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
95.07: Manipulating the fear memory trace in mice
Location: Halls B-H
">*D. TALIAZ1,2, A. RASHID1,2, A. YIU1,2, B. ROTH3, P. FRANKLAND1,2, S. JOSSELYN1,2; 1The Hosp. for Sick Children, Toronto, ON, Canada; 2Univ. of Toronto, Toronto, ON, Canada; 3Univ. of North Carolina At Chapel Hill, Chapel Hill, NC
Abstract Body: Fear is essential for the survival of any organism. Examining how fear memories are normally formed, stored and potentially changed will help us to understand normal brain function as well as provide insights into when this process goes awry, as in anxiety disorders. Recently, our lab showed that the transcription factor CREB (cAMP/Ca++ responsive element binding protein) plays an important role in the formation of long-term fear memory. We showed that increasing CREB expression in a small subset of lateral amygdala (LA) neurons (~10-20%) enhances formation of fear memory, and that selectively ablating these neurons essentially “erased” the fear memory. These findings suggest that LA neurons overexpressing CREB are selectively recruited to the fear memory trace and that these neurons are necessary for the subsequent expression of fear. However, it is unknown whether these neurons are sufficient to induce a fear memory. Here we asked whether artificial activation of LA neurons overexpressing CREB at the time of fear memory training is sufficient to induce fear in the absence of external cues. To overexpress CREB in a small, random subpopulation of LA neurons we used Herpes Simplex Virus (HSV), and to artificially activate these neurons we co-expressed an hM3Dq receptor, a Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Activation of hM3Dq by a systemic injection of the synthetic ligand Clozapine-N-Oxide (CNO), a chemical which is otherwise inert, increase excitability of neurons expressing this DREADD. We observed that post-training activation of LA neurons overexpressing CREB (but not GFP) is sufficient to enhance fear when mice are tested in the training context and induce fear when mice are tested in a novel context. In addition, post-training activation of a random subset of LA neurons (GFP-hM3Dq) interfered with expression of a previously acquired tone fear memory. Together, these findings suggest that manipulating the small population of LA neurons that make up a fear memory trace may have profound behavioral consequences.
Lay Language Summary:Manipulating a fear memory:Implications for understanding and treating PTSD Our research shows that it is possible to “turn on” or “turn off” fearful memories in mice. Although memories of fearful events are essential for our very survival (you only want to touch a hot stove once to remember later that hot stoves should not be touched), in some people the processing of fearful memories is disturbed which can lead to severe disorders that disrupt daily functioning. Many disorders, including post-traumatic stress disorder (PTSD) and other anxiety disorders, involve deficits in the ability to encode and correctly retrieve fearful memories. Therefore, understanding how the brain normally encodes, stores and retrieves fearful information is crucial to both understanding these disorders and also the first step towards developing novel treatments. To study fear in mice, we subject them to Pavlovian fear conditioning, in which a previously neutral stimulus (such as a tone) is paired with an aversive event (a mild electrical shock which does not hurt the mouse, but does scare it). Following this pairing, subsequent exposure of the animal to the once innocuous tone elicits intense fear, which may correspond to PTSD. 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. We previously showed it is possible to “pre-select” exactly which neurons become part of a fear memory by overexpressing a certain protein (called CREB) in the brains of mice. These neurons that we pre-selected are 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. That is, mice no longer showed fear when played the tone previously paired with the aversive event. Here, rather than permanently kill these pre-selected fear memory cells, we activated them (but only them). In this circumstance, mice showed a fear even in a non-fearful situation. That is, the mice behaved as if they heard the tone, even in silence. This finding may be analogous to PTSD in which a previously fearful memory is recalled in non-fear inducing situations. PTSD became a formal diagnosis in the DSM (Diagnostic and Statistical Manual of Mental Disorders) in 1980, but many agree that this crippling disorder has been with us for much longer. For instance, an Egyptian combat veteran (circa 1000 BC) wrote about similar symptoms induced by combat. PTSD induced by combat and other traumatic experiences has a long history, but we know very little of how it is caused and may be treated. NIMH director Dr. Tom Insel stressed the urgency of the PTSD resulting from current combat when he wrote that “today, more soldiers are dying from suicide than combat”. In addition to combat, however, PTSD may result from traumatic experiences such as rape or mugging, car or plane accidents and natural disasters. The estimated lifetime prevalence of PTSD in the US is roughly 7.8% (Kessler et al., 1995). Because PTSD may severely interfere with a person’s ability to function, this disorder exacts an enormous personal toll on affected individuals and their families and produces significant societal problems that cost millions of dollars. Current available treatments are, at best, only partially effective. A key to understanding, and therefore, developing novel and targeted treatments for PTSD is to examine how a traumatic event is coded and stored in the brain. Our results mimic critical aspects of PTSD and as such, provide a starting point for investigating novel treatments.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit