Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation

Neuroscience and Biobehavioral Reviews 71 (2016) 48–57

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Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation Mariella Bodemeier Loayza Careaga, Carlos Eduardo Neves Girardi, Deborah Suchecki ∗ Departamento de Psicobiologia – Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil

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Article history: Received 7 January 2016 Received in revised form 20 July 2016 Accepted 16 August 2016 Available online 31 August 2016 Keywords: Fear conditioning Extinction Reconsolidation PTSD Memory persistence

a b s t r a c t Careaga MBL, Girardi CEN, Suchecki D. Understanding posttraumatic stress disorder through fear conditioning, extinction and reconsolidation. NEUROSCI BIOBEHAV REV −Posttraumatic stress disorder (PTSD) is a psychopathology characterized by exacerbation of fear response. A dysregulated fear response may be explained by dysfunctional learning and memory, a hypothesis that was proposed decades ago. A key component of PTSD is fear conditioning and the study of this phenomenon in laboratory has expanded the understanding of the underlying neurobiological changes in PTSD. Furthermore, traumatic memories are strongly present even years after the trauma and maintenance of this memory is usually related to behavioral and physiological maladaptive responses. Persistence of traumatic memory may be explained by a dysregulation of two memory processes: extinction and reconsolidation. The former may explain the over-expression of fear responses as an imbalance between traumatic and extinction memory. The latter, in turn, explains the maintenance of fear responses as a result of enhancing trauma-related memories. Thus, this review will discuss the importance of fear conditioning for the establishment of PTSD and how failure in extinction or abnormal reconsolidation may contribute to the maintenance of fear response overtime. © 2016 Published by Elsevier Ltd.

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Posttraumatic stress disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Associative learning and PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 2.1. Key brain structures for fear conditioning and their relation to PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 2.1.1. Hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 2.1.2. Amygdala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 2.1.3. Prefrontal cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Extinction learning and PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Reconsolidation and PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Conclusions and further directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

1. Posttraumatic stress disorder PTSD is a fear-based disorder that can be induced by exposure to extreme aversive events, such as war, sexual violence or

∗ Corresponding author at: Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Psicobiologia, Rua Napoleão de Barros, 925, São Paulo 04024-002, São Paulo, Brazil. E-mail address: [email protected] (D. Suchecki). http://dx.doi.org/10.1016/j.neubiorev.2016.08.023 0149-7634/© 2016 Published by Elsevier Ltd.

life-threatening accidents (e.g., motor vehicle accidents). These situations usually overcome the individual’s coping responses, leading to behavioral and psychological alterations (for review, see Huether, 1996). The last edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) developed by the American Psychiatric Association (APA) reclassified PTSD as a stress or trauma disorder, with the following core features: – Re-experiencing symptoms of the aversive event, by means of nightmares, flashbacks and intrusive memories.

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– Effort to avoid reminders of the event including places, thoughts and people. – Hyperarousal symptoms related to physiological manifestations, such as hypervigilance, irritability, impaired concentration, increase in startle response and anger outbreak. Although not all people exposed to extreme stressful events develop PTSD, this is the fourth most common psychiatric disorder in the USA(Breslau et al., 1991; Kessler et al., 1995). Epidemiological studies in the general population reveal that before the September 11 attacks 5–6% of men and 10–14% of women exhibited lifetime PTSD symptoms (Breslau et al., 1991; Kessler et al., 1995; Resnick et al., 1993). Few months after the attacks, a crosssectional web-based survey with2273 participants used a PTSD checklist and found a probable PTSD prevalence of 11.2% in New York residents (Schlenger et al., 2002). A subsequent study by Galea (2003) found a decline in PTSD symptoms prevalence in the general population of New York six months after September 11; however, those who were directly involved in the attacks still met PTSD criteria. The deleterious impact of traumatic events is also seen in low and middle-income countries, such as Brazil, Chile and Mexico. The Brazilian population is daily exposed to threatening events, including kidnapping, vehicle accidents and robbery with or without weapon. Ribeiro et al. (2013) conducted a cross-sectional survey with a probabilistic representative sample in São Paulo and Rio de Janeiro, the two largest Brazilian metropolis, and found high lifetime prevalence for traumatic exposure (nearly 90% of the sample) and higher lifetime prevalence estimates of PTSD among women than men in both cities. Moreover, they found an association between psychiatric disorders, such as social phobia, panic disorder and major depression and the three clusters of traumatic events (assaultive violence, other injury, sudden death), suggesting that these events may increase the likelihood of developing mental disorders. Comorbidity is often reported and over 90% of PTSD patients have at least 1 lifetime comorbid psychiatric disorder (Kessler et al., 1995). Major depressive disorder, alcohol abuse and/or dependence and anxiety disorder are commonly diagnosed in PTSD patients (Chilcoat and Breslau, 1998; Raboni et al., 2014). In the past years, establishment of animal models has been essential to investigate the underlying mechanisms of this disorder. Animal and human studies reveal that the etiology and symptomatology of PTSD involve several brain areas and behavioral systems, some of them related to learning and memory processes. In this regard, we should be aware that some PTSD symptoms are closely linked to associative (e.g., fear conditioning), whereas others are connected to non-associative learning (e.g., sensitization, habituation). Nonetheless, some symptoms are not explained by learning processes, e.g., guilt, shame (for review, see Lissek and van Meurs, 2015). In this review, we will focus our attention on a memory interpretation for PTSD, exploring memory processes that could explain maintenance of some PTSD symptoms, including non-associative and mainly associative learning. 2. Associative learning and PTSD Classical conditioning is a form of associative learning in which two or more stimuli are paired, with a change in the salience of the conditioned stimulus. Ivan Petrovich Pavlov (1849–1936) was the first to study this form of learning, when he observed, in dogs, that a neutral stimulus (e.g., sound – known after conditioning as conditioned stimulus – CS) was able to trigger physiological and behavioral changes after being associated to a biological relevant stimulus (food – known as unconditioned stimulus – US). After pairing of both stimuli, CS led to behavioral or physiological changes known as conditioned responses (CR) (for review, see VanElzakker

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et al., 2014). Classical conditioning can also be established by using aversive stimuli as the US, forming what is known as classical fear conditioning(for review, see Maren, 2001). Currently, in animal studies on fear conditioning, neutral stimuli, such as a tone, light or the environment as a whole are paired with a noxious stimulus, usually, foot shock. As a result of this association, CS acquires aversive properties and induces fear responses that in rodents usually include freezing behavior (Blanchard and Blanchard, 1972), potentiated startle (Hitchcock and Davis, 1986), ultrasonic distress vocalization (Blanchard et al., 1991) and changes in heart and respiratory rates and in blood pressure (Iwata et al., 1986; Kapp et al., 1979). Classical fear conditioning paradigm is one of the most employed models to study learning and emotional memory and is a powerful tool to reveal the neurobiological underpinnings of psychiatric disorders in which strong emotional memory component is present, such as in PTSD. In this disorder, cues/stimuli present in the environment at the time of the trauma, e.g., loud sounds, objects, are associated with the aversive experience (e.g., assault, kidnap), leading to physiological and behavioral reactions. For this reason, fear conditioning is pointed out as an outstanding memory feature of PTSD that can explain re-experiencing and, in part, avoidance symptoms (for review, see VanElzakker et al., 2014; Yehuda and LeDoux, 2007). In the past years, the neurobiological mechanisms of fear conditioning were extensively studied and some key brain structures were identified. Interestingly, these brain areas have also been implicated in PTSD. 2.1. Key brain structures for fear conditioning and their relation to PTSD 2.1.1. Hippocampus The hippocampus is located in the temporal lobe and has an important role in the regulation of the neuroendocrine stress response, learning and memory (for review, see Maren, 2001; McEwen et al., 1992). It is involved in certain forms of conditioned fear that depend on contextual processing, such as contextual fear conditioning (Kim et al., 1993; Maren et al., 1997; Phillips and LeDoux, 1992). In rodents, electrolytic lesion of the dorsal hippocampus impairs acquisition and expression of contextual fear memory, whereas tone fear conditioning is spared (Phillips and LeDoux, 1992). This effect is clearly seen when the lesion takes place prior to training in a spatial memory task, but not always when it is done several weeks after the training (Broadbent et al., 2006; Debiec et al., 2002; Maren et al., 1997). Recently, Goshen et al. (2011) assessed the role of the hippocampus on retrieval of remote memories in mice (memories evaluated weeks or months after acquisition) and observed that inhibition of the dorsal hippocampus during the test impaired contextual memory retrieval even nine weeks after training, suggesting that the hippocampus still plays a relevant role in retrieval of older memories. Interestingly, this impairing effect has only been observed with the use of optogenetic tools, which provide a fast inhibition, but not with pharmacological inhibition with tetrodotoxin (TTX), a selective blocker of sodium channels, and CNQX, a glutamate receptor antagonist. The authors suggest that differential effects observed with these manipulations can be explained by compensatory mechanisms that can only be engaged by pharmacological inhibition (Goshen et al., 2011). The hippocampus plays an important role in the regulation of the hypothalamic- pituitary-adrenal (HPA) axis, participating in the glucocorticoids (GCs) negative feedback loop (Herman et al., 1989; for review, see Jacobson and Sapolsky, 1991). This negative feedback regulation is mainly mediated by type II glucocorticoids receptors present in a high density in this structure (Reul and De Kloet, 1985). It is well established, in animals, that exposure to high GCs levels or chronic stress leads to deleterious changes in the

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hippocampus, such as neuronal loss (Sapolsky et al., 1990), shrinkage of apical dendrites of pyramidal cells in the CA3 region of the ˜ dorsal hippocampus (Magarinos and McEwen, 1995) and impairment of long-term potentiation (LTP) (Diamond and Rose, 1994). In healthy human beings, this effect is corroborated by a study showing that three days of hydrocortisone administration (160 mg/day, v.o.) results in reduced hippocampal volume, without changes in brain volume (Brown et al., 2015). PTSD patients usually exhibit abnormalities in cortisol secretion and HPA axis activity when compared to healthy subjects (Elzinga et al., 2003; Stoppelbein et al., 2012; Yehuda, 2002; Yehuda et al., 2005), although the reports are controversial. Some studies have reported low or unchanged baseline cortisol levels in PTSD patients (Eckart et al., 2009; Yehuda et al., 1996), whereas others have found higher levels during or after exposure to trauma-related cues (Elzinga et al., 2003; Stoppelbein et al., 2012). Despite this controversy, reduced hippocampal volume and metabolism during traumatic memory recall has been reported (Bremner et al., 1999a) and cross-sectional meta-analysis studies demonstrate reduced left and right hippocampal volumes in PTSD patients, compared to nonexposed and trauma-exposed control individuals (Kitayama et al., 2005; Smith, 2005). These findings may indicate that smaller hippocampal volume in PTSD patients can be the outcome of mediators other than excessive GCs, including elevated corticotrophin releasing factor (CRF) levels in the cerebrospinal fluid (CSF) compared to non-PTSD individuals (Bremner et al., 1997). Elevated brain levels of CRF are thought to play a role in hippocampal atrophy, since mice overexpressing CRF shows reduced hippocampus size (Goebel et al., 2010) and exogenous synthetic CRF treatment blunts dendritic growth in hippocampal cell cultures (Chen et al., 2004). Thus, high GCs, as well as CRF, levels during or shortly after the confrontation with traumatic reminders could contribute to hippocampal alterations in PTSD patients, which in turn could explain some symptoms, such as memory fragmentation and total amnesia of the traumatic event (Weiss, 2007). However, monozygotic twin studies are helpful to disentangle whether reduced hippocampal volume is a pre-existing risk factor for the development of PTSD or a consequence of the disorder. Two studies using pairs of monozygotic twins discordant for traumaexposure, e.g., one of the co-twins was exposed to the traumatic event, having developed PTSD or not, reached the conclusion that reduced hippocampal volume is a pre-existing condition and a risk factor for development of PTSD (Gilbertson et al., 2002; Pitman et al., 2006). High GCs levels may also influence the formation of the traumatic memory, since these hormones modulate memory consolidation, a phase in which the learned information becomes consolidated in a more stable memory trace (Davis and Squire, 1984). Previous animal studies show opposing effects of GCs in low and high aversive tasks, being the former related to impaired consolidation and the latter, with enhanced consolidation (Conrad et al., 1996; Kaouane et al., 2012; Roozendaal and McGaugh, 1997). In humans, GCs elevation facilitates consolidation of emotional but not neutral material (Cahill et al., 2003), and this finding points out to an important role of GCs in consolidation of emotional information. Besides GCs, the noradrenergic system plays a key role in modulating the consolidation process. Systemic administration of adrenaline after inhibitory avoidance training enhances the performance of animals in this task (Gold and Van Buskirk, 1975), an effect that is dependent of the ␤-adrenergic signaling in the amygdala (Liang et al., 1986). 2.1.2. Amygdala Pharmacological, neurophysiological and lesion studies attribute to the amygdala a key role in fear conditioning (Blanchard and Blanchard, 1972; Davis, 1997; for review, see Fendt and

Fanselow, 1999). This structure receives sensory information from various brain areas, such as hippocampus, neocortex and thalamus, and projects to diverse regions that mediate specific fear responses (LeDoux, 1996). Some authors defend the hypothesis that CS–US association during conditioning is formed in the basolateral complex of the amygdala (BLA), specifically in the lateral nucleus (LA) (Aggleton, 2000; LeDoux, 1996; but see, McGaugh, 2000). The BLA consists mostly of glutamatergic projection neurons, with minor GABAergic interneurons; it is connected with the central nucleus (CeA), a region composed mostly by GABAergic neurons, thought to be the main output structure of the amygdala (for review, see Sah et al., 2003). Besides these nuclei, the amygdala is also composed by intercalated cell masses (ITCs), which are groups of GABAergic interneurons that surround the BLA and seem to influence the interaction between the BLA and CeA (for review, see Ehrlich et al., 2009). Amygdala hyperresponsiveness is often observed in PTSD patients compared to healthy individuals and combat-exposure veterans without PTSD (Liberzon et al., 1999; Rauch et al., 2000). In human studies, trauma-related imagery (Shin et al., 1997), fear conditioning (Bremner et al., 2005), combat-related sounds (Bremner et al., 1999b; Liberzon et al., 1999), emotional faces (Koch et al., 2015) increase amygdala function. Even at rest (Chung et al., 2006) the amygdala seem to be hyperfunctional, although some studies do not find exacerbated amygdala response (Bremner et al., 1999b; Lanius et al., 2007). Interestingly, the increased amygdala activity may result from reduced function of brain structures that inhibit the amygdala, most notably the hippocampus and medial prefrontal cortex (mPFC), and a failure in regulation of amygdala function is thought to contribute to its hyperresponsiveness, which may account for persistence of traumatic memories and exaggerated fear responses (Shin and Liberzon, 2010). Since the amygdala plays an important role in fear conditioning, a dysfunction in this structure may account for increased fear conditioning in PTSD patients, which in turn may contribute to the formation of a strong memory of the event. In this regard, there are conflicting animal studies about the role of this area in the consolidation of emotional events. On one hand, McGaugh and colleagues propose a modulatory role of the amygdala on emotional memory consolidation, by showing that lesion in the BLA blocks the enhancing effect of a GR agonist infused into the hippocampus in the inhibitory avoidance task (Roozendaal and McGaugh, 1997). They also showed that post-training infusions of noradrenaline enhance consolidation in an aversive Y-maze (LaLumiere et al., 2003). On the other hand, LeDoux and colleagues propose that emotional memory acquisition and consolidation occurs in the amygdala. They demonstrated that intra-LA infusion immediately after training of anisomycin, a protein synthesis inhibitor, or Rp-cAMPS, a PKA inhibitor, impair consolidation of auditory fear conditioning (Schafe and LeDoux, 2000). Maren et al. (2003) extended these findings and reported that protein synthesis in the amygdala is also necessary for consolidation of contextual fear conditioning. From the studies that reveal the importance of the noradrenergic system in emotional memory consolidation (Gold and Van Buskirk, 1975; Liang et al., 1986), Pitman (1989) postulated that overstimulation of stress neuromodulators and hormones, such as noradrenaline, occurs in PTSD, leading to a phenomenon termed over consolidation. This exaggerated consolidation can contribute to the formation of a strong memory of the event that may persist over time and be expressed by means of re-experiencing symptoms, such as intrusive memory. It is well established that stressful situations modify amygdala morphology. In rats, acute immobilization stress induces spine formation in the BLA 10 days later and reduction in the time spent in the open arms of the elevated plus-maze (EPM), whereas chronically (2 h per 10 consecutive days), the stressor produces the same

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Fig. 1. Schematic representation of the relationship among the main structures participating in enhanced (A) or reduced fear response (B).Black arrows represent excitatory inputs and brown lines, inhibitory inputs. Filled arrows and lines represent strong, whereas dashed arrows and lines represent weak influences of one structure on the other. Enhanced fear response is expected when both infralimbic (IL) part of the medial prefrontal cortex (mPFC) and hippocampus feebly inhibit the amygdala, which becomes more activated (A). The contrary is proposed to happen in reduced fear response, where increased activity of the IL and hippocampus reduces amygdala activation (B).

modifications one day after the end of the protocol (Mitra et al., 2005). Thus, a single and intense aversive condition can lead to morphological changes in the BLA and its exaggerated function might be evident in some PTSD symptoms, such as intrusive memories, increased startle response and sympathetic nervous system activation, which increases respiration and heart rates, sweating and skin conductance (for review, see Lang et al., 2000). Interestingly, administration of corticosterone in the 12 h preceding exposure to a single immobilization session prevents the behavioral and morphological changes mentioned above, suggesting that increased GCs levels protects the brain against the effects of stress (Rao et al., 2012). This finding is in line with clinical reports showing that administration of hydrocortisone immediately after a traumatic event (Zohar et al., 2011) or during septic shock (Schelling et al., 2001) reduces the likelihood of development of PTSD. Some of the aforementioned symptoms might also be explained by a non-associative process termed fear sensitization, by which the presentation of an aversive stimulus (foot shock) leads to increment of the defensive behavioral response to neutral or innocuous stimuli (Kandel and Schwartz, 1982). Sensitization is also observed in animal models of PTSD, in which rodents exhibit fear response to unknown, but potentially harmful, stimuli (Girardi et al., 2013; Siegmund and Wotjak, 2007). This non-associative process is pointed out as an important feature of PTSD, since trauma survivors show increased autonomous arousal in the aftermath of a traffic accident and PTSD patient’s amygdala response habituates

slower to trauma reminders but also to trauma-unrelated cues (e.g., fearful faces) (Shalev et al., 2000; Shin et al., 2005). 2.1.3. Prefrontal cortex Human studies show that the PFC coordinate execution of actions (for review, see Fuster, 2001) and regulate fear expression of previously learned information in rodents (Almada et al., 2015). Rodent studies demonstrate that the prelimbic (PL) division of the mPFC, a homologous to human dorsal anterior cingulate cortex (dACC), is important for conditioned fear expression, since its microstimulation increases, whereas its inactivation decreases freezing response (Corcoran and Quirk, 2007; Vidal-Gonzalez et al., 2006). As the PL sends excitatory projections to the BLA (BrinleyReed et al., 1995), it is proposed to modulate fear expression. The infralimbic (IL) cortex, another subdivision of the mPFC and homologous to the human ventromedial prefrontal cortex (vmPFC), also plays a role in conditioned fear expression and its microstimulation reduces freezing response in rats (Vidal-Gonzalez et al., 2006). Previous anatomical studies suggest that afferents from the IL are found in the medial ITC (mITC) (Mcdonald et al., 1996; Pinard et al., 2012). A recent study in mice, however, questioned these finding, by demonstrating, with optogenetic technique, that IL projects to the basal amygdala pyramidal neurons (Strobel et al., 2015). There is evidence of reduced activation or failure to activate the mPFC when PTSD patients are exposed to reminders of the trauma (Bremner et al., 1999a,b) or to negative, non-traumatic, stimuli

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(Lanius et al., 2003). Interestingly, mPFC activation is inversely correlated with PTSD symptoms severity (Dickie et al., 2008) and is positively associated with improvement of PTSD symptoms (Felmingham et al., 2007). In addition, the mPFC also plays an important role in extinction and PTSD patients usually exhibit impairment of fear extinction in conditioning tasks (Blechert et al., 2007; Peri et al., 1999). As will be discussed below, extinction failure has been proposed to be mechanism by which fear conditioning could lead to persistence of the traumatic memory. The integrated involvement of these structures in fear conditioning and in PTSD is presented in Fig. 1.

3. Extinction learning and PTSD Extinction is a learning process by which repeated presentation of the CS without the US reduces the expression of the conditioned response (for review, see Myers and Davis, 2002). The study of extinction also began with Pavlov, when he observed diminished conditioned salivary response of his dog with repeated presentation of the food-signaling cue in the absence of food (for review, see VanElzakker et al., 2014). Since Pavlov’s seminal research, extinction process has being observed across tasks (aversive and appetitive) and species (from invertebrates to humans) (Eckstein et al., 2015; Quinn et al., 1974; Todd et al., 2012) and has been postulate to act on the original CS-US association inhibiting its expression (for review, see Bouton, 1993). This inhibitory theory suggests that during extinction a new relationship is established between the CS and US by which the CS no longer predicts the occurrence of the US (CS-no US). Furthermore, this extinction memory trace may also compete with the original fear memory trace for fear expression (for review, see Bouton, 2004; Myers and Davis, 2002). Thus, if extinction memory is strong enough and is retrieved, fear expression can be suppressed. On the other hand, fear can be expressed if extinction acquisition (i.e., the learning process that takes place during extinction training) or extinction retention (i.e., the assessment of extinction learning through its recall at some point after extinction training) is impaired (for review, see Milad et al., 2006). Empirical observations reveal that the extinguished CR can be recovered under certain circumstances, evidencing that the original memory is not erased by the extinction process (Corcoran and Maren, 2004; Rescorla and Heth, 1975). Recovery of the fear response has an important clinical implication, inasmuch as some behavioral therapies, such as prolonged exposure therapy, which are based on extinction, often fail to permanently suppress fear, resulting in the recovery of fear-related symptoms (Vervliet et al., 2013). Spontaneous recovery, reinstatement and renewal are the main phenomena by which extinguished CR is recovered. While the former is related to the passage of time (Rescorla, 2004), in reinstatement, presentation of the US can re-establish the CR (Bouton and Bolles, 1979), and in renewal, the CR is renewed when the formerly extinguished CS is encountered in a different context from which extinction took place (Bouton and Bolles, 1979; Rescorla, 2004). PTSD patients usually exhibit persistence of the traumatic memory for months, years or decades after the traumatic event. To explain this phenomenon some authors propose that failure of extinction-dependent mechanisms leads to resistance of the traumatic memory to extinction over time. Pitman’s group proposed the conditionability hypothesis, in which the traumatic memory is acquired in a strong process resulting in resistance to extinction, i.e., in the competition between memory traces, the original CS–US overlaps the CS–no US learned in extinction. A study by Orr and colleagues (Orr et al., 2000) showed that PTSD patients had

higher heart rate and skin conductance responses during conditioning than non-PTSD individuals. Interestingly, these responses were still higher during extinction trails, suggesting that individuals with PTSD are more “conditionable” and are resistant to extinction. Apart from the previously reported findings, studies with PTSD patients reveal no differences in the acquisition phase of conditioning (Blechert et al., 2007; Milad et al., 2008, 2009). A second hypothesis, proposed by Davis et al. (2000) and by Jovanovic and Ressler (2010), postulates that inhibitory fear mechanisms, such as extinction, are impaired in PTSD. Experimental investigation of these inhibitory mechanisms employs, mainly, extinction learning and conditioned inhibition paradigms. Conditioned inhibition refers to a learning process by which a neutral CS gains the ability to inhibit responses induced by signals that predict aversive or rewarding stimuli (Rescorla, 1969). In this learning paradigm, a negative association is established between the CS and the aversive US and, for that reason, the CS becomes a positive predictor for safety and reduces the expression of conditioned fear responses. As in this paradigm a specific signal is associated to protection, it has been proposed that conditioning inhibition may represent a form of learned safety (Cándido et al., 2004). Using a learned safety paradigm in mice, Rogan et al. (2005) showed that safety learning depressed CS-evoked field potentials in the LA and this electrophysiological measure was associated with a reduction in fear response. Conversely, increased CS-evoked field potentials was found in the Caudato-putamen area (CP), a region pointed out as candidate for safety conditioning information (Campeau et al., 1997). Safety learning in mice increases the expression of the brain derived neurotrophic factor (BDNF) in the hippocampus and results in survival of newborn cells in this brain area (Pollak et al., 2008). As mentioned above, PTSD patients usually exhibit impairment of fear extinction in conditioning tasks (Blechert et al., 2007). In conditioned inhibition paradigm, in which the subjects may learn that a specific signal represents safety, Jovanovic et al. (2009) found that patients with mild symptoms were able to inhibit fear, whereas those with severe symptoms were not, endorsing the hypothesis of inhibition failure to explain PTSD. A third hypothesis proposed by Eysenck (1979) states that CR can acquire distressing properties acting as a US-substitute in the absence of the original US. According to this hypothesis, the extinction process should be slower since CS-induced reactions during extinction are strong enough to act as an aversive reinforcement. Eysenck went further and predicted an enhancement of the conditioned fear response with repeated presentation of the CS, an effect he termed “fear incubation”. Several studies investigated Eysenck’s incubation hypothesis and some of them support his concept fully or partially (Sandin and Chorot, 1989; Sandin and Chorot, 2002), whereas others reject it (Nicholaichuk et al., 1982). Fear incubation can also designate an increase of the conditioned fear response in the absence of the CS presentation. This concept of fear incubation is also supported by animal studies. Wotjak and colleagues explored this phenomenon in a mouse model of PTSD by showing that mice exposed to an intense foot shock exhibited long lasting behavioral changes, such as a persistent fear response to trauma reminders and an increasing sensitized fear response to a neutral stimulus. Interestingly, mice exposed to the traumatic situation also present disruption in social behavior 28 days after the trauma (Siegmund and Wotjak, 2007). Fear incubation was also showed in a conditioned odor avoidance task, in which mice exhibited generalization of odor avoidance 28 days after training an effect that was alleviated with chronic fluoxetine treatment (Pamplona et al., 2011). In another study, Pickens et al. (2009) showed that the conditioned response was higher at 31 and 61 than at 2 or 15 days post-training, suggesting that fear incubation took place. Delayed fear response recapitulates one of the main symptoms of PTSD, e.g. deferred manifestation of symptoms (American Psychiatric Association, 2013).

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Besides the abovementioned hypotheses, in the past ten years, some studies have shown impaired extinction recall in PTSD patients. Milad et al. (2008) submitted 14 pairs of twins, discordant for combat exposure, to fear conditioning and measured skin conductance response (SCR). One-half of the combat exposed siblings were diagnosed with PTSD (PTSD + ) and the other half, not (PTSD-). The authors observed that PTSD+ siblings presented higher SCR during extinction recall than their co-twins and PTSD-combat veterans. This result suggests that impaired extinction retention present in PTSD is not due to preexisting risk factors, such as genetic background, but to trauma exposure. Moreover, impaired extinction recall observed in PTSD patients can be explained by dysfunctional activation of brain areas that mediate fear extinction. During extinction recall, PTSD patients exhibit less activation of the vmPFC and hippocampus and greater activation of the dACC (Milad et al., 2009). Taking these findings together, impairment of extinction retention could explain why traumatic memory persists in PTSD; in other words, if extinction learning is not retained by the individual, extinction cannot inhibit learned fear, leading to the persistent manifestation of fear responses, even after the extinction training (Milad et al., 2009). Apart from all of the hypotheses that try to explain how traumatic memory persists in PTSD, the importance of extinction in this disorder is also revealed by the use of behavioral therapies based on this process. The development of new and more effective approaches to treat PTSD is a main concern and there has been a major effort to understand the underlying mechanisms of extinction. Nowadays, a promising area for pharmacological treatment is the enhancement of extinction process (for review, see Fitzgerald et al., 2014), which is strengthen by the finding that d-cycloserine, a NMDA partial receptor agonist, combined with virtual reality exposure is effective to reduce PTSD symptoms (Difede et al., 2013). In rodents, d-cycloserine infused into the BLA facilitates extinction of contextual fear conditioning but has no effect in conditioning taste aversion task (Akirav et al., 2009). Although extinction has its importance to PTSD and aids to understand some of the observed alterations, this memory process does not modify the original memory trace (i.e., the traumatic memory). In the past few years, interference with the reconsolidation process has gained attention, as a promising alternative to treat fear-related disorders, because it represents an opportunity to modify the original fear memory. Reconsolidation is also another learning mechanism that could explain de persistence of trauma over time.

4. Reconsolidation and PTSD For a long time, it was thought that, once consolidated, memories would be difficult to disrupt, leading to a permanent non-changeable memory trace (Glickman, 1961; McGaugh, 1966). A significant discovery in the memory field was that consolidated memories may undergo a transient state after retrieval, when they are susceptible to interference and from which they are restored into a stable memory trace. This phenomenon, known as reconsolidation, represents a temporary opportunity in which pharmacological or behavioral manipulations can be applied to target the labile memory. In the clinical field, manipulations targeting reconsolidation are thought to be useful in modifying aversive memories that are related to anxiety disorder or PTSD, leading to more effective treatments (Nader et al., 2013; for review, see Vermetten et al., 2014). Although the reconsolidation process is known since the 1960 s (Misanin et al., 1968; Schneider and Sherman, 1968), only recently its underlying mechanisms began to be investigated. One main mechanism of reconsolidation involves protein synthesis, since administration of anisomycin

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weakens the original memory trace in rodents (Nader et al., 2000). Besides protein synthesis, neurotransmitters systems, such as the noradrenergic, also play an important role in reconsolidation. Przybyslawski et al. (1999) were one of the first to demonstrate the noradrenergic regulation of emotional memory reconsolidation. In their study, post-retrieval administration of propranolol, a non-selective ␤-adrenergic receptor antagonist, impaired the performance of rats in a positively reinforced radial maze task and in the inhibitory avoidance learning. Debiec et al. (2002, 2011) went further and investigated the effects of disruption or enhancement of fear memory reconsolidation in auditory fear conditioning in rats, using noradrenergic antagonist and agonist. Post-retrieval treatment with propranolol impaired fear memory expression and this effect was observed even when the reactivation session was conducted two months after training. Moreover, the results obtained with systemic treatment were replicated when the drug was infused into the LA and BA, suggesting the involvement of these areas in the modulation of aversive memory reconsolidation ¸biec and Ledoux, 2004). In a subsequent study, these authors (De investigated the effects of noradrenergic enhancement on fear memory, using intra-amygdala administrations of isoproterenol, a ␤-adrenergic receptor agonist. Post-retrieval infusion of isoproterenol into the lateral amygdala enhances long-term fear memory ˛ and makes it resistant to extinction (Debiec et al., 2011). From these findings, the authors propose that reconsolidation is an important process for maintenance of fear memory and this process is noradrenergic-dependent. Human studies on reconsolidation interference using noradrenergic agents point out to dissociation between fear response, mediated by the amygdala, and declarative memory of the aversive event, dependent on the hippocampus. Kindt et al. (2009) showed that an oral administration of propranolol prior to reactivation reduces fear expression leaving declarative memory of the learned association intact. Another study from the same group (Soeter and Kindt, 2010) also demonstrate this dissociation, since propranolol administration prior to reactivation blunts startle fear response even one month after learning but does not reduced skin conductance. The authors suggest that the effects of propranolol are restricted to fear response, since, in humans, startle potentiation is a reliable index of fear (Hamm and Weike, 2005), whereas skin conductance response is associated with contingency learning, e.g., the declarative memory formed during conditioning that dependents on the functional integrity of the hippocampus (Hamm and Vaitl, 1996; Weike et al., 2007). Clinical studies with PTSD patients reveal that elevated noradrenaline levels in the cerebrospinal fluid correlate positively with symptoms severity (Geracioti et al., 2001; for review, see Strawn and Geracioti, 2008). Moreover, it has been suggested that increased noradrenergic activity during the traumatic experience may enhance the encoding of trauma-related memory and that trauma-induced enhancement of memory encoding may contribute to traumatic memory persistence (O’Donnell et al., 2004). Studies with PTSD patients using reconsolidation interference have yielded controversial results. On one hand, Brunet et al. (2008) observed that post-retrieval oral administration of propranolol reduces the physiological responses (heart rate, skin conductance and left corrugator electromyogram) during a script-driven imagery test. On the other hand, Wood et al. (2015) reported that administration of propranolol, mifepristone (a glucocorticoid receptor antagonist) or mifepristone plus d-cycloserine during traumatic memory reactivation had no effect on the physiological responses (heart rate, skin conductance and facial electromyogram) one week after reactivation in a script-driven traumatic mental imagery. A recent review about medication as a preventive treatment for PTSD did not find a strong evidence for propranolol as an effective strategy to preclude the onset of PTSD (Amos et al., 2014).

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It is important to bear in mind that the disagreement observed between these studies could stem from methodological differences, such as administration design and inclusion criteria used for subject selection. Besides noradrenergic agents, other drugs stand out as promising for PTSD treatment, such as hydrocortisone. Stress doses of hydrocortisone have been proposed to treat PTSD (Schelling et al., 2001). Administration of high levels of cortisol has opposing effects on the consolidation and retrieval of emotional arousing situations (for review, see de Quervain et al., 2009). High levels of GCs are thought to enhance the initial consolidation of traumatic events, but data from animal studies indicate that high levels of GCs have a deleterious effect on memory retrieval (de Quervain et al., 1998; Roozendaal et al., 2003). A recent study demonstrated that hippocampal infusion of GCs increased fear response to low shock intensity, while reducing this response in high shock intensity when animals were exposed to the context, indicating an impairment in the discrimination of the threat predictor (Kaouane et al., 2012). Because of their effects, these hormones may disrupt the reexperiencing and reconsolidating processes that take place after consolidation of the aversive memory (de Quervain et al., 2009). One of the most effective treatments for PTSD is eye desensitization and memory reprocessing (EMDR) (Bisson and Andrew, 2005; Bisson et al., 2007; Rhudy et al., 2010; Van Etten and Taylor, 1998). This psychotherapy involves alternated bilateral sensorial stimulation while the traumatic event is recalled and processed (Shapiro, 1996). According to Francine Shapiro, who developed the therapy, “Processing (or reprocessing) is thus defined as the forging of the associations required for learning to take place as the information pertaining to the traumatic event is adaptively resolved” (Shapiro, 1999), e.g., when the patient ceases to present emotional reactions while retrieving the traumatic situation. In a recent study, our group showed that EMDR improved indices of anxiety, depression and perception of the traumatic event. Interestingly, this therapy also lowered heart rate during recalling of the traumatic event (Raboni et al., 2014), in agreement with the shift in the sympathetic/parasympathetic activity toward increased parasympathetic tonus previously reported in PTSD patients (Dunn et al., 1996; Elofsson et al., 2008; Sack et al., 2007). This reduction in sympathetic tonus parallels the results shown by Brunet et al. (2008) and could be responsible for the changes of fear memory observed with EMDR therapy. Increased amygdala activation is a hallmark of PTSD either at resting (Rabinak et al., 2011) or after stimulus provocation (El Khoury-Malhame et al., 2011). EMDR also shifts the activity of limbic emotion-related structures toward cortical regions involved with cognitive and associative processes, leading to improvement of the cognitive and sensorial processing of the traumatic event (Pagani et al., 2012). Therefore, although not confirmed yet, EMDR is a type of cognitive therapy that could involve memory reconsolidation to produce positive results in PTSD patients. The reconsolidation field is still vastly unknown and its relation to PSTD waits for more studies to clarify the role of this memory process in this disorder. Further pre-clinical and clinical studies would be valuable to address this question and to expand our knowledge about reconsolidation and the underlying mechanisms related to PTSD.

5. Conclusions and further directions The study of fear conditioning has expanded our knowledge about the underlying mechanisms associated to PTSD. Animal models developed in the past years have been essential to this area and many of them have aided the understanding of the contribution of fear conditioning to PTSD onset and symptoms persistence. Dys-

functional activation of the amygdala, hippocampus and PFC found in animal and human studies points out to the important contribution of these brain areas to PTSD and its symptomatology. Beyond that, the study of post-retrieval processes, such as extinction and reconsolidation, has shed some light to important bonds that PTSD may have with these two processes, which, in turn, may contribute to the maintenance of fear responses. Acknowledgements Mariella Bodemeier Loayza Careaga is the recipient of a Ph.D. fellowship from the National Research Council (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq), Carlos Eduardo Neves Girardi is the recipient of a post-doc fellowship from Fundac¸ão de Amparo à Pesquisa de São Paulo (FAPESP), and Deborah Suchecki is the recipient of a Research Fellowship CNPq. References Aggleton, J., 2000. The Amygdala: A Functional Analysis, 2nd ed. Oxford University Press. Akirav, I., Segev, A., Motanis, H., Maroun, M., 2009. D-Cycloserine into the BLA reverses the impairing effects of exposure to stress on the extinction of contextual fear, but not conditioned taste aversion. Learn. Mem. 16, 682–686, http://dx.doi.org/10.1101/lm.1565109. Almada, R.C., Coimbra, N.C., Brandão, M.L., 2015. Medial prefrontal cortex serotonergic and GABAergic mechanisms modulate the expression of contextual fear: intratelencephalic pathways and differential involvement of cortical subregions. Neuroscience 284, 988–997, http://dx.doi.org/10.1016/j. neuroscience.2014.11.001. American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. American Psychiatric Association, pp. 271–278. Amos, T., Stein, D.J., Ipser, J.C., 2014. Pharmacological interventions for preventing post-traumatic stress disorder (PTSD). Cochrane database Syst. Rev., http://dx. doi.org/10.1002/14651858.cd006239.pub2, CD006239. Bisson, J., Andrew, M., 2005. Psychological treatment of post-traumatic stress disorder (PTSD). Cochrane Database Syst. Rev., http://dx.doi.org/10.1002/ 14651858.cd003388.pub2, CD003388. Bisson, J.I., Ehlers, A., Matthews, R., Pilling, S., Richards, D., Turner, S., 2007. Psychological treatments for chronic post-traumatic stress disorder: systematic review and meta-analysis. Br. J. Psychiatry 190, 97–104, http://dx. doi.org/10.1192/bjp.bp.106.021402. Blanchard, D.C., Blanchard, R.J., 1972. Innate and conditioned reactions to threat in rats with amygdaloid lesions. J. Comp. Physiol. Psychol. 81, 281–290, http://dx. doi.org/10.1037/h0033521. Blanchard, R.J., Blanchard, D.C., Agullana, R., Weiss, S.M., 1991. Twenty-two kHz alarm cries to presentation of a predator, by laboratory rats living in visible burrow systems. Physiol. Behav. 50, 967–972, http://dx.doi.org/10.1016/00319384(91)90423-L. Blechert, J., Michael, T., Vriends, N., Margraf, J., Wilhelm, F.H., 2007. Fear conditioning in posttraumatic stress disorder: evidence for delayed extinction of autonomic, experiential, and behavioural responses. Behav. Res. Ther. 45, 2019–2033, http://dx.doi.org/10.1016/j.brat.2007.02.012. Bouton, M.E., Bolles, R.C., 1979. Contextual control of the extinction of conditioned fear. Learn. Motiv., http://dx.doi.org/10.1016/0023-9690(79)90057-2. Bouton, M.E., 1993. Context, time, and memory retrieval in the interference paradigms of Pavlovian learning. Psychol. Bull. 114, 80–99. Bouton, M.E., 2004. Context and behavioral processes in extinction. Learn. Mem. 11, 485–494, http://dx.doi.org/10.1101/lm.78804. Bremner, J.D., Licinio, J., Darnell, A., Krystal, J.H., Owens, M.J., Southwick, S.M., Nemeroff, C.B., Charney, D.S., 1997. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am. J. Psychiatry 154, 624–629, http://dx.doi.org/10.1176/ajp.154.5.624. Bremner, J.D., Narayan, M., Staib, L.H., Southwick, S.M., McGlashan, T., Charney, D.S., 1999a. Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am. J. Psychiatry 156, 1787–1795. Bremner, J.D., Staib, L.H., Kaloupek, D., Southwick, S.M., Soufer, R., Charney, D.S., 1999b. Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study. Biol. Psychiatry 45, 806–816, http://dx. doi.org/10.1016/S0006-3223(98)00297-2. Bremner, J.D., Vermetten, E., Schmahl, C., Vaccarino, V., Vythilingam, M., Afzal, N., Grillon, C., Charney, D.S., 2005. Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychol. Med. 35, 791–806, http://dx.doi.org/10.1017/S0033291704003290. Breslau, N., Davis, G.C., Andreski, P., Peterson, E., 1991. Traumatic events and posttraumatic stress disorder in an urban population of young adults. Arch.

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