Maren, S. Neurobiology of Pavlovian fear conditioning. Annu. Rev. Neurosci. 24, 897−931

Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109-1109, USA.
Annual Review of Neuroscience (Impact Factor: 19.32). 02/2001; 24(1):897-931. DOI: 10.1146/annurev.neuro.24.1.897
Source: PubMed


Learning the relationships between aversive events and the environmental stimuli that predict such events is essential to the survival of organisms throughout the animal kingdom. Pavlovian fear conditioning is an exemplar of this form of learning that is exhibited by both rats and humans. Recent years have seen an incredible surge in interest in the neurobiology of fear conditioning. Neural circuits underlying fear conditioning have been mapped, synaptic plasticity in these circuits has been identified, and biochemical and genetic manipulations are beginning to unravel the molecular machinery responsible for the storage of fear memories. These advances represent an important step in understanding the neural substrates of a rapidly acquired and adaptive form of associative learning and memory in mammals.

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    • "In this procedure , a neutral conditioned stimulus ( CS , tone ) that has been paired with an aversive unconditioned stimulus ( US , footshock ) comes to elicit conditioned fear responses , including freezing , increases in acoustic startle , and changes in heart rate and blood pressure ( LeDoux , 2000 ; Maren , 2001 ; Fanselow and Poulos , 2005 ) . After fear conditioning , male and female rats show a dramatic sex difference in levels of contextual freezing : females express significantly lower levels of freezing in the conditioning context compared to males ( Maren et al . "
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    ABSTRACT: Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry.
    Frontiers in Behavioral Neuroscience 08/2015; 9:205. DOI:10.3389/fnbeh.2015.00205 · 3.27 Impact Factor
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    • "Alternatively, it is possible that inhibiting the memory engram in the dentate gyrus was sufficient to suppress contextual fear memory, supporting recent studies demonstrating causality between c-fos-activated cells in the dentate gyrus and memory engrams (Liu et al., 2012; Ramirez et al., 2013). The hippocampus is an essential structure for contextual fear learning (Anagnostaras et al., 2001; Maren, 2001). Primarily, this is based on the fact that hippocampal lesions disrupt contextual fear learning. "
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    ABSTRACT: Lesion studies suggest that an alternative system can compensate for damage to the primary region employed when animals acquire a memory. However, it is unclear whether functional compensation occurs at the cellular ensemble level. Here, we inhibited the activities of a specific subset of neurons activated during initial learning by utilizing a transgenic mouse that expresses tetanus toxin (TeNT) under the control of the c-fos promoter. Notably, suppression interfered with relearning while sparing the ability to acquire and express fear memory for a distinct context. These results suggest that the activity of the initial ensemble is preferentially dedicated to the same learning and that it is not replaceable once it is allocated. Our results provide substantial insights into the machinery underlying how the brain allocates individual memories to discrete neuronal ensembles and how it ensures that repetitive learning strengthens memory by reactivating the same neuronal ensembles. Copyright © 2015 The Author. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(3). DOI:10.1016/j.celrep.2015.03.042 · 8.36 Impact Factor
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    • "During auditory fear conditioning , tone information reaches the amygdala via direct projections from the auditory thalamus (AT) and auditory cortex (AC), predominantly synapsing within the basolateral amygdala (BLA) (LeDoux et al., 1991; Romanski et al., 1993; Romanski and LeDoux, 1993; Sah et al., 2003). Sensory information is processed within the amygdala, and projections from the central amygdala (CeA), the main output region of the amygdala, trigger the physiological responses associated with the fear response (Davis and Whalen, 2001; Maren, 2001). The BLA is a cortical-like structure, and glutamatergic pyramidal neurons form the major population of neurons within it ($80%) (McDonald, 1982; Sah et al., 2003). "
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    ABSTRACT: The basolateral amygdala (BLA) and prefrontal cortex (PFC) are partners in fear learning and extinction. Intercalated (ITC) cells are inhibitory neurons that surround the BLA. Lateral ITC (lITC) neurons provide feed-forward inhibition to BLA principal neurons, whereas medial ITC (mITC) neurons form an inhibitory interface between the BLA and central amygdala (CeA). Notably, infralimbic prefrontal (IL) input to mITC neurons is thought to play a key role in fear extinction. Here, using targeted optogenetic stimulation, we show that lITC neurons receive auditory input from cortical and thalamic regions. IL inputs innervate principal neurons in the BLA but not mITC neurons. These results suggest that (1) these neurons may play a more central role in fear learning as both lITCs and mITCs receive auditory input and that (2) mITC neurons cannot be driven directly by the IL, and their role in fear extinction is likely mediated via the BLA. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(9). DOI:10.1016/j.celrep.2015.02.008 · 8.36 Impact Factor
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