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BackgroundIn both rodents and humans, the basolateral amygdala (BLA) is essential for encoding and retrieving conditioned fear memories. Although the BLA is a putative storage site for these memories, recent evidence suggests that they become independent of the BLA with the passage of time.MethodsWe systematically examined the role for the BLA in the retrieval of recent (1 day) and remote (2 weeks) fear memory using optogenetic, electrophysiological, and calcium imaging methods in male and female Long-Evans rats. Critically, we used a behavioral design that permits within-subjects comparison of recent and remote memory at the same time point; freezing behavior served as the index of learned fear.ResultsWe found that BLA c-Fos expression was similar after the retrieval of recent or remote fear memories. Extracellular single-unit recordings in awake, behaving animals revealed that single BLA neurons exhibit robust increases in spike firing to both recent and remote conditional stimuli (CSs). Fiber photometry recordings revealed that these patterns of activity emerge from principal neurons. Consistent with these results, optogenetic inhibition of BLA principal neurons impaired conditioned freezing to both recent and remote CSs. There were no sex differences in any of the measures or manipulations.ConclusionsThese data reveal that BLA neurons encode both recent and remote fear memories, suggesting substantial overlap in the allocation of temporally distinct events. This may underlie the broad generalization of fear memories across both space and time. Ultimately, these results provide evidence that the BLA is a long-term storage site for emotional memories.

Soft skills encompassing conscientiousness, lifelong learning, communication, creativity, and teamwork are beneficial to success in work and life. The education policy in Nigeria on teacher education stipulates that students should learn basic soft skills at universities as performance improvement tools for teaching, but for the most part teacher education programmes do not include such skills. The aim of the study reported on here was to assess whether the soft skills curriculum and instruction course has been effectively implemented in university teacher education programmes. This course is theory based designed to inculcate soft skills in would-be teachers within 2 semesters. We used paper questionnaires and performed data analysis by way of partial least square structural equation modelling (PLS-SEM) using SmartPLS software in a non-experimental procedure with a total of 722 prospective teachers. The analysis revealed that prospective teachers gained moderate soft skills, which, in turn, benefited them in classroom control and, ultimately, teaching success in terms of lesson planning, development, and results. It is fair to suggest that the PLS-SEM model shows that participation in the curriculum and instruction course generates different kinds of benefits to teachers at the same time.

Significance Fear relapse represents a significant problem for individuals suffering from stress- and trauma-related disorders such as posttraumatic stress disorder. Here, we show that locus coeruleus norepinephrine activation produces fear relapse in rats. In addition, locus coeruleus activation inverts neuronal firing properties of the prelimbic and infralimbic cortices to drive this fear relapse. Elevated noradrenergic tone and subsequent changes in prefrontal firing properties represent a therapeutic target for combating fear relapse., The medial prefrontal cortex (mPFC) plays an essential role in regulating emotion, including inhibiting fear when danger has passed. The extinction of fear, however, is labile and a number of factors, including stress, cause extinguished fear to relapse. Here we show that fear relapse in rats limits single-unit activity among infralimbic (IL) neurons, which are critical for inhibiting fear responses, and facilitates activity in prelimbic (PL) neurons involved in fear expression. Pharmacogenetic activation of noradrenergic neurons in the locus coeruleus mimics this shift in reciprocal IL–PL spike firing, increases the expression of conditioned freezing behavior, and causes relapse of extinguished fear. Noradrenergic modulation of mPFC firing represents a mechanism for relapse and a potential target for therapeutic interventions to reduce pathological fear.

Post-traumatic stress disorder (PTSD) afflicts approximately 8% of the United States population and represents a significant public health burden, but the underlying neural mechanisms of this and other anxiety- and stressor-related disorders are largely unknown. Within the last few decades, several preclinical models of PSTD have been developed to help elucidate the mechanisms underlying dysregulated fear states. One brain area that has emerged as a critical mediator of stress-related behavioral processing in both clinical and laboratory settings is the bed nucleus of the stria terminalis (BNST). The BNST is interconnected with essential emotional processing regions, including prefrontal cortex, hippocampus and amygdala. It is activated by stressor exposure and undergoes neurochemical and morphological alterations as a result of stressor exposure. Stress-related neuro-peptides including corticotropin-releasing factor (CRF) and pