Contextual control of extinction.  When a conditioned stimulus (CS) undergoes extinction, the loss of fear to that CS is limited to the context in which extinction occurs.  As a result, fear to an extinguished CS returns when it is encountered anywhere other than the place in which it was extinguished.  In humans, the context-dependence of extinction may limit the efficacy of treatments for anxiety disorders.  For example, exposure therapy may reduce fear in the treatment context, but this fear reduction may not generalize to other contexts.  In the last 10 years, our work has revealed an essential role for the hippocampus in the context-dependence of extinction. For example, reversible inactivation of the hippocampus prevents the renewal of fear outside of the extinction context, and also prevents the modulation of amygdala spike firing by contextual cues.  Yet the network of brain structures regulating the contextual control of extinction likely involves other brain structures, including the prefrontal cortex.  Indeed, we have shown that c-fos expression in subregions of the prefrontal cortex increases after the retrieval of both fear and extinction memories.  We are now combining single-unit recordings, cellular imaging, anatomical disconnections, and tract tracing to to understand the pathways by which the hippocampus interacts with the amygdala and prefrontal cortex to regulate the contextual control of extinction.  This work is currently funded by a major NIH grant (R01MH065961, “Neural Substrates of Contextual Memory in Fear Extinction”). 

Projects. The research in our lab is centered on understanding the neural substrates of Pavlovian fear conditioning and extinction.  We use sophisticated behavioral designs in combination with reversible brain lesions, systemic and intracranial pharmacology, immunohistochemistry, and in vivo single-unit recording to address these questions.  The majority of our work is conduced in rats and mice, although we are now extending this work to humans in collaboration with other groups on campus.

Resistance to extinction.  It is well known that memory is susceptible to disruption soon after it is acquired.  This suggests that administering extinction soon after fear conditioning might disrupt memory consolidation and encourage the erasure of fear memory.  However, we have found that recent fear is resistant to extinction.  Several projects in the lab are now focused on understanding this ‘immediate extinction deficit’.  This work suggests that fear conditioning may temporarily take the prefrontal cortex offline (stress is known to perturb prefrontal cortical function).  For example, neuronal correlates of extinction, such as bursting in prefrontal neurons, is reduced during immediate extinction.  Drugs that reduce GABAergic transmission or enhance glutamatergic transmission in the prefrontal cortex attenuate the immediate extinction deficit.  These results suggest that failures of fear extinction in patients with post-traumatic stress disorder, for example, might be due to stress-related prefrontal dysfunction.


Synaptic plasticity and learning.  How are fear and extinction memories encoded in the brain?  Our laboratory has a long standing interest in understanding the synaptic mechanisms for fear conditioning and extinction.  Years ago we demonstrated NMDA receptor-dependent long-term potentiation in hippocampal projections to the amygdala, and ongoing projects are examining the contribution of synaptic plasticity in the amygdala to fear conditioning and extinction.  For example, we recently discovered a dissociation in the role of basolateral and central amygdaloid NMDA receptors in extinction learning, which has implications for understanding which synapses in the amygdala participate in extinction learning.  Protein synthesis is also essential for the consolidation of fear and extinction memories, and understanding how it contributes to the stability of memory may yield insights into mechanisms for memory erasure.


Publications.  The laboratory has published over 100 peer-reviewed articles in outlets including Neuron, PNAS, Journal of Neuroscience, and Learning and Memory.  Publications from the lab can be browsed on PubMed.


Funding.  Research in the laboratory has been continuously funded by the National Institutes of Health since 1996. 

 

Emotion and Memory Systems Laboratory

Department of Psychology • Texas A&M University

Stephen Maren, PhD

Professor of Psychology and Neuroscience