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Fear renewal is defined as return of the conditioned fear responses after extinction when a conditioned stimulus (CS) is given outside of the extinction context. Previously, we have suggested that extinction induces S-nitrosylation of GluA1 in the lateral amygdala (LA), and that the extinction-induced S-nitrosylation of GluA1 lowers the threshold of GluA1 phosphorylation (at Ser 831) which is required for fear renewal. This fits nicely with the fact that fear renewal is induced by weak stimuli. However, it has not been tested whether S-nitrosylation of GluA1 in the LA is indeed required for fear renewal. In the present study, we used three different chemicals to impede protein S-nitrosylation via distinct mechanisms. Fear renewal was inhibited by microinjection of 7-Nitroindazole (nNOS inhibitor), and ZL006 (a blocker of PSD-95-nNOS interaction) before fear renewal. Furthermore, fear renewal was also attenuated by microinjection of a strong antioxidant (N-acetyl cysteine), which scavenges reactive oxygen including nitric oxide, into the LA before each extinction training. These findings suggest that protein S-nitrosylation is required for fear renewal. • Inhibition of nNOS in the LA attenuated fear renewal. • Disruption of PSD-95-nNOS interaction in the LA inhibited fear renewal. • NO scavenging in the LA during extinction inhibited subsequent fear renewal. [ABSTRACT FROM AUTHOR]

Rationale: Stress disorders cause abnormal regulation of fear-related behaviors. In most rodent models of these effects, stress was administered before fear conditioning, thereby assessing its impact on both the formation and extinction of fear memories, not the latter alone. Here, we dissociated the two processes by also administering stress after fear conditioning, and then compared how pre-conditioning versus post-conditioning exposure to chronic stress affects subsequent acquisition and recall of fear extinction.Methods: Male Wistar rats were subjected to chronic immobilization stress (2 h/day, 10 days); the morphological effects of which were analyzed using modified Golgi-Cox staining across brain areas mediating the formation and extinction of fear memories. Separate groups of rats underwent fear conditioning followed by acquisition and recall of extinction, wherein stress was administered either before or after fear conditioning.Results: When fear memories were formed after chronic stress, both acquisition and retrieval of extinction was impaired. Strikingly, these deficits were absent when fear memories were formed before the same stress. Chronic stress also reduced dendritic spine density in the infralimbic prefrontal cortex, but enhanced it in the basolateral amygdala.Conclusion: Chronic stress, administered either before or after fear learning, had distinct effects on the acquisition and recall of fear extinction memories. Stress also strengthened the structural basis of synaptic connectivity in the amygdala, but weakened it in the prefrontal cortex. Thus, despite eliciting a specific pattern of brain region-specific morphological changes, the timing of the same stress gave rise to strikingly different behavioral effects on the extinction of fear. [ABSTRACT FROM AUTHOR]

Fear learning and extinction are controlled by the activity of three interconnected regions: the amygdala, hippocampus, and prefrontal cortex. Of these, the medial prefrontal cortex modulates specific aspects in fear and extinction via a top-down regulation. In recent years, extensive progress has been made in our understanding of the neural circuits that mediate fear-related behaviors and their modulation by ascending systems. The development of new experimental techniques is now revealing the details of the intrinsic circuits within these structures as well as the connections between them. Here, we highlight recent advances in our understanding of how the prefrontal cortex may mediate such a top-down regulation. [ABSTRACT FROM AUTHOR]

Background: Comorbidity of anxiety disorders, stressor- and trauma-related disorders, and substance use disorders is extremely common. Moreover, therapies that reduce pathological fear and anxiety on the one hand, and drug-seeking on the other, often prove short-lived and are susceptible to relapse. Considerable advances have been made in the study of the neurobiology of both aversive and appetitive extinction, and this work reveals shared neural circuits that contribute to both the suppression and relapse of conditioned responses associated with trauma or drug use.Objectives: The goal of this review is to identify common neural circuits and mechanisms underlying relapse across domains of addiction biology and aversive learning in preclinical animal models. We focus primarily on neural circuits engaged during the expression of relapse.Key findings: After extinction, brain circuits involving the medial prefrontal cortex and hippocampus come to regulate the expression of conditioned responses by the amygdala, bed nucleus of the stria terminalis, and nucleus accumbens. During relapse, hippocampal projections to the prefrontal cortex inhibit the retrieval of extinction memories resulting in a loss of inhibitory control over fear- and drug-associated conditional responding.Conclusions: The overlapping brain systems for both fear and drug memories may explain the co-occurrence of fear and drug-seeking behaviors. [ABSTRACT FROM AUTHOR]

Objective: Neurons in PL and IL project densely to two areas implicated in active avoidance: the basolateral amygdala (BLA) and the ventral striatum (VS). We therefore combined c-Fos immunohistochemistry with retrograde tracers to characterize signaling in platform-mediated active avoidance.Methods: Male rats  were infused with retrograde tracers (CTB, FB) into basolateral amygdala and ventral striatum and conditioned to avoid tone-signaled footshocks by stepping onto a nearby platform. In a subsequent test session, rats received either 2 unreinforced tones (avoidance retrieval) or 15 unreinforced tones (avoidance extinction) followed by analysis of c-Fos combined with fluorescent imaging of retrograde tracers.Results: Retrieval of avoidance did not activate IL neurons, but did activate PL neurons projecting to BLA, and to a lesser extent VS. Extinction of avoidance activated IL neurons projecting to both BLA and VS, as well as PL neurons projecting to VS.Conclusions: Our observation that avoidance retrieval is signaled by PL projections to BLA suggests that PL may modulate VS indirectly via BLA, and agrees with other findings implicating BLA in active avoidance. Less expected was the signaling of extinction via PL inputs to VS, which may converge with IL inputs to VS to inhibit expression of avoidance. [ABSTRACT FROM AUTHOR]

The basolateral amygdala complex (BLA) and infralimbic region of the prefrontal cortex (IL) play distinct roles in the extinction of Pavlovian conditioned fear in laboratory rodents. In the past decade, research in our laboratory has examined the roles of these brain regions in the re-extinction of conditioned fear: i.e., extinction of fear that is restored through re-conditioning of the conditioned stimulus (CS) or changes in the physical and temporal context of extinction training (i.e., extinction of renewed or spontaneously recovered fear). This paper reviews this research. It has revealed two major findings. First, in contrast to the acquisition of fear extinction, which usually requires neuronal activity in the BLA but not IL, the acquisition of fear re-extinction requires neuronal activity in the IL but can occur independently of neuronal activity in the BLA. Second, the role of the IL in fear extinction is determined by the training history of the CS: i.e., if the CS was novel prior to its fear conditioning (i.e., it had not been trained), the acquisition of fear extinction does not require the IL; if, however, the prior training of the CS included a series of CS-alone exposures (e.g., if the CS had been pre-exposed), the acquisition of fear extinction was facilitated by pharmacological stimulation of the IL. Together, these results were taken to imply that a memory of CS-alone exposures is stored in the IL, survives fear conditioning of the CS, and can be retrieved and strengthened during extinction or re-extinction of that CS (regardless of whether the extinction is first- or second-learned). Hence, under these circumstances, the initial extinction of fear to the CS can be facilitated by pharmacological stimulation of the IL, and re-extinction of fear to the CS can occur in the absence of a functioning BLA. [ABSTRACT FROM AUTHOR]

Highlights: [•] Amygdala gamma oscillations are enhanced following auditory fear conditioning. [•] Amygdala gamma oscillations during extinction learning are associated with spontaneous fear recovery. [•] Amygdala gamma oscillations are locally generated. [•] Maintenance of amygdala gamma oscillations during extinction learning linearly predicts spontaneous fear recovery. [Copyright &y& Elsevier]

Highlights: [•] The medial prefrontal cortex is required for spatial memory extinction. [•] The amygdala complex was activated after spatial memory extinction. [•] The lateral mammillary nucleus is involved in spatial memory extinction. [ABSTRACT FROM AUTHOR]

Highlights: [•] C57BL/6 mice acquired conditioned fear and subsequent fear extinction that were retained weeks later. [•] During retention testing, dendritic spines and intersections were measured in basolateral amygdala neurons. [•] Fear conditioning increased spines and intersections and fear extinction reversed these effects. [ABSTRACT FROM AUTHOR]

