work we try to understand how the brain encodes and remembers information. Our previous work in mice found that although there are millions of brain cells (or neurons) in the mouse brain (and even more in the human brain), only a few of them are necessary to form a fear memory. In fact, we showed it is possible to “pre-select” which neurons become part of fear memory by overexpressing a certain protein (called CREB) in the brains of mice. These neurons that we pre-selected were hugely important to that memory, because killing just this tiny portion of all the neurons in the entire brain disrupted the memory, as if it had been erased. We applied a similar strategy to examine a cocaine-cue memory. When mice are given cocaine in a certain environment, the environment tends to take on the rewarding properties of cocaine. Mice remember this powerful cocaine-cue memory (even when they no longer are given cocaine exposure to this environmental cue alone induces a craving-like behavior). Similar to our fear studies, we found that we could pre-select the very tiny portion of neurons in the brain that coded this cocaine-cue memory. Now that we could determine where in the brain this memory was stored, we could manipulate and even erase it! If we permanently killed or even temporarily silencing this tiny portion of pre-selected neurons mice behaved as if they had never received cocaine. Although we don’t see a future in which we kill neurons in a human in order to help treat addiction or prevent drug-related relapse, our findings offer proof-of-principle that future treatments for this disabling disorder need not affect the entire body or even entire brain. Our results indicate that a critical component of a cocaine memory may reside in a small portion of neurons and that treatments could be targeted to just these cells.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit