Lesions of the Basal Amygdala Block Expression of Conditioned Fear But Not Extinction

Ponce School of Medicine and Health Sciences, Ponce, Ponce, Puerto Rico
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2005; 25(42):9680-5. DOI: 10.1523/JNEUROSCI.2600-05.2005
Source: PubMed


Although the role of the amygdala in acquisition of conditioned fear is well established, there is debate concerning the intra-amygdala circuits involved. The lateral nucleus of the amygdala (LA) is thought to be an essential site of plasticity in fear conditioning. The LA has both direct and indirect [via the basal nuclei; basal amygdala (BA)] projections to the central nucleus (Ce) of the amygdala, an essential output for fear behaviors. Lesions of the LA or Ce prevent acquisition of conditioned freezing to a conditioned stimulus, but BA lesions do not, suggesting that the BA is not normally involved in fear conditioning. If true, posttraining BA lesions should also have no effect. Replicating previous studies, we found that rats given electrolytic BA lesions before training acquired conditioned fear normally. They also showed normal long-term retention and extinction of conditioned fear. Unexpectedly, BA lesions made after training completely blocked expression of conditioned fear. Despite this deficit, lesioned rats were able to learn a new tone-shock association. Thus, although the LA-Ce system is sufficient for fear acquisition in the absence of the BA, it is not sufficient when the BA is present, suggesting that the BA is an important site of plasticity in fear conditioning. The pattern of lesion deficits we observed (after but not before training) might be explained by homeostatic mechanisms that balance plasticity over multiple inputs, regulating the influence of the BA and LA onto Ce output neurons.

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    • "Neural representations of appetitive and aversive USs have been identified in the BLA (Belova et al., 2007; Bermudez and Schultz, 2010; Knapska et al., 2007; Livneh and Paz, 2012; Muramoto et al., 1993; Paton et al., 2006; Romanski et al., 1993; Uwano et al., 1995; Wolff et al., 2014). Pharmacologic silencing and lesions of the BLA impair aversive conditioning and some forms of appetitive conditioning (Amano et al., 2011; Ambroggi et al., 2008; Anglada-Figueroa and Quirk, 2005; Balleine and Killcross, 2006; Hatfield et al., 1996; Maren et al., 2001). Optogenetic activation of random populations of neurons in the lateral amygdala can entrain a neutral tone to elicit freezing behavior (Johansen et al., 2010; Yiu et al., 2014), and activation of different populations of BLA neurons or their distinct projections can elicit either anxiety-related or self-stimulation behaviors (Felix-Ortiz et al., 2013; Kim et al., 2013; Namburi et al., 2015; Stuber et al., 2011; Tye et al., 2011). "
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    ABSTRACT: Stimuli that possess inherently rewarding or aversive qualities elicit emotional responses and also induce learning by imparting valence upon neutral sensory cues. Evidence has accumulated implicating the amygdala as a critical structure in mediating these processes. We have developed a genetic strategy to identify the representations of rewarding and aversive unconditioned stimuli (USs) in the basolateral amygdala (BLA) and have examined their role in innate and learned responses. Activation of an ensemble of US-responsive cells in the BLA elicits innate physiological and behavioral responses of different valence. Activation of this US ensemble can also reinforce appetitive and aversive learning when paired with differing neutral stimuli. Moreover, we establish that the activation of US-responsive cells in the BLA is necessary for the expression of a conditioned response. Neural representations of conditioned and unconditioned stimuli therefore ultimately connect to US-responsive cells in the BLA to elicit both innate and learned responses. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 07/2015; 162(1):134-145. DOI:10.1016/j.cell.2015.06.027 · 32.24 Impact Factor
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    • "LA is required for Pavlovian conditioning, AA, and PIT (Nader et al., 2001; Choi et al., 2010; Lazaro-Munoz et al., 2010; Campese et al., 2014). BA is required for AA and expression of Pavlovian conditioning (Anglada-Figueroa and Quirk, 2005; Choi et al., 2010; Lazaro-Munoz et al., 2010). And CeA is required for Pavlovian conditioning and PIT, but opposes AA expression (Nader et al., 2001; Choi et al., 2010; Lazaro-Munoz et al., 2010). "
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    ABSTRACT: Pavlovian conditioned stimuli (CSs) play an important role in the reinforcement and motivation of instrumental active avoidance (AA). Conditioned threats can also invigorate ongoing AA responding [aversive Pavlovian-instrumental transfer (PIT)]. The neural circuits mediating AA are poorly understood, although lesion studies suggest that lateral, basal, and central amygdala nuclei, as well as infralimbic prefrontal cortex, make key, and sometimes opposing, contributions. We recently completed an extensive analysis of brain c-Fos expression in good vs. poor avoiders following an AA test (Martinez et al., 2013, Learning and Memory). This analysis identified medial amygdala (MeA) as a potentially important region for Pavlovian motivation of instrumental actions. MeA is known to mediate defensive responding to innate threats as well as social behaviors, but its role in mediating aversive Pavlovian-instrumental interactions is unknown. We evaluated the effect of MeA lesions on Pavlovian conditioning, Sidman two-way AA conditioning (shuttling) and aversive PIT in rats. Mild footshocks served as the unconditioned stimulus in all conditioning phases. MeA lesions had no effect on AA but blocked the expression of aversive PIT and 22 kHz ultrasonic vocalizations in the AA context. Interestingly, MeA lesions failed to affect Pavlovian freezing to discrete threats but reduced freezing to contextual threats when assessed outside of the AA chamber. These findings differentiate MeA from lateral and central amygdala, as lesions of these nuclei disrupt Pavlovian freezing and aversive PIT, but have opposite effects on AA performance. Taken together, these results suggest that MeA plays a selective role in the motivation of instrumental avoidance by general or uncertain Pavlovian threats.
    Frontiers in Behavioral Neuroscience 09/2014; 8:329. DOI:10.3389/fnbeh.2014.00329 · 3.27 Impact Factor
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    • "Recent findings suggest that PL and IL cortices have opposite effects on fear responses (Vidal-Gonzalez et al., 2006; Laurent and Westbrook, 2009; Sierra-Mercado et al., 2011). PL sends excitatory projections to BA (Vertes, 2004; Likhtik et al., 2005), a region necessary for fear expression (Anglada-Figueroa and Quirk, 2005), whereas IL projects to GABAergic (gamma-aminobutyric acid) cells in CeL, which inhibits CeM outputs and consequently fear expression (Royer and Pare, 2002; Quirk et al., 2003; Amano et al., 2010). It was somewhat surprising, therefore, that dorsal-VS DBS increased Fos expression in PL as well as IL. "
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    ABSTRACT: Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces the symptoms of treatment-resistant obsessive compulsive disorder (OCD), and improves response to extinction-based therapies. We recently reported that DBS-like stimulation of a rat homologue of VC/VS, the dorsal-VS, reduced conditioned fear and enhanced extinction memory (Rodriguez-Romaguera et al., 2012). In contrast, DBS of the ventral-VS had the opposite effects. To examine possible mechanisms of these effects, we assessed the effects of VS DBS on the expression of the neural activity marker Fos and brain-derived neurotrophic factor (BDNF), a key mediator of extinction plasticity in prefrontal-amygdala circuits. Consistent with decreased fear expression, DBS of dorsal-VS increased Fos expression in prelimbic and infralimbic prefrontal cortices and in the lateral division of the central nucleus of amygdala, an area that inhibits amygdala output. Consistent with improved extinction memory, we found that DBS of dorsal-VS, but not ventral-VS, increased neuronal BDNF expression in prelimbic and infralimbic prefrontal cortices. These rodent findings are consistent with the idea that clinical DBS of VC/VS may augment fear extinction through an increase in BDNF expression.
    Frontiers in Behavioral Neuroscience 08/2013; 7:102. DOI:10.3389/fnbeh.2013.00102 · 3.27 Impact Factor
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