Schafe GE, Nader K, Blair HT, LeDoux JE. Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci 24: 540-546

W.M. Keck Foundation, Laboratory of Neurobiology, Center for Neural Science, New York University, New York, NY 10003, USA.
Trends in Neurosciences (Impact Factor: 13.56). 10/2001; 24(9):540-6. DOI: 10.1016/S0166-2236(00)01969-X
Source: PubMed

ABSTRACT Pavlovian fear conditioning has emerged as a leading behavioral paradigm for studying the neurobiological basis of learning and memory. Although considerable progress has been made in understanding the neural substrates of fear conditioning at the systems level, until recently little has been learned about the underlying cellular and molecular mechanisms. The success of systems-level work aimed at defining the neuroanatomical pathways underlying fear conditioning, combined with the knowledge accumulated by studies of long-term potentiation (LTP), has recently given way to new insights into the cellular and molecular mechanisms that underlie acquisition and consolidation of fear memories. Collectively, these findings suggest that fear memory consolidation in the amygdala shares essential biochemical features with LTP, and hold promise for understanding the relationship between memory consolidation and synaptic plasticity in the mammalian brain.

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    • "Post-traumatic stress disorder (PTSD), a trauma-and stress-related disorder which is estimated to affect as much as 8% of the adult U.S. population (Kessler et al., 2012), is characterized by intense fear and avoidance, hyper-arousal, and the maladaptive and frequent reexperiencing of a traumatic event (Yehuda, 2002; Yehuda & LeDoux, 2007). Given that fearful, traumatic memories are a core feature of this disorder, a major focus of PTSD research at the pre-clinical level has been to understand how associative fear memories are formed and stored in the brain (Schafe et al., 2001; Rodrigues et al., 2004; Sears et al., 2014), and how they might be erased (Quirk et al., 2010; Maren, 2011; Sandkuhler & Lee, 2013). While this work has progressed rapidly in recent years, few pharmacological compounds have emerged that are readily applicable for use in a clinical setting. "
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    ABSTRACT: Curcumin, a yellow-pigment compound found in the popular Indian spice turmeric (Curcuma longa), has been extensively investigated for its anti-inflammatory, chemopreventative and antidepressant properties.Here, we examined the efficacy of dietary curcumin at impairing the consolidation and reconsolidation of a Pavlovian fear memory, a widely studied animal model of traumatic memory formation in post-traumatic stress disorder (PTSD).We show that a diet enriched with 1.5% curcumin preventsthe training-related elevation in the expression of the immediate early genes (IEGs) Arc/Arg3.1 and Egr-1 in the lateral amygdala (LA)and impairs the'consolidation' of an auditory Pavlovian fear memory; short-term memory (STM) is intact, while long-term memory (LTM) is significantly impaired. Next, we show that dietary curcuminimpairs the 'reconsolidation' of a recently formed auditory Pavlovian fear memory; fear memory retrieval (reactivation)and post-reactivation (PR)-STM are intact, while PR-LTM is significantly impaired. Additional experiments revealed that dietary curcumin is also effective at impairing the reconsolidation of an older, well-consolidated fear memory. Further, we observed that fear memories that fail to reconsolidate under the influence of dietary curcumin are impaired in an enduring manner; unlike extinguished fear memories they are not subject to reinstatement or renewal. Collectively, our findings indicate that a diet enriched with curcumin is capable of impairing fear memory consolidation and reconsolidation processes, findings which may have important clinical implications for the treatment of disorders such as PTSD that are characterized by unusually strong and persistently reactivated fear memories.Neuropsychopharmacology accepted article preview online, 28 November 2014. doi:10.1038/npp.2014.315.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2014; 40(5). DOI:10.1038/npp.2014.315 · 7.05 Impact Factor
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    • "The amygdala has an established role in fearconditioning paradigms (Blair et al., 2001; Schafe et al., 2001; Maren and Quirk, 2004; Johansen et al., 2010) and is a likely site for the storage of these types of memory (Rogan et al., 1997; Fanselow and LeDoux, 1999; Blair et al., 2001). However, a less well defined yet highly important role of the amygdala is its ability to influence other forms of memory, particularly when the learning episode has a degree of emotional context (Paz et al., 2006). "
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    ABSTRACT: Experiences with a high degree of emotional salience are better remembered than events that have little emotional context and the amygdala is thought to play an important role in this enhancement of memory. Visual recognition memory relies on synaptic plasticity in the perirhinal cortex but little is known about the mechanisms that may underlie emotional enhancement of this form of memory. There is good evidence that noradrenaline acting via β-adrenoceptors can enhance memory consolidation. In the present study we examine the role of β-adrenoceptors in synaptic plasticity at the amygdala-perirhinal pathway (LA-PRh) and compare this to mechanisms of intra-perirhinal (PRh-PRh) synaptic plasticity. We demonstrate that activity-dependent PRh-PRh LTP does not rely on β1- or β2-adrenoceptors and that LA-PRh LTP relies on β1-adrenoceptors but not β2-adrenoceptors. We further demonstrate that application of the β-adrenoceptor agonist isoprenaline produces lasting PRh-PRh potentiation but only transient potentiation at the LA-PRh input. However, at the LA-PRh input, combining stimulation that is subthreshold for LTP induction with isoprenaline results in long-lasting potentiation. Isoprenaline-induced and isoprenaline plus subthreshold stimulation-induced potentiation in the PRh-PRh and LA-PRh inputs, respectively were both dependent on activation of NMDARs, voltage gated calcium channels and PKA. Understanding the mechanisms of amygdala-perirhinal cortex plasticity will allow a greater understanding of how emotionally-charged events are remembered.
    Neuroscience 05/2014; 273(100). DOI:10.1016/j.neuroscience.2014.04.070 · 3.36 Impact Factor
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    • "Principal cells of lateral and basolateral nuclei (BLA) receive glutamatergic inputs from thalamus and cortex conveying information about the CS and US (Sah et al., 2008, 2003; Marek et al., 2013). These neurons form fear memories in an NMDA receptor-dependent manner (Schafe et al., 2001; Maren and Quirk, 2004). A network of GABAergic interneurons regulates activity of these cells and fear learning (Marek et al., 2013). "
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    ABSTRACT: Fear learning occurs in response to positive prediction error, when the expected outcome of a conditioning trial exceeds that predicted by the conditioned stimuli present. This role for error in Pavlovian association formation is best exemplified by the phenomenon of associative blocking, whereby prior fear conditioning of conditioned stimulus (CS) A is able to prevent learning to CSB when they are conditioned in compound. The midline and intralaminar thalamic nuclei (MIT) are well-placed to contribute to fear prediction error because they receive extensive projections from the midbrain periaqueductal gray-which has a key role in fear prediction error-and project extensively to prefrontal cortex and amygdala. Here we used an associative blocking design to study the role of MIT in fear learning. In Stage I rats were trained to fear CSA via pairings with shock. In Stage II rats received compound fear conditioning of CSAB paired with shock. On test, rats that received Stage I training expressed less fear to CSB relative to control rats that did not receive this training. Microinjection of bupivacaine into MIT prior to Stage II training had no effect on the expression of fear during Stage II and had no effect on fear learning in controls, but prevented associative blocking and so enabled fear learning to CSB. These results show an important role for MIT in predictive fear learning and are discussed with reference to previous findings implicating the midline and posterior intralaminar thalamus in fear learning and fear responding.
    Frontiers in Behavioral Neuroscience 05/2014; 8:148. DOI:10.3389/fnbeh.2014.00148 · 3.27 Impact Factor
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