Neuronal signaling of fear memory. Nature Reviews

Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109, USA.
Nature reviews Neuroscience (Impact Factor: 31.43). 12/2004; 5(11):844-52. DOI: 10.1038/nrn1535
Source: PubMed


The learning and remembering of fearful events depends on the integrity of the amygdala, but how are fear memories represented in the activity of amygdala neurons? Here, we review recent electrophysiological studies indicating that neurons in the lateral amygdala encode aversive memories during the acquisition and extinction of Pavlovian fear conditioning. Studies that combine unit recording with brain lesions and pharmacological inactivation provide evidence that the lateral amygdala is a crucial locus of fear memory. Extinction of fear memory reduces associative plasticity in the lateral amygdala and involves the hippocampus and prefrontal cortex. Understanding the signalling of aversive memory by amygdala neurons opens new avenues for research into the neural systems that support fear behaviour.

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Available from: Stephen Maren
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    • "The ventral hippocampus (vHPC) and the basolateral amygdala (BLA) are part of an extensive neural circuit encoding emotional memories (Fanselow, 2010; Maren and Quirk, 2004). This circuit can be dysfunctional in neuropsychiatric disorders in humans (Phelps, 2004; Richardson et al., 2004) and in animal models (Ghosh et al., 2013; Santos et al., 2013; Zhang et al., 2014). "
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    ABSTRACT: The dynamic interactions between hippocampus and amygdala are critical for emotional memory. Theta synchrony between these structures occurs during fear memory retrieval and may facilitate synaptic plasticity, but the cellular mechanisms are unknown. We report that interneurons of the mouse basal amygdala are activated during theta network activity or optogenetic stimulation of ventral CA1 pyramidal cell axons, whereas principal neurons are inhibited. Interneurons provide feedforward inhibition that transiently hyperpolarizes principal neurons. However, synaptic inhibition attenuates during theta frequency stimulation of ventral CA1 fibers, and this broadens excitatory postsynaptic potentials. These effects are mediated by GABAB receptors and change in the Cl− driving force. Pairing theta frequency stimulation of ventral CA1 fibers with coincident stimuli of the lateral amygdala induces long-term potentiation of lateral-basal amygdala excitatory synapses. Hence, feedforward inhibition, known to enforce temporal fidelity of excitatory inputs, dominates hippocampus-amygdala interactions to gate heterosynaptic plasticity. Video Abstract
    Full-text · Article · Sep 2015 · Neuron
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    • "The systemic effects of SB 242084 may help elucidate some of the anatomical loci of fear discrimination learning. The basolateral amygdala, a critical site of neuroplasticity mediating the acquisition and recall of conditioned fear in rodents (Maren and Quirk, 2004) and humans (Milad et al., 2006; Rauch, et al., 2006b), is the locus of 5-HT action for stressor-induced anxiety (Christianson et al., 2010), stressor enhanced fear (Baratta et al., 2015) and selective serotonin reuptake inhibitor induced anxiety (Vicente and Zangrossi, 2012). Regarding reversal learning, the orbital frontal cortex, which is critical for task response switching as predicted values change (for reviews see Schoenbaum et al., 2011; McDannald et al., 2014) is also modulated by the 5-HT 2C receptor, with SB 242084 improving reversal learning when applied by local microinjection (Boulougouris and Robbins, 2010). "
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    ABSTRACT: The capacity to discriminate between safety and danger is fundamental for survival, but is disrupted in individuals with posttraumatic stress disorder (PTSD). Acute stressors cause a release of serotonin (5-HT) in the fore-brain, which is one mechanism for enhanced fear and anxiety; these effects are mediated by the 5-HT2C receptor. Using a fear discrimination paradigm where a danger signal conditioned stimulus (CS+) co-terminates with a mild footshock and a safety signal (CS-) indicates the absence of shock, we demonstrate that danger/safety discrimination and fear inhibition develop over the course of 4 daily conditioning sessions. Systemic administration of the 5-HT2C receptor antagonist SB 242084 (0.25 or 1.0 mg/kg) prior to conditioning reduced behavioral freezing during conditioning, and improved learning and subsequent inhibition of fear by the safety signal. Discrimination was apparent in the first recall test, and discrimination during training was evident after 3 days of conditioning versus 5 days in the vehicle treated controls. These results suggest a novel therapeutic use for 5-HT2C receptor antagonists to improve learning under stressful circumstances. Potential anatomical loci for 5-HT2C receptor modulation of fear discrimination learning and cognitive performance enhancement are discussed. Ethical Statement: John P. Christianson and Allison R. Foilb, the authors, verify that animal research was carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) and all procedures involving animals were reviewed and approved by the Boston College Animal Care and Use Committee. All efforts were made to limit the number of animals used and their suffering.
    Full-text · Article · Sep 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
    • "However, it remains to be elucidated whether mGluR2/3 is required for fear extinction and, if it is required, through which mechanisms it contributes. Ample evidence suggests that extinction training results in the formation of extinction memory that inhibits original fear memory (Myers and Davis, 2002; Maren and Quirk, 2004; Ehrlich et al, 2009), and the extinction memory is thought to be encoded in the prefrontal cortex and amygdala intercalated neurons (Milad and Quirk, 2002; Likhtik et al, 2008; Pare and Duvarci, 2012). In addition, fear extinction also involves weakening of the original fear memory encoded in the LA: long-term potentiation of synaptic efficacy at both thalamic input synapses onto the LA (T-LA synapses) and C-LA synapses encodes conditioned fear memory (Quirk et al, 1997; Rogan et al, 1997; Tsvetkov et al, 2002; Sah and Lopez De Armentia, 2003; Schroeder and Shinnick-Gallagher, 2005), and depotentiation or long-term depression at T-LA synapses contributes to fear extinction (Lin et al, 2005; Kim et al, 2007b; Dalton et al, 2008; see also Hong et al, 2009; Kim et al, 2010). "
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    ABSTRACT: Various subtypes of metabotropic glutamate receptors (mGluRs) have been implicated in fear extinction, but mGluR2/3 subtype has not been tested. Here, we found that microinjection of an mGluR2/3 antagonist, LY341495, into the lateral amygdala (LA), but not into the adjacent central amygdala (CeA), impaired extinction retention without affecting within-session extinction. In contrast, we failed to detect any significant changes in motility and anxiety during a period when extinction training or retention was performed after LY341495 injection, suggesting that the effect of LY341495 is specific to conditioned responses. Subsequently, on the basis of a previous finding that a long-term potentiation of presynaptic efficacy at cortical input synapses onto the lateral amygdala (C-LA synapses) supports conditioned fear, we tested the hypothesis that activation of mGluR2/3 leads to fear extinction via a long-term weakening of presynaptic functions at C-LA synapses. Fear extinction produced a decrease in C-LA synaptic efficacy, whereas LY341495 infusion into the LA blocked this extinction-induced C-LA efficacy decrease without altering synaptic efficacy at other LA synapses. Furthermore, extinction enhanced paired pulse ratio (PPR) of EPSCs, which inversely correlates with presynaptic release probability, whereas LY341495 infusion into the LA attenuated the extinction-induced increase in PPR, suggesting the presence of mGluR2/3-dependent presynaptic changes after extinction. Consistently, extinction occluded a presynaptic form of depression at C-LA synapses, whereas the LY341495 infusion into the LA rescued this occlusion. Together, our findings suggest that mGluR2/3 is required for extinction retention and that the mGluR2/3 action is mediated by the long-term weakening of release probability at C-LA synapses.Neuropsychopharmacology advance online publication, 17 June 2015; doi:10.1038/npp.2015.145.
    No preview · Article · May 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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