Modulation of the extinction of fear learning

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Review

Modulation of the extinction of fear learning Jociane C. Myskiw ∗ , Ivan Izquierdo ∗ , Cristiane R.G. Furini ∗ Instituto Nacional de Neurociência Translacional, CNPq, and Centro de Memória, Instituto do Cérebro, Pontifícia Universidade Católica de Rio Grande do Sul, Porto Alegre, RS 90610-000, Brazil

a r t i c l e

i n f o

Article history: Received 28 July 2013 Received in revised form 1 April 2014 Accepted 2 April 2014 Available online xxx Keywords: Histamine H2 receptors Endocannabinoid receptors Dopaminergic D1 receptors ␤-Noradrenergic receptors Behavioral tagging of extinction State dependency of extinction

a b s t r a c t We review recent work on extinction learning with emphasis on its modulation. Extinction is the learned inhibition of responding to previously acquired tasks. Like other forms of learning, it can be modulated by a variety of neurotransmitter systems and behavioral procedures. This bears on its use in the treatment of fear memories, particularly in posttraumatic stress disorder (PTSD), for which it is the treatment of choice, often under the name of exposure therapy. There have not been many laboratories interested in the modulation of extinction, but the available data, although not very abundant, are quite conclusive. Most studies on the nature of extinction and on its modulation have been carried out on fear motivated behaviors, possibly because of their applicability to the therapy of PTSD. A role for d-serine and the glycine site of NMDA receptors has been ascertained in two forms of extinction in the ventromedial prefrontal cortex, basolateral amygdala and dorsal hippocampus. The serine analog, d-cycloserine, has received clinical trials as an enhancer of extinction. The brain histaminergic system acting via H2 receptors, and the endocannabinoid system using CB1 receptors in the ventromedial prefrontal cortex, hippocampus and basolateral amygdala enhance extinction. Dopaminergic D1 and ␤-noradrenergic receptors also modulate extinction by actions on these three structures. Isolated findings suggest roles for on serotonin-1A, dopaminergic-D2 and ␣- and ␤-noradrenergic receptors in extinction modulation. Importantly, behavioral tagging and capture mechanisms in the hippocampus have been shown to play a major modulatory role in extinction. In addition, extinction of at least one aversive task (inhibitory avoidance) can be made state dependent on peripheral epinephrine. © 2014 Published by Elsevier Inc.

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Neural mechanisms of extinction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Effects of novelty on extinction, and behavioral tagging of extinction learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Modulation of extinction by neurotransmitter and neuromodulator systems: catecholamines, d-serine and cycloserine, histamine, cannabinoids, BDNF, glucocorticoids, others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Modulation of extinction by state-dependency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Epigenetics in extinction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Closing comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction Pavlov discovered extinction first in alimentary and subsequently in footshock-motivated classical conditioning at the

∗ Corresponding authors. Tel.: +55 51 3320 3336. E-mail addresses: jociane [email protected] (J.C. Myskiw), [email protected] (I. Izquierdo), [email protected] (C.R.G. Furini).

beginning of the 20th century (see Pavlov, 1927). Starting in 1937, his disciple Jerzy Konorski (for many, the discoverer of instrumental conditioning) made several fundamental additional findings on extinction (Konorski, 1948) and, decades later, Rescorla (2001, 2004) added other findings that shaped the knowledge and understanding of this important form of learning into what we think of it today. Perhaps the single most important additional finding since its discovery is the fact that extinction suffers spontaneous recovery, which indicates that it does not consist of an

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attenuation or erasure of a previously acquired memory, but rather on the inhibition of its expression. Other phenomena that point in the same direction are renewal (recovery of extinction by a change of context, Bouton and Ricker, 1994), reinstatement (recovery of the original task by exposure to the unconditioned stimulus, Bouton, 2004; Thanellou and Green, 2011), and the quickness of reacquisition of the original response after extinction (Izquierdo et al., 1965). These findings show that extinction is by no means a form of forgetting, but rather a form of inhibitory learning (Pavlov, 1927; Milad and Quirk, 2012; Myskiw et al., 2013a,b).

2. Neural mechanisms of extinction Pavlov postulated that both conditioning and extinction depend on physiological changes in the cerebral cortex, by which he and his followers understood mainly the neocortex. Beginning with Brenda Milner’ key findings on patient H.M. and her suggestions on the role of the temporal lobe in memory formation (see Penfield and Milner, 1958; Squire, 2009), the participation of the hippocampus and other areas of the limbic system began to be viewed as important for learning processes. The main structures that were recognized by modern lesion, recording and microinfusion studies as crucial for the extinction of fear-motivated memories were the ventromedial prefrontal cortex (vmPFC, Santini et al., 2001), the hippocampus in humans (Milad et al., 2007) or the dorsal hippocampus (D-HIPP, Vianna et al., 2001) in rats and the basolateral amygdala (BLA, Vianna et al., 2004); and, for the extinction of conditioned taste aversion, the insular cortex (Berman and Dudai, 2001) or, more probably, the insular cortex together with the hippocampus and the entorhinal cortex, Garcia-Delatorre et al., 2010). A role for the entorhinal cortex in the extinction of inhibitory avoidance learning has been proposed in other tasks too (Bevilaqua et al., 2006); such a role was to be presumed from the multiple interconnections of that area with the hippocampus and with the rest of the cortex (Green, 1964). Changes in neuronal activity during extinction were studied at the single cell level in the vmPFC (Milad and Quirk, 2002; Santini et al., 2008; Li et al., 2009) and mostly at the electroencephalographic level in the hippocampus (see Green, 1964). Two hallmarks of memory consolidation are the involvement of N-methyl-d-aspartate (NMDA) glutamatergic synapses in its early phases, and protein synthesis in the neuronal system(s) that participate in that process (Izquierdo and Medina, 1997; Kandel and Squire, 2000; Izquierdo et al., 2006). It was recently found that the consolidation of two different fear extinction tasks is enhanced by the immediate posttraining microinfusion of d-serine into the vmPFC, the D-HIPP or the BLA, and is blocked by that of AP5 (2 amino-5 phosphono-pentanoic acid). d-Serine is a co-agonist acting at the glycine receptor site of the NMDA receptor, and AP5 is an antagonist at the glutamate (or NMDA) receptor site itself (Fiorenza et al., 2012). There is no evidence or suggestion that glutamatergic transmission at any of these sites precedes or depends on that at any of the others. The consolidation of extinction memory transfers it from a NMDA receptor-independent into a NMDA receptor-dependent process in the vmPFC (Quirk, 2002). In D-HIPP, BLA (Igaz et al., 2002; Szapiro et al., 2003; Vianna et al., 2004; Tronson et al., 2009) and vmPFC (Mueller et al., 2008) activation of RNA synthesis, of the cAMPdependent protein kinase (PKA) and of the extracellular regulated kinases (Erk, Erk1) are as necessary for extinction as they are for LTP (long-term potentiation) and LTD (long-term depression) in some of those structures as well as in a variety of forms of learning (Izquierdo and Medina, 1997; Izquierdo et al., 2006; see also Potter et al., 2013). Extinction is widely regarded as secondary to LTD or to long-term depotentiation, at least in the hippocampus and

amygdala (Tsumoto, 1990; Gruart et al., 2006; Dalton et al., 2008, 2012; Azad et al., 2008). Ribosomal protein synthesis occurs early on after the acquisition of extinction of various fear-motivated tasks and is necessary for its consolidation in the vmPFC (Santini et al., 2001), D-HIPP (Vianna et al., 2001) and BLA (Vianna et al., 2004). The microinfusion of the ribosomal protein synthesis inhibitor, anisomycin immediately after extinction training into any of these three sites hinders the extinction of contextual fear conditioning and of inhibitory avoidance learning (Santini et al., 2001; Vianna et al., 2001, 2004; Myskiw et al., 2013a,b). In addition, as occurs in numerous other forms of learning, the microinfusion into D-HIPP or BLA of inhibitors of the various protein kinase-dependent signaling pathways that regulate protein synthesis (Szapiro et al., 2003; Vianna et al., 2004) hinders the consolidation of extinction learning. Their influence has been much less studied in the vmPFC (see, however, Rudenko et al., 2013). As has been repeatedly described for a variety of tasks (e.g. Yin et al., 1994; Bernabeu et al., 1997), the extinction of spatial learning of mice in a Morris water maze is accompanied by a long-lasting posttraining increase of pCREB (phosphorylated cAMP-response element binding protein) in the lateral amygdala (Porte et al., 2011). The first session of extinction of inhibitory avoidance, in which this task is consolidated, is also followed by an increase of pCREB in D-HIPP (Szapiro et al., 2002). As has been suggested for a variety of tasks (Yin et al., 1994; Bernabeu et al., 1997; Izquierdo and Medina, 1997), pCREB has been attributed a key role in consolidation in the extinction of spatial memory too (Porte et al., 2011). Memory consolidation coexists with NMDA receptordependent plastic processes such as LTP and LTD mostly in the hippocampus (Izquierdo and Medina, 1995, 1997; Malenka and Bear, 2004; Gruart et al., 2006; Whitlock et al., 2006; Izquierdo et al., 2006) and, in the case of fear memories, also in the lateral or basolateral amygdala (Dalton et al., 2008, 2012). There are several hypotheses on the role of the interconnection of D-HIPP, BLA and vmPFC in the consolidation of conditioned fear memories and on the consolidation of their extinction. A recent very articulate account by Sotres-Bayon et al. (2012) suggests that the hippocampus and BLA gate activity in the vmPFC. What part of this putative function is played by hippocampal and amygdala NMDA-dependent plasticity is not really known; what is known is that this plasticity seems to be necessary both at the time of the original consolidation of the fear-motivated tasks and at the time of the consolidation of their extinction (see Maren, 2011; Myskiw et al., 2013a,b respectively). Recent evidence indicates that amygdalar NMDA GluN2A and GluN2B receptors play separate roles in the induction of LTP and the initial consolidation of fear motivated tasks, and of LTD and the consolidation of the extinction of conditioned fear respectively (Dalton et al., 2012). The possibility that LTD may underlie extinction has been hinted at by many over the years, particularly at times in which extinction was confused with forgetting (e.g. Tsumoto, 1990). The actual connection between LTD and extinction was only demonstrated to a reasonable extent by Dalton et al. (2008, 2012) in recent experiments. Parenthetically, perhaps contrarily to what would have been expected from studies suggesting a role for LTP in regular consolidation and of LTD in extinction (see above), there is an increase of a slow hyperpolarizing after potential in layers II, III and IV of vmPFC neurons in the consolidation of fear conditioning, with reduced intrinsic excitability of the neurons, and a reduction of that after potential with increased neuron excitability of those neurons (Santini et al., 2008). Gruart et al. (2006) observed an increase of the CA3 field potential evoked by CA1 stimulation in D-HIPP during the acquisition of

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a conditioned trace eyeblink response in mice which they viewed as representative of LTP, followed by a decrease of the size of the evoked potential during extinction, attributable to depotentiation or LTD. The same electrophysiological phenomena were observed in learning and extinction of an object recognition task (LTP and LTD respectively) (Clarke et al., 2010). Human fMRI studies and electrophysiological studies in laboratory animals have contributed to the schematic postulation of circuits for the extinction of fear extinction (Phelps et al., 2004; Milad et al., 2007). Other forms of extinction have not been studied in this connection. There is consensus that fear extinction is initiated by inhibition of the vmPFC neurons where this behavior is believed to be initiated by NMDA-dependent plasticity (Santini et al., 2001; Burgos-Robles et al., 2007). The inhibition of the vmPFC neurons involved in fear extinction occurs as a result of feedback fibers coming from the amygdala (Pape and Pare, 2010; see Phelps et al., 2004) and hippocampus (Milad et al., 2007), in the rat possibly D-HIPP. There are two-way monosynaptic connections between the hippocampus and the vassal and other nuclei of the amygdala (Saunders et al., 1988), as well as various indirect connections (Van Hoesen, 1985). The consolidation of extinction of conditioned fear tasks requires NMDA receptors in the vmPFC, BLA and D-HIPP (Santini et al., 2001; Fiorenza et al., 2012). Blockade of these receptors in any of the three brain regions shortly after extinction learning inhibits the expression of the extinction measured hours or days later. The NMDA receptors presumably participate in plastic synaptic events in the CA3-CA1 connection in the hippocampus (Gruart et al., 2006) and in synapses in the lateral (Li et al., 2009; Dalton et al., 2008, 2012) or basolateral amygdala (Vianna et al., 2001, 2004); these plastic events probably consist of LTP in the original fear-motivated learning tasks and in LTD or depotentiation in their extinction (Dalton et al., 2008, 2012). In addition, the consolidation of fear extinction learning requires ribosomal protein synthesis in vmPFC (Santini et al., 2001), D-HIPP (Vianna et al., 2001) and BLA (Vianna et al., 2004). These characteristics (need for intact glutamatergic NMDA receptors, need for NMDA receptordependent LTD or depotentiation [or even LTP], need for ribosomal protein synthesis in restricted brain areas) are typical of a large variety of learnings. In the case of extinction, the brain areas are those mentioned (Fiorenza et al., 2012); their mode of interaction and the consecutive or simultaneous nature of such interaction is still in the terrain of hypotheses (Sotres-Bayon et al., 2012; see references in Myskiw et al., 2013a,b). The outputs of the amygdala to the vmPFC have been better studied than those from the hippocampus; but there is little doubt that D-HIPP biochemical activity (Tronson et al., 2009) plays a key role in extinction. The input from the vmPFC to the temporal lobe to initiate extinction reaches basal (Senn et al., 2014) and/or central amygdala nucleus cells (Haubensak et al., 2010). The functioning of these and other components of these circuits have been hypothesized by Li et al. (2009), Pape and Pare (2010) and Cho et al. (2013). Amygdalar LTD plays a role (Dalton et al., 2012) but the precise nature of this role remains hypothetical. Concerning the role of the inputs from the amygdala (and hippocampus) to the vmPFC, hypotheses range from regular inhibitory connections (Amir et al., 2011) to modulation (Pape et al., 2005) to gating (Haubensak et al., 2010). None has been so far been incontrovertibly proven and several of these roles might actually coexist. The best known proposals of vmPFC-amygdala-hippocampus circuits in extinction are those of Li et al. (2009), Haubensak et al. (2010), Pape and Pare (2010), Senn et al. (2014) and Cho et al. (2013). It should be pointed out that there are several types of LTP and LTD, some dependent on NMDA receptors and some not (Abarbanel et al., 2002; Rush et al., 2002; Otani et al., 2002; Kombian and Malenka, 1994; Klyubin et al., 2013). The plastic events in D-HIPP, BLA or other sites of the amygdala and vmPFC thought to play a role

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in extinction (mostly LTD) are of the NMDA-dependent type (see above).

3. Effects of novelty on extinction, and behavioral tagging of extinction learning Maren (2013) found that inhibition of the hippocampus by muscimol hinders the return of fear to a conditioned stimulus (CS) by a change of context (renewal) (i.e., when the CS itself is unexpected), or when unexpected stimuli, such as a loud white noise (that Pavlov would have called an external disinhibition) accompany the CS. He claimed that “ultimately, a violation of expectations about when, where, and with what other stimuli an extinguished CS will occur may form the basis of spontaneous recovery, renewal, and external disinhibition”. The hippocampus is involved in the perception and recognition of novelty (Netto et al., 1985; Lipp et al., 1987; Myhrer, 1988). Myskiw et al. (2013a,b) found that exposure for very short periods to a novel experience (a large wooden box in which the animals had never been before) transiently enhances extinction of a fear motivated task similar to the one used by Maren (2013), and explained this by a process of behavioral tagging. Behavioral tagging is the application of the principles of synaptic tagging and capture as described by Frey and Morris (1997), Frey and Frey (2008) and Barco et al. (2008) to behavior. Ballarini et al. (2009), Moncada et al. (2011) and Almaguer-Melián et al. (2012) proposed that this memory-reinforcing effect of novelty could be explained by mechanisms outlined in the ‘synaptic tagging hypothesis.’ According to this hypothesis, memory is sustained by a transient plasticity change at activated synapses which produce locally proteins as synaptic tags. These tags are able to capture other proteins, synthetized at other synapses in which LTP- or LTD-dependent learning has also occurred; the taggingand capture-process enhances the function of the tagged synapses (Barco et al., 2008). Myskiw et al. (2013a,b) used this explanation to account for the enhancement of extinction caused by the interpolated and unexpected brief exposure to a novel environment. In addition they found that the protein tags generated by extinction do not, and the synaptic proteins synthetized by novelty do, depend on extra-ribosomal rapamycin-sensitive translation, such as occurs in the hippocampus after learning in several tasks (see Myskiw et al., 2008). The findings on behavioral tagging, particularly those on the effect of novelty on fear extinction (Myskiw et al., 2013a,b), are of importance because they may help to understand and answer old questions on the interaction of consecutive and simultaneous but unrelated behaviors (e.g., Izquierdo and Netto, 1985; Netto et al., 1985), and may bear on the problem of the expected versus unexpected nature of behaviorally relevant stimuli (Maren, 2013). Behavioral tagging experiments suggest the possibility of a major modulation of exposure therapy or other forms of applied extinction in the treatment of the often psychologically crippling influence of persistent unwanted memories on the everyday life of millions of people and animals. It is possible that the interpolation of a seemingly trivial novel experience in the course of an otherwise lengthy and complex treatment may enhance its effects. Crucial to the effectiveness of the interpolation of novelty in the middle of an on-going extinction process is the preciseness of its timing. An interpolated novelty affects extinction at a relatively long but nevertheless restricted time window of hours (Myskiw et al., 2013a,b), just like the timing between two LTP and/or LTD episodes must be rather precise within well-defined limits in order to obtain facilitation of the tagged hippocampal synaptic plastic process by the converging interpolated one (Frey and Frey, 2008; Barco et al., 2008).

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4. Modulation of extinction by neurotransmitter and neuromodulator systems: catecholamines, d-serine and cycloserine, histamine, cannabinoids, BDNF, glucocorticoids, others In the past 30 years there have been major advances in the demonstration of the role of neurotransmitter, neuromodulator and hormonal systems, all of them in turn regulated by peripheral hormones, in the modulation of memory consolidation (McGaugh, 2000, 2004, 2013; Izquierdo et al., 2006; Roozendaal and McGaugh, 2011). The consolidation of extinction learning in particular has been much less studied than that of other forms of learning (Fiorenza et al., 2012). There have been a number of isolated observations on the role of one or other substance and/or receptor in the modulation of extinction, but there is still a scarcity of systematic studies of this question. Michael Davis and his coworkers were the first to realize that given the importance of glutamate NMDA receptors in the construction and extinction of conditioned fear responses in the amygdala, an indirect agonist at the glycine site of such receptors, such as d-cycloserine (Davis, 2011), was likely to modulate extinction. In vivo, the main physiological agonist at that site is the amino acid d-serine (Fiorenza et al., 2012), but cycloserine had the advantage that it could be tested in humans right away because/in its case the preclinical and clinical requisites for the approval of a drug for use in clinical trials had been carried out years before, when the drug was released as a tuberculostatic agent. d-Cycloserine indeed proved to be an enhancer of extinction in laboratory animals and in humans (Ledgerwood et al., 2005; Davis, 2011), but perhaps its full potential was not explored because knowledge about the nuances of extinction learning and its interaction with other posttraining events such as reconsolidation (Schiller et al., 2010; Izquierdo and Myskiw, 2011) or with other tasks or stimuli (Myskiw et al., 2013a,b) was not sufficient when it was tested. Sure enough, the physiological agonist at the glycine site of NMDA receptors, d-serine given immediately after extinction training in two different tasks (the extinction of contextual fear and that of one-trial inhibitory avoidance) also enhances the consolidation of this form of learning, whereas the NMDA receptor antagonist, AP5, hinders the retention of extinction in two different tasks (Fiorenza et al., 2012). The neurotransmitters most widely studied on memory consolidation are acetylcholine, norepinephrine, dopamine, serotonin and histamine, each acting on various receptors, and the endocannabinoid anandamide acting on CB1 receptors. The most studied neuromodulatory substance is the brain derived neurotrophic factor (BDNF). Corticoids and circulating epinephrine are the hormones best studied for their action on memory consolidation (see McGaugh, 2000, 2004, 2013; Roozendaal and McGaugh, 2011; Rosa et al., 2013). Cholinergic influences on extinction have been studied in detail by Tronson, Radulovic and their collaborators. They used treatments that affect the medial septum, which is the source of cholinergic innervation of the hippocampus, and the CA1 neurons that these fibers innervate (Tronson et al., 2009). It must be reminded here that early neuroanatomical findings cast doubt as to whether medial septal projections to CA1 are at all significant, inasmuch as they are relatively scarce and fibers from the medial septum preferentially reach CA3 or at the most CA2 (see Green, 1964). The data of Tronson et al. (2009) leave, however, little doubt that principal CA1 cells do participate in fear conditioning and extinction through a number of well-defined biochemical steps, and that this is regulated in both cases by cholinergic fibers from the septum. Main hippocampal CA1 neurons respond to fear conditioning by a coordinated activation of multiple protein kinases and immediate early genes, such as c-Fos, enabling rapid

and lasting consolidation of contextual fear memory. The extracellular signal-regulated kinase (Erk) additionally acts as a central mediator of fear extinction (see also Bonini et al., 2011). Tronson et al. (2009) used mouse models of conditioning and extinction of fear, and determined the time course of c-Fos and Erk activity, their cellular overlap, and regulation by afferent cholinergic input from the medial septum. Analyses of cFos(+) and pErk(+) cells by immunofluorescence revealed predominant nuclear activation of either protein during conditioning and extinction of fear, respectively. Transgenic cFos-LacZ mice were used to label in vivo Fos(+) hippocampal cells during conditioning followed by phosphorylated Erk immunostaining after extinction. These signaling molecules were activated in segregated populations of hippocampal principal neurons. Furthermore, immunotoxin-induced lesions of medial septal neurons, providing cholinergic input into the hippocampus, selectively abolished Erk activation and extinction of fear without affecting cFos responses and conditioning. So they concluded that extinction mechanisms based on Erk signaling involve a specific population of CA1 principal neurons distinctively regulated by afferent cholinergic input from the medial septum. There have not been studies pointing to such definite cellular processes in extinction and their modulation in any other region or cell group of the brain, which clearly points to a major influence of hippocampal CA1 neurons in conditioned fear and its extinction. Recently, a role for muscarinic receptors in the vmPFC has been suggested for fear extinction by Santini et al. (2012); independently of their role suggested by Tronson et al. (2009). The ␣1-noradrenergic receptor blocker, prazosin, given systemically, hindered extinction of conditioned fear but not of cocaine conditioned place preference, even though it might reduce the persistence of extinction of the latter task (Bernardi and Lattal, 2010). The effect on extinction of the ␣2 antagonist, yohimbine is, at best, doubtful (Mueller et al., 2009); it has been, however, recommended for clinical trials (see Holmes and Quirk, 2010). The effects of norepinephrine itself, or of the ␤1,2 noradrenergic antagonists, propranolol and timolol, have been much more extensively studied, but it cannot be said that they are any clearer. For example, in a very careful study, Berlau and McGaugh (2006) reported that the infusion of 1 ␮g of norepinephrine into the right but not the left BLA enhanced extinction of contextual fear conditioning, whereas that of a ␤-blocking dose of propranolol had no effect. In the same task, as well as in the extinction of an inhibitory avoidance task, Fiorenza et al. (2012) found that the ␤ blocker, timolol (1 ␮g) enhanced extinction of contextual fear and inhibitory avoidance when given in the BLA and blocked it when given into D-HIPP, whereas that same dose of norepinephrine was ineffective upon extinction of both tasks. Debiec et al. (2011) have reported that norepinephrine in the amygdala enhances reconsolidation, i.e., a process whose outcome is the opposite of extinction (Nader, 2003). So it is difficult to conclude much about the role of endogenous norepinephrine in the modulation of extinction except that it appears to have effects dependent on ␤ receptors on the extinction of two different tasks, but what these effects are is at least difficult to conclude. Possibly differences in rat strain may account for the different results obtained by both groups, as has happened over the years with many substances, among which epinephrine and the opioid peptides; the animals used in the two studies indeed belong to different strains. Mueller et al. (2008) showed that ␤-noradrenergic receptors, PKA, RNA synthesis, and protein synthesis in vmPFC are necessary for extinction learning of a contextual fear task. As a ␤ blocker they used propranolol. The biochemical findings were obtained using blockers of PKA action and RNA and protein synthesis similar to those used in previous studies on the D-HIPP and BLA (Vianna et al., 2001, 2004; Szapiro et al., 2003). The possibility that serotonin-1A receptors may regulate extinction was raised by Saito and his coworkers (2013), who investigated

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the influence of i.p. injections of the serotonin-1A antagonist, tandospirone given before or after the first extinction session of a fear task in animals previously exposed to a footshock at the age of 3 weeks. Interestingly, the task was found to be accompanied by dopamine release in the medial PFC. Dopamine is one of the most widely studied modulators of memory consolidation (see McGaugh, 2000, 2013). A time-honored approach to the study of dopamine D1/D5 receptor involvement in the consolidation of one or other behavioral task is to infuse the well-known agonist of these receptors, SKF38393, or the also well-known antagonist, SCH23390, into D-HIPP, BLA, the vmPFC or other structures immediately after training and then analyze their effects on retention at a test carried out on the next day (see Beninger and Nakonechny, 1996; Izquierdo et al., 2006). This was applied recently to the analysis of the consolidation of extinction of contextual fear conditioning and of inhibitory avoidance. The D1 agonist, SKF38393 enhanced the consolidation of extinction of contextual fear but not that of the inhibitory avoidance task when given posttraining into the D-HIPP but not into BLA or vmPFC; the D1 antagonist impaired extinction consolidation in the inhibitory avoidance task when given into any of the three tasks (Fiorenza et al., 2012). Clearly, dopamine-D1 modulation of the extinction of these two tasks was different in each of them, regardless of the similitude of both. A recent paper by Mueller et al. (2010) shows an inhibitory effect of the D2 antagonist, raclopride, when given into the vmPFC before an extinction session. For reasons discussed by McGaugh (1973) and Izquierdo et al. (2006), it is difficult to interpret the effect of pre-test drug administrations in terms of mechanisms involved; they could be due to performance or memory effects or to a mix of both. Glucocorticoids, for example, generally enhance consolidation when given posttraining, and impair retrieval when given pre-test (see Roozendaal and McGaugh, 2011; Atsak et al., 2012). Aside from d-serine (see above), the best studied brain neurotransmitters for their effects on the consolidation of extinction are histamine and the endocannabinoid, anandamide. There are very few but very conclusive papers on histamine and many, including a few with some dissonant voices, on endo- or exocannabinoids, whose effect on fear extinction has been a major field of study since 2002. When given into D-HIPP after the first of two extinction sessions of one-way step-down inhibitory avoidance, histamine enhanced retention of the task in the second session in a dosedependent fashion. The effect was mimicked by the histamine N-methyltransferase inhibitor SKF91488 and the H2 receptor agonist dimaprit, reversed by the H2 receptor antagonist ranitidine, and unaffected by the H1 antagonist pyrylamine, the H3 antagonist thioperamide and the antagonist at the NMDA receptor (NMDAR) polyamine-binding site ifenprodil. Neither the H1 agonist 2-(2-pyridyl) ethylamine nor the NMDAR polyamine-binding site agonist spermidine affected the consolidation of extinction/in this experiment while the H3 receptor agonist imetit hampered it. (Others have, however, reported an enhancing effect of spermidine on the extinction of contextual fear conditioning, see Gomes et al., 2010). Extinction induced the phosphorylation of Erk1 in D-HIPP while intra-D-HIPP infusion of the Mek inhibitor U0126 into D-HIPP blocked extinction of the avoidance response. The extinction-induced phosphorylation of Erk1 was enhanced by histamine and dimaprit and blocked by ranitidine administered to dorsal CA1 after non-reinforced retrieval. Taken together, the data indicate that the hippocampal histaminergic system modulates the consolidation of fear extinction through a mechanism involving the H2-dependent activation of Erk signaling (Bonini et al., 2011). The involvement of Erk fits with the findings of Tronson et al. (2009) commented above.

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More recently, we studied the action of the histamine enhancer SKF91488 and the histamine H2 receptor antagonist ranitidine given posttraining into D-HIPP, BLA or vmPFC extinction of contextual fear conditioning as well as in that of inhibitory avoidance. The brain histamine system projects from the tuberomamillary nucleus to many areas of the brain, including those responsible for many forms of learning (Passani and Blandina, 2011; Blandina et al., 2012). This system modulates the consolidation of many tasks, from inhibitory avoidance to object recognition and spatial tasks (Passani and Blandina, 2011; Benetti and Izquierdo, 2013; Benetti et al., 2013; Munari et al., 2013). SKF91488 enhanced, and the H2 antagonist, blocked memory consolidation of the two forms of extinction in all three areas of the brain. Thus, together with d-serine, endogenous histamine appears as the most generalized, powerful and consistent positive modulator of the memory consolidation of extinction (Fiorenza et al., 2012). As mentioned above, at least in the hippocampus, this modulation appears to be mediated by Erk, secondarily to cholinergic stimulation (Tronson et al., 2009). A very large number of studies mainly by Marsicano et al. (2002) starting over 20 years ago, have pointed to a key role for anandamide and the CB1 receptor in fear extinction, mainly in D-HIPP and BLA, and, as recently observed (Do Monte et al., 2013) in vmPFC. In the hippocampus, the action of cannabinoids on CB1 receptors leads to an LTD (Azad et al., 2004), which could very well explain the extinction. Delta (9)-tetrahydrocannabinol and other cannabinoids share the enhancing effect of the endogenous substance anandamide on fear extinction (see Wojtak, 2005; Marsicano and Lutz, 2006; Marsicano and Lafenêtre, 2009). Interestingly, the endocannabinoid-mediated mechanisms do not explain extinction of alimentary learning (Hölter et al., 2005), which suggests that extinction is not a unitary phenomenon, and that different processes mediate and/or regulate the extinction of alimentary and fear-motivated behaviors. There have been very few dissonant voices in the field of cannabinoids and extinction. One is the report by Ashton et al. (2008) that delta(9)-tetrahydrocannabinol may actually depress fear extinction in rats. The cannabinoids have been used for a number of years with a degree of success as adjuncts in the treatment of PTSD with exposure therapy, along with dcycloserine, risperidone and other agents (Kerbage and Richa, 2013; Rabinak and Phan, 2013; Rabinak et al., 2013). Perhaps, cannabidiol is the cannabinoid with better chances to become a useful therapeutic tool because of its lack of psychotropic activity (Das et al., 2013). Several studies have addressed the question of glucocorticoid modulation of the consolidation of fear extinction, inasmuch as these substances are customarily released into the circulation by anxiogenic or painful stimuli such as are used in aversive learning situations. The role of glucocorticoids in the modulation of memory consolidation in general has been amply studied in recent years. Post-training glucocorticoid agonists have been known for some time to strengthen the consolidation of emotionally arousing experiences, but not that of low-arousing experiences. Pre-test glucocorticoids usually hinder retrieval (Schwabe et al., 2012; Atsak et al., 2012). They require arousal induced activation both of the basolateral amygdala (Setlow et al., 2000) and of the nucleus accumbens shell to do so (Roozendaal et al., 2001; see also Sarabdjitsingh et al., 2012). In the latter case they enhance the consolidation both of appetitive and aversive learning (Wichmann et al., 2012). Cannabinoid receptors may have an opposite influence to that of the glucocorticoids in memory processing in the amygdala (Ramot and Akirav, 2012) and elsewhere (Roozendaal and McGaugh, 2011; Atsak et al., 2012). Some assorted data suggest a role for hippocampal or extrahippocampal BDNF in the modulation of extinction (Peters et al., 2010; Sakata et al., 2013), as it has in several other forms of learning (Alonso et al., 2005; Komulainen et al., 2008; Pluchino et al.,

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2013). In all the correlative studies between BDNF and learning variables the modulatory action of the former is usually attributed to its known stimulant effect on recently activated synapses (Lu et al., 2013). To summarize aside from a few systematic studies (Fiorenza et al., 2012), the evidence for neurotransmitter, neuromodulator and hormone involvement in extinction processes has been sporadic, and is limited to the extinction of fear-motivated memories. The most consistent findings are on the seemingly rather universal positive modulatory influence of d-serine and its derivatives on the glycine site of NMDA receptors, of cannabinoid receptor mediated modulation, and of histamine acting at H2 receptors in D-HIPP, BLA and vmPFC. Assorted but consistent data point to a role for BDNF-mediated, dopaminergic, noradrenergic and cholinergic receptor-mediated modulation, and for the glucocorticoids in at least in D-HIPP and vmPFC. In all, it can be said that the consolidation and perhaps the execution of extinction learning are strongly modulated brain functions.

5. Modulation of extinction by state-dependency Learning processes can be modulated by state-dependency. This arises from the incorporation of the action of exogenous (Overton, 1978) or endogenous substances (Zornetzer, 1978; Izquierdo, 1984) to the tasks being learned as part of the constellation of conditioned stimuli, and then act as retrieval cues. Zornetzer (1978) suggested that the endogenous neurohumoral and hormonal states at the time of consolidation may act as cues and generate state dependency. One of us (Izquierdo, 1984; Izquierdo and Dias, 1983) showed that this can be the case for a number of endogenously released substances in inhibitory avoidance learning. We have recently reported that it can also be the case for the consolidation and retrieval of the extinction of this behavior (Rosa et al., 2013). We found that if the extinction of one-trial inhibitory avoidance in rats is consolidated under a high dose of epinephrine (E) injected i.p., the readministration of that agent at the time of extinction testing 24 h later is followed by a better extinction retention performance than when animals are tested in the absence of peripherally injected E. Both when E is given posttraining and when it is given prior to extinction testing it appears to act via the endogenous release of norepinephrine in the nucleus tractus solitarius (NTS) → locus coeruleus → hippocampus/amygdala (HIPP/BLA) pathway. This pathway plays a role in the learning of inhibitory avoidance (Williams and McGaugh, 1992, 1993; MelloCarpes and Izquierdo, 2013). Blockade of this pathway at the time of extinction retrieval markedly attenuates the restorative effect of E on it (Rosa et al., 2013).