Background: Like fear conditioning, the acquisition phase of extinction involves new learning that is mediated by the amygdala. During extinction training, the conditioned stimulus is repeatedly presented in the absence of the unconditioned stimulus, and the expression of previously learned fear gradually becomes suppressed. Our previous study revealed that chronic treatment with a selective serotonin reuptake inhibitor (SSRI) impairs the acquisition of auditory fear conditioning. To gain further insight into how SSRIs affect fear learning, we tested the effects of chronic SSRI treatment on the acquisition of extinction. Methods: Rats were treated chronically (22 days) or subchronically (9 days) with the SSRI citalopram (10 mg/kg/day) before extinction training. The results were compared with those after chronic and subchronic treatment with tianeptine (10 mg/kg/day), an antidepressant with a different method of action. The expression of the NR2B subunit of the N-methyl-D-aspartate receptor in the amygdala was examined after behavioral testing. Results: Chronic but not subchronic administration of citalopram impaired the acquisition of extinction and downregulated the NR2B subunit of the N-methyl-D-aspartate receptor in the lateral and basal nuclei of the amygdala. Similar behavioral and molecular changes were found with tianeptine treatment. Conclusions: These results provide further evidence that chronic antidepressant treatment can impair amygdala-dependent learning. Our findings are consistent with a role for glutamatergic neurotransmission in the final common pathway of antidepressant treatment. [ABSTRACT FROM AUTHOR]

Knowing when and where to express fear is essential to survival. Recent work in fear extinction paradigms reveals that the contextual regulation of fear involves a neural network involving the hippocampus, medial prefrontal cortex, and amygdala. The amygdaloid basal nuclei (BA) receive convergent input from the ventral hippocampus (VH) and prelimbic (PL) prefrontal cortex and may integrateVHand PL input to regulate fear expression. To examine the functional organization of this neural circuit, we used cellular imaging of c-fos expression in anatomically defined neuronal populations and circuit disconnections to identify the pathways involved in the contextual control of extinguished fear. Before behavioral testing, we infused a retrograde tracer into the amygdala to label BA-projecting neurons in VH and PL. Rats then underwent fear conditioning and extinction and were tested for their fear to the extinguished conditioned stimulus (CS) in either the extinction context or in another context; freezing behavior served as the index of conditional fear. CS presentation outside the extinction context renewed conditional freezing and was associated with significantly more c-fos expression in BA-projecting neurons in theVHand PL than that induced by CS presentation in the extinction context.Wenext examined whether direct or indirect projections of VH to BA mediate fear renewal. Interestingly, disconnections of the VH from either the BA or PL eliminated renewal. These findings suggest that convergent inputs from both the VH and PL in the BA mediate the contextual control of fear after extinction. [ABSTRACT FROM AUTHOR]

Abstract: Extinction reflects a decrease in the conditioned response (CR) following non-reinforcement of a conditioned stimulus. Behavioral evidence indicates that extinction involves an inhibitory learning mechanism in which the extinguished CR reappears with presentation of an unconditioned stimulus. However, recent studies on fear conditioning suggest that extinction erases the original conditioning if the time interval between fear acquisition and extinction is short. The present study examined the effects of different intervals between acquisition and extinction of the original memory in conditioned taste aversion (CTA). Male Long-Evans rats acquired CTA by associating a 0.2% sucrose solution with malaise induced by i.p. injection of 4 ml/kg 0.15 M LiCl. Two different time intervals, 5 and 24 h, between CTA acquisition and extinction were used. Five or 24 h after CTA acquisition, extinction trials were performed, in which a bottle containing 20 ml of a 0.2% sucrose solution was provided for 10 min without subsequent LiCl injection. If sucrose consumption during the extinction trials was greater than the average water consumption, then rats were considered to have reached CTA extinction. Rats subjected to extinction trials lasting 24 h, but not 5 h, after acquisition re-exhibited the extinguished CR following injection of 0.15 M LiCl alone 7 days after acquisition. Extracellular signal-regulated kinase (ERK) in the medial prefrontal cortex (mPFC) and basolateral nucleus of the amygdala (BLA) was examined by Western blot after the first extinction trial. ERK activation in the mPFC was induced after the extinction trial beginning 5 h after acquisition, whereas the extinction trial performed 24 h after acquisition induced ERK activation in the BLA. These data suggest that the original conditioning can be inhibited or retained by CTA extinction depending on the time interval between acquisition and extinction and that the ERK transduction pathway in the mPFC and BLA is differentially involved in these processes. [Copyright &y& Elsevier]

Abstract: In this study, we investigated how midazolam and d-cycloserine regulate the tonic activity and/or phasic reactivity of brain neurotransmitter systems to fear-evoking stimuli in rats with varying intensities of a fear response. We used a new animal model composed of high (HR) and low (LR) anxiety rats, selected according to their behaviour in the contextual fear test (i.e., the duration of a freezing response was used as a discriminating variable). In these rats, we examined the effects of both drugs on the release of glutamate and GABA in the basolateral amygdala (BLA) during the first extinction trial of a conditioned fear test. The results showed that administration of d-cycloserine (15mg/kg, i.p.) significantly enhanced the inhibition of an aversive context-induced freezing response observed during the extinction session in HR and LR rats. In contrast, midazolam (0.75mg/kg, i.p.) accelerated the attenuation of fear responses only in HR rats. The less anxious behaviour of LR animals given saline was accompanied by elevated basal levels of glutamate in the BLA, in comparison with HR rats, and a stronger elevation of GABA in response to contextual fear. In HR animals, the pretreatment of rats with d-cycloserine and midazolam significantly increased the local concentration of GABA and inhibited the expression of contextual fear. These findings suggest that animals more vulnerable to stress have innate deficits in brain systems that control the activity of the BLA mediating the central effect of stress. These results contribute to our understanding of observed individual differences in the effects of anxiolytic drugs among patients with anxiety disorders. [Copyright &y& Elsevier]

Abstract: Fear conditioning is accepted as a useful experimental paradigm to investigate anxious disorders following stress. In this field it is important to understand the mechanisms underlying the extinction of conditioned fear. In the rat it has been shown that the amygdalar basolateral nucleus plays a crucial role in all memorization phases of this type of memory (acquisition, consolidation, retrieval, and also reconsolidation and extinction). Recent results show that both the substantia nigra and nucleus basalis magnocellularis, two sites strongly connected with the basolateral amygdala are also involved in the consolidation of contextual fear conditioning. The aim of the present work is to investigate if latter two sites, besides the basolateral amygdala, are also involved in the extinction of the conditioned fear response. The results show that tetrodotoxin-induced inactivation of post-extinction training of either site does not impair the extinction process, which instead is impaired by inactivation of the basolateral amygdala. Thus, the present results confirm previous ones which show that diverse memorization phases (post-acquisition consolidation, extinction, reconsolidation) may be sustained by different neural sites and circuits. [ABSTRACT FROM AUTHOR]

Research with adult animals suggests that extinction depends, at least partly, on new inhibitory learning that is specific to the context in which it is learned. However, several recent studies show that extinction processes are dissociated across development. The present article reviews research on the behavioral and neurobiological mechanisms underlying extinction in developing rats. To summarize, postweanling aged rats (i.e., 24-day-olds) display adult-like extinction in that they show renewal, reinstatement, spontaneous recovery, and compound summation of extinguished stimuli. However, preweanling aged rats (i.e., 17-day-olds) do not show any of those behavioral phenomena. Pharmacological studies also show that reducing N-methyl-D-aspartate, γ-aminobutryic acid, and opioid neurotransmission impairs extinction in 24-day-old rats, but extinction in P17 rats is only affected by the blocking of opioid neurotransmission. Lastly, extinction in 24-day-old rats involves the amygdala and the ventromedial prefrontal cortex (vmPFC), which are critical brain areas in the neural circuitry of extinction in adult rats. Interestingly, extinction in 17-day-old rats involves the amygdala but not the vmPFC. The existing models of extinction cannot account for these developmental differences. These findings showing that distinct processes mediate extinction at different stages of development may have significant clinical implications, which are discussed in this review. [Copyright &y& Elsevier]

Whereas the neuronal substrates underlying the acquisition of auditory fear conditioning have been widely studied, the substrates and mechanisms mediating the acquisition of fear extinction remain largely elusive. Previous reports indicate that consolidation of fear extinction depends on the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) signalling pathway and on protein synthesis in the medial prefrontal cortex (mPFC). Based on experiments using the fear-potentiated startle paradigm suggesting a role for neuronal plasticity in the basolateral amygdala (BLA) during fear extinction, we directly addressed whether MAPK/ERK signalling in the basolateral amygdala is necessary for the acquisition of fear extinction using conditioned freezing as a read-out. First, we investigated the regional and temporal pattern of MAPK/ERK activation in the BLA following extinction learning in C57Bl/6J mice. Our results indicate that acquisition of extinction is associated with an increase of phosphorylated MAPK/ERK in the BLA. Moreover, we found that inhibition of the MAPK/ERK signalling pathway by intrabasolateral amygdala infusion of the MEK inhibitor, U0126, completely blocks acquisition of extinction. Thus, our results indicate that the MAPK/ERK signalling pathway is required for extinction of auditory fear conditioning in the BLA, and support a role for neuronal plasticity in the BLA during the acquisition of fear extinction. [ABSTRACT FROM AUTHOR]