Multiple neural systems exist within the human brain that allow us to learn and remember. At the present time it is not entirely clear how the many different forms of human memory relate directly to structures and circuits in the brain. The long-term goal of this study is to understand the neural mechanisms underlying a specific form of memory, aversive Pavlovian conditioning, in human subjects. The ability to learn associations through Pavlovian conditioning is shared by a wide variety of organisms but very little is known about the neurobiological substrates of this process in humans. Our general approach is to use state of the art whole brain functional magnetic resonance imaging (fMRI) to identify brain regions and circuits that contribute to the acquisition and performance of fear conditioning. Functional maps of brain areas in which activity is directly related to exposure to the CS+ or CS- in a differential conditioning paradigm will be constructed. Similar techniques are used to characterize brain areas in which activity is best related to autonomic fear responses versus cognitive awareness of the relationship between programmed stimuli. This phase of the project will focus on a series of predictions regarding the roles of the amygdala, hippocampus, frontal cortex, and cingulate cortex based on our progress during the last funding period and current knowledge from laboratory animal studies and other human memory paradigms. We will further evaluate our findings related to localized frontal lobe activity specifically related to contingency awareness and declarative memory. We will explore the dynamics of learning-related stimulus representations in primary sensory cortex. We will compare an auditory fear conditioning procedure with visual stimulus conditioning, and we will conduct studies related the mechanisms of fear extinction and long-term memory retrieval. The results will enable significant advancement in understanding;1) the relationship between declarative and procedural memory systems, 2) the role of awareness in learning, 3) the comparative neuroanatomy of memory, and 4) the brain mechanisms of fear and anxiety. Our work should be particularly useful in improving the ability to translate fundamental results from laboratory animal models of memory and emotion directly to healthy humans as well as patient populations. The research described here has direct implications for understanding basic brain mechanisms of memory and anxiety in humans. This work may provide valuable insights into new treatments for diseases and disorders that affect memory and emotion. Our approach to these issues represents an important step toward the application of a large body of basic research in laboratory animals to clinical and experimental questions in people.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Vicentic, Aleksandra
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University of Wisconsin Milwaukee
Schools of Arts and Sciences
United States
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Hopkins, Lauren S; Schultz, Douglas H; Hannula, Deborah E et al. (2015) Eye Movements Index Implicit Memory Expression in Fear Conditioning. PLoS One 10:e0141949
Balderston, Nicholas L; Schultz, Douglas H; Hopkins, Lauren et al. (2015) Functionally distinct amygdala subregions identified using DTI and high-resolution fMRI. Soc Cogn Affect Neurosci 10:1615-22
Gilmartin, Marieke R; Balderston, Nicholas L; Helmstetter, Fred J (2014) Prefrontal cortical regulation of fear learning. Trends Neurosci 37:455-64
Schultz, Douglas H; Balderston, Nicholas L; Geiger, Jennifer A et al. (2013) Dissociation between implicit and explicit responses in postconditioning UCS revaluation after fear conditioning in humans. Behav Neurosci 127:357-68
Balderston, Nicholas L; Schultz, Douglas H; Baillet, Sylvain et al. (2013) How to detect amygdala activity with magnetoencephalography using source imaging. J Vis Exp :
Balderston, Nicholas L; Schultz, Doug H; Helmstetter, Fred J (2013) The effect of threat on novelty evoked amygdala responses. PLoS One 8:e63220
Schultz, Douglas H; Balderston, Nicholas L; Helmstetter, Fred J (2012) Resting-state connectivity of the amygdala is altered following Pavlovian fear conditioning. Front Hum Neurosci 6:242
Jarome, Timothy J; Kwapis, Janine L; Werner, Craig T et al. (2012) The timing of multiple retrieval events can alter GluR1 phosphorylation and the requirement for protein synthesis in fear memory reconsolidation. Learn Mem 19:300-6
Balderston, Nicholas L; Schultz, Doug H; Helmstetter, Fred J (2011) The human amygdala plays a stimulus specific role in the detection of novelty. Neuroimage 55:1889-98
Balderston, Nicholas L; Helmstetter, Fred J (2010) Conditioning with masked stimuli affects the timecourse of skin conductance responses. Behav Neurosci 124:478-89

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