6. Epigenetics in extinction A recent article (Lattal and Wood, 2013) points to possible relations between epigenetic changes and memory reconsolidation and extinction. Epigenetics has been attributed a role in individual susceptibility to PTSD (Zovkic et al., 2013). The role of epigenetics in learning and memory processes is fast becoming an important topic of research (Stafford and Lattal, 2011; Stafford et al., 2013). A role of histone acetylation in extinction has been demonstrated by Lattal’ group in the hippocampus/vmPFC circuit (Stafford et al., 2013). The findings on a possible role of epigenetics in extinction signal just the beginning of a potentially very important liner of research; but not yet more than that. Further work along that line is desirable.

7. Closing comments Clearly, extinction, like most if not all other forms of learning, can be modulated by influences on its consolidation period. This possibility, which had been largely unexplored and thereby ignored for decades (see Fiorenza et al., 2012), has been recently investigated by several laboratories. At least three major forms of modulation have been described: by neurotransmitter systems, by synaptic or behavioral tagging, and by state dependency. All of them were described in the extinction of fear-motivated behaviors; modulation of extinction of alimentary learning has been practically not investigated. This overwhelming preference for the study of extinction of fearmotivated tasks is due to the fact that it is used as the basis of the so-called exposure therapy of PTSD and other fear memories (Milad and Quirk, 2012; Myskiw et al., 2013a,b). The extinction of alimentary learnings is not used clinically yet. The three best studied neurotransmitter systems in the modulation of extinction are the brain cannabinoid and histaminergic system and the intrinsic neuromodulatory system of the glycine receptor site at NMDA glutamatergic synapses. The endocannabinoid/cb1 receptor system is rather widespread all over the body (Marsicano and Lutz, 2006; Marsicano and Lafenêtre, 2009) and enhances the extinction of fear- but not alimentary-motivated learnings. The brain histaminergic system projects from the tuberomamillary nucleus (Passani and Blandina, 2011) to the vmPFC, hippocampus, and BLA among many other brain areas, and is now known to modulate the consolidation of a variety of brain behaviors through different receptor types (Blandina et al., 2012; Benetti et al., 2013; Benetti and Izquierdo, 2013). It modulates extinction by an action on histaminergic H2 receptors in the three mentioned areas (Bonini et al., 2011; Fiorenza et al., 2012); histamine or an inhibitor of its catabolism enhance, and H2 receptor antagonists inhibit, extinction when infused into these three brain areas. D-serine appears to be the natural agonist at the glycine sites of NMDA receptors. As such, it regulates LTP (Henneberger et al., 2010) and enhances some forms of learning. It enhances the extinction of two different fear-motivated tasks; the NMDA receptor blocker, AP5, has an opposite effect (Fiorenza et al., 2012). The D-serine analog, D-cycloserine, shares its extinction enhancer effect and has been tested clinically (Davis, 2011). Dopamine D1 receptor agonists enhance, and D1 or D2 antagonists impede, fear extinction in some but probably not all tasks, in vmPFC, BLA and/or D-HIPP (Fiorenza et al., 2012; Mueller et al., 2010). ␤-Noradrenergic receptors in D-HIPP and BLA modulate extinction; although in the latter there have been discrepancies between different studies (Berlau and McGaugh, 2006; Fiorenza et al., 2012). Cholinergic muscarinic receptors, glucocorticoids and BDNF affect extinction in the same direction as they do with other forms of learning. Thus, concerning the modulation of extinction by neurotransmitter systems, the two most consistent and reliable systems are the brain histaminergic system, and the d-serine-glycine site of AMPA receptors system, both of which are enhancing. Modulation by behavioral tagging-and-capture, i.e. by concomitant exposure to novelty (Myskiw et al., 2013a,b), and modulation by induced state-dependency on peripheral epinephrine (Rosa et al., 2013) are strong, in both cases facilitatory, and quite consistent. It is difficult at this time to envisage a way to up- or down-regulate the therapeutic influence of extinction on the retrieval of fear motivated behavior as in the exposure therapy as applied to PTSD (Milad and Quirk, 2012; Myskiw et al., 2013a,b). Perhaps the easiest and most straightforward contribution could be that of the interpolation of novelty in a session of extinction; but this will have to be tried. Over the recent years, the application of pharmacological means to heighten or modify the course of

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