It is clear that repeated exposure to stress increases the risk of developing and expressing symptoms of human disorders of fear and anxiety;however, little is known about the mechanisms by which this occurs. Many studies have shown that numerous brain areas, including the hippocampus, are adversely impacted by chronic stress. For example, chronic stress has been directly linked to atrophy of neuronal processes, reduction of neural plasticity, and deficits in behavioral performance on mnemonic tasks. However, recent data indicates that one brain region, the amygdala, exhibits a relatively unique response to chronic stress. That is, chronic stress causes growth of dendritic processes in amygdala neurons and increases in anxiety. These findings suggest the intriguing hypothesis that chronic stress produces fundamentally opposing effects in the hippocampus and amygdala. We have behavioral data supporting this hypothesis: Chronic stress enhances amygdala-dependent delay fear conditioning but impairs hippocampus-dependent trace fear conditioning. In this proposal, we will combine sophisticated multi-site tetrode recording techniques and cutting-edge molecular methods (viral-mediated gene transfer) with immunohistochemical and behavioral techniques in rats to further examine this hypothesis and explore two mechanisms by which opposing effects may occur. First, we will characterize chronic stress-induced changes in both spontaneous and associative spike firing in the hippocampus and amygdala. Second, we will determine whether glucocorticoids, making up one component of the neuroendocrine response to stress, produce opposing effects on electrophysiological, behavioral, and gene expression measures in the amygdala and hippocampus. Third, we will determine the contribution of growth hormone, a gene that is oppositely regulated in the hippocampus and amygdala after chronic stress, to stress- induced changes in behavioral measures of fear memory. Because of the important role that the amygdala plays in regulating anxiety and fear, experiments assessing the unique effects of chronic stress on the amygdala may shed light on the specific mechanisms by which chronic stress exacerbates mental illnesses such as post-traumatic stress disorder. Identifying mechanisms by which stress exacerbates fear may lead to new therapeutic targets for the treatment of mental illness.

Public Health Relevance

This research will compare the impact of chronic and intense stress on the hippocampus and amygdala and determine the contribution of glucocorticoids (a hormone secreted in response to stress) and growth hormone (a hormone that is uniquely upregulated in the amygdala after chronic stress) to these effects. This work will shed light on the multiple ways in which chronic stress can enhance fear and anxiety, and it will identify novel therapeutic strategies by which stress-enhancement of fear memory may be reduced. This is particularly important as chronic stress is a potent trigger for affective mental illnesses such as post-traumatic stress disorder (PTSD), but the mechanisms by which stress triggers this class of mental illnesses is unknown.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Vicentic, Aleksandra
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts Institute of Technology
Organized Research Units
United States
Zip Code
Amadi, Ugwechi; Lim, Seh Hong; Liu, Elizabeth et al. (2017) Hippocampal Processing of Ambiguity Enhances Fear Memory. Psychol Sci 28:143-161
Harmatz, Elia S; Stone, Lauren; Lim, Seh Hong et al. (2017) Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory. Biol Psychiatry 81:1003-1013
Correia, Susana S; Goosens, Ki A (2016) Input-specific contributions to valence processing in the amygdala. Learn Mem 23:534-43
Baratta, Michael V; Kodandaramaiah, Suhasa B; Monahan, Patrick E et al. (2016) Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory. Biol Psychiatry 79:814-822
Gisabella, B; Farah, S; Peng, X et al. (2016) Growth hormone biases amygdala network activation after fear learning. Transl Psychiatry 6:e960
Correia, Susana S; McGrath, Anna G; Lee, Allison et al. (2016) Amygdala-ventral striatum circuit activation decreases long-term fear. Elife 5:
Varela, Carmen; Weiss, Sarah; Meyer, Retsina et al. (2016) Tracking the Time-Dependent Role of the Hippocampus in Memory Recall Using DREADDs. PLoS One 11:e0154374
Lee, Graham; Goosens, Ki A (2015) Sampling blood from the lateral tail vein of the rat. J Vis Exp :e52766
Wickersham, Ian R; Sullivan, Heather A; Pao, Gerald M et al. (2015) Lentiviral vectors for retrograde delivery of recombinases and transactivators. Cold Spring Harb Protoc 2015:368-74
Meyer, R M; Burgos-Robles, A; Liu, E et al. (2014) A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear. Mol Psychiatry 19:1284-94

Showing the most recent 10 out of 13 publications