Project 1: Probing Circuits of Normal and Pathological Fear Through Studies of  Fear Conditioning
                        -- J. LeDoux, NYU

Overview of Project 1

Literature cited in project 1 in grant proposal

Relevant reviews of the literature

---Neural basis of fear conditioning

---Brain and emotion

Overview of Project 1

Threatening stimuli, which are prominent in the lives of patients with fear disorders, trigger stress reactions, and stress, in turn, is believed to exacerbate symptoms in psychiatric patients, including those with pathological fear. In this project, we therefore pursue the neural basis of fear, and interactions between fear and stress, in an effort to better understand the biological underpinnings of pathological fear. To do this we build upon the progress that has been achieved in understanding fear networks through studies of classical fear conditioning, especially in experimental animals (for review, see LeDoux, '96; Maren and Fanselow, '96; Davis, '94). This work has shown that fear conditioning involves the relay of sensory information from processing areas of the thalamus and cortex to the lateral nucleus of the amygdala (LA), the transfer of signals over intraamygdala pathways to the central nucleus of the amygdala (CE), and the control of fear responses by way of projections from CE to various brainstem targets. Recent studies of fear conditioning in humans also implicate the amygdala (see Phelps, '97; LaBar et al, '98; Buchel et al, '98). Two additional areas connected with the amygdala have been implicated in important aspects of fear conditioning in rats. In particular, damage to the hippocampus interferes with contextual processing in fear (see Phillips and LeDoux, '92, '95; Kim and Fanselow, '92; Maren and Fanselow, 96; Frankland et al, '97; Maren et al, '98), and damage to the medial prefrontal cortex (mPFC) disrupts fear regulation, leading to an exacerbation of fear and/or an inability to extinguish fear (Morgan et al, 92; Morgan and LeDoux, '94; see also Gewirtz and Davis, '97). Both of these latter areas, as well as the amygdala, are involved in regulating the effects of stress (e.g. McEwen and Sapolsky, '95; Herman and Cullinan, '97; Dallman et al, '91'; Diorio et al, '93). In the studies below, we explore the contributions of the amygdala, hippocampus, and mPFC to fear conditioning, and to interactions between fear and stress, in rats and humans. The first set of studies will use functional imaging (fMRI) to obtain more detailed understanding of the circuits in the human brain that are normally involved in fear conditioning. In this work, LeDoux continues an on-going collaboration with Liz Phelps of Yale on the neural systems underlying fear conditioning in humans (Phelps is being recruited at NYU and could well be an on-site collaborator by the time the proposal is funded). Phelps has performed several fMRI studies, including a recent fMRI study of fear conditioning (LaBar et al, '98). Phelps and LeDoux will interact with clinical colleagues in the Center (Silbersweig, Stern, and Gorman) in the design and execution of the research, as the results will influence the manner in which fear conditioning procedures will be implemented in the clinical studies of patients with fear disorders in Project 2. We next turn to experimental animals (rats) to examines interactions between fear and stress in the brain. Studies 2 and 3 pursue a two-part hypothesis. The first part is that the amygdala plays a key role in triggering stress responses to threatening stimuli (Study 2). The second is that stress, once triggered, has opposite effects on the amygdala and hippocampus, leading to an impairment in hippocampal-mediated and a facilitation or potentiation of amygdala-mediated aspects of fear conditioning (Study 3). These studies will be achieved by collaborations with other basic scientists in the Center (McEwen and Morrison). In Study 3 we also examine the effects of hippocampal or mPFC damage on the stress-induced potentiation of amygdala function. This latter experiment is directly related to our clinical hypotheses (see Overview and Project 2), which propose that pathologic fear involves amygdala potentiation together with either hippocampal impairment (leading to exaggerated fear free of contextual constraints) or mPFC impairment (leading to exaggerated and difficult to extinguish fear). The final set of studies seeks to further link the neurobiology of fear and stress to pathological fear in humans by examining the effects of clinically efficacious drugs (especially SSRIs) on stress-induced changes in fear and on the physiology and anatomy of fear circuits. Collaborations with both the clinical and basic science members of the Center will be required to perform these last studies.

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-- Neural basis of fear conditioning
-- Brain and emotion

Reviews on the neural basis of fear conditioning:

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Davis, M. (1992). The role of the amygdala in conditioned fear. The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction.

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Fendt, M. and M. S. Fanselow (1999). "The neuroanatomical and neurochemical basis of conditioned fear." Neurosci Biobehav Rev 23(5): 743-60.

Fanselow, M. S. and J. E. LeDoux (1999). "Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala." Neuron 23(2): 229-32.

LeDoux, J. E. (1992). Emotion and the Amygdala. The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. J. P. Aggleton. New York, Wiley-Liss, Inc.: 339-351.

LeDoux, J. E. (2000). "Emotion circuits in the brain." Annu Rev Neurosci 23: 155-84.

Maren, S. and M. S. Fanselow (1996). "The amygdala and fear conditioning: Has the nut been cracked?" Neuron 16: 237-240.

Maren, S. (1999). "Long-term potentiation in the amygdala: a mechanism for emotional learning and memory." Trends Neurosci 22(12): 561-567.

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LeDoux, J. E. (1994). "Emotion, memory and the brain." Scientific American 270: 32-39. LeDoux, J. E. (1996). The Emotional Brain. New York,

Simon and Schuster. LeDoux, J. E. (2000). "Emotion circuits in the brain." Annu Rev Neurosci 23: 155-84.

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