Morgan MA, Schulkin J, LeDoux JE. Ventral medial prefrontal cortex and emotional perseveration: the memory for prior extinction training. Behav Brain Res 146: 121-130

Department of Psychology, New York University, New York, NY, USA.
Behavioural Brain Research (Impact Factor: 3.03). 12/2003; 146(1-2):121-30. DOI: 10.1016/j.bbr.2003.09.021
Source: PubMed


Several years ago, we found that lesions of ventral medial prefrontal cortex (mPFCv) disrupted performance during the extinction component of a classical fear conditioning task without affecting acquisition performance. We called this emotional perseveration, hypothesizing that mPFCv may normally act to inhibit fear responses to a conditioned stimulus (CS) when the CS no longer signals danger. Subsequent studies have supported this hypothesis, showing that mPFCv is crucial for the memory of prior extinction training. The present study examined the effects of mPFCv lesions made after training. Such lesions resulted in reduced freezing to contextual stimuli and normal responding to the CS presented alone during a retention test. Rats were then subjected to extinction trials (CS without US) over multiple days. In contrast to pre-training lesions, post-training lesions had little effect on extinction rate. All rats were given additional training. Lesioned rats expressed greater fear reactions than controls, indicating that prior extinction was less effective in them. Lesioned rats also showed resistance to extinction during reextinction trials, confirming our earlier finding that lesions made before training weaken the effectiveness of extinction trials. These results suggest three conclusions. First, an intact mPFCv during acquisition may protect the animal from prolonged responding during extinction trials following brain insult. Second, changes in mPFCv may predispose subjects toward enhanced fear reactions that are difficult to extinguish when reexposed to fearful stimuli, due to a diminished capacity to benefit from the fear-reducing impact of prior extinction experience. Third, contextual cues processed by mPFCv may influence extinction performance.


Available from: Jay Schulkin, Aug 18, 2014
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    • "The vmPFC activates GABAergic intercalated cells in the amygdala which in turn inhibit the central nucleus of the amygdala (Quirk et al., 2006; Sotres-Bayon et al., 2007). Evidence for this model has been provided by lesion studies (Morgan and LeDoux, 1993; Quirk et al., 2000; Morgan et al., 2003; Lebron et al., 2004). For example Morgan and LeDoux (1993) showed that rats with lesions of the medial PFC were resistant to extinction learning in a delay fear conditioning paradigm. "
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    ABSTRACT: Extinction is an important mechanism to inhibit initially acquired fear responses. There is growing evidence that the ventromedial prefrontal cortex (vmPFC) inhibits the amygdala and therefore plays an important role in the extinction of delay fear conditioning. To our knowledge, there is no evidence on the role of the prefrontal cortex in the extinction of trace conditioning up to now. Thus, we compared brain structures involved in the extinction of human delay and trace fear conditioning in a between-subjects-design in an fMRI study. Participants were passively guided through a virtual environment during learning and extinction of conditioned fear. Two different lights served as conditioned stimuli (CS); as unconditioned stimulus (US) a mildly painful electric stimulus was delivered. In the delay conditioning group (DCG) the US was administered with offset of one light (CS+), whereas in the trace conditioning group (TCG) the US was presented 4 s after CS+ offset. Both groups showed insular and striatal activation during early extinction, but differed in their prefrontal activation. The vmPFC was mainly activated in the DCG, whereas the TCG showed activation of the dorsolateral prefrontal cortex (dlPFC) during extinction. These results point to different extinction processes in delay and trace conditioning. VmPFC activation during extinction of delay conditioning might reflect the inhibition of the fear response. In contrast, dlPFC activation during extinction of trace conditioning may reflect modulation of working memory processes which are involved in bridging the trace interval and hold information in short term memory.
    Frontiers in Human Neuroscience 05/2014; 8:323. DOI:10.3389/fnhum.2014.00323 · 3.63 Impact Factor
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    • "Studies in animals (Maren & Quirk, 2004; Pare et al., 2004) and humans (Phelps & LeDoux, 2005) indicate that interactions between the medial prefrontal cortex (mPFC) and the amygdala are critically involved in extinction learning (Morgan et al., 1993; LeDoux, 2000; Quirk et al., 2003; Rosenkranz et al., 2003). Specifically, recent studies have established a role for the infralimbic prefrontal cortex (IL) in consolidation of fear extinction (Milad & Quirk, 2002; Morgan et al., 2003; Sierra-Mercado et al., 2006). Previous studies also implicate mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways in consolidation of auditory and contextual fear conditioning (Schafe et al., 2000; Trifilieff et al., 2006), as well as extinction of conditioned fear in the mPFC, BLA, "
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    ABSTRACT: D-cycloserine (DCS) is currently under clinical trials for a number of neuropsychiatric conditions and has been found to augment fear extinction in rodents and exposure therapy in humans. However, the molecular mechanism of DCS action in these multiple modalities remains unclear. Here, we describe the effect of DCS administration, alone or in conjunction with extinction training, on neuronal activity (c-fos) and neuronal plasticity [phospho-extracellular signal-regulated kinase (pERK)] markers using immunohistochemistry. We found that intraperitoneal administration of DCS in untrained young rats (24-28 days old) increased c-fos- and pERK-stained neurons in both the prelimbic and infralimbic division of the medial prefrontal cortex (mPFC) and reduced pERK levels in the lateral nucleus of the central amygdala. Moreover, DCS administration significantly increased GluA1, GluN1, GluN2A, and GluN2B expression in the mPFC. In a separate set of animals, we found that DCS facilitated fear extinction and increased pERK levels in the infralimbic prefrontal cortex, prelimbic prefrontal cortex intercalated cells and lateral nucleus of the central amygdala, compared with saline control. In the synaptoneurosomal preparation, we found that extinction training increased iGluR protein expression in the mPFC, compared with context animals. No significant difference in protein expression was observed between extinction-saline and extinction-DCS groups in the mPFC. In contrast, in the amygdala DCS, the conjunction with extinction training led to an increase in iGluR subunit expression, compared with the extinction-saline group. Our data suggest that the efficacy of DCS in neuropsychiatric disorders may be partly due to its ability to affect neuronal activity and signaling in the mPFC and amygdala subnuclei.
    European Journal of Neuroscience 03/2013; 37(11). DOI:10.1111/ejn.12197 · 3.18 Impact Factor
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    • "Although further studies are necessary to understand the complex mechanisms underlying conditioned lick suppression, our results suggest that chronic treatment with EGb modulates conditioned suppression by modulating the neural circuits implicated in anxiety and fear, particularly the AC, DH and PFC (LeDoux, 2000; Graeff et al., 2003; Morgan et al., 2003; Quirk and Gehlert, 2003; McGaugh, 2004; Sierra-Mercado et al., 2006). "
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    ABSTRACT: Our group previously demonstrated that short-term treatment with a standardized extract of Ginkgo biloba (EGb) changed fear-conditioned memory by modulating gene expression in the hippocampus, amygdaloid complex and prefrontal cortex. Although there are few controlled studies that support the long-term use of EGb for the prevention and/or treatment of memory impairment, the chronic use of Ginkgo is common. This study evaluated the effects of chronic treatment with EGb on the conditioned emotional response, assessed by the suppression of ongoing behavior and in the modulation of gene and protein expression. Male adult Wistar rats were treated over 28 days and assigned to five groups (n = 10) as follows: positive control (4 mg kg−1 Diazepam), negative control (12% Tween 80), EGb groups (0.5 and 1.0 g kg−1) and the naïve group. The suppression of the licking response was calculated for each rat in six trials. Our results provide further evidence for the efficacy of EGb on memory. For the first time, we show that long-term treatment with the highest dose of EGb improves the fear memory and suggests that increased cAMP-responsive element-binding protein (CREB)-1 and glial fibrillary acidic protein (GFAP) mRNA and protein (P < 0.001) in the dorsal hippocampus and amygdaloid complex and reduced growth and plasticity-associated protein 43 (GAP-43) (P < 0.01) in the hippocampus are involved in this process. The fear memory/treatment-dependent changes observed in our study suggest that EGb might be effective for memory enhancement through its effect on the dorsal hippocampus and amygdaloid complex.
    Neuroscience 01/2013; 235:70–86. DOI:10.1016/j.neuroscience.2013.01.009 · 3.36 Impact Factor
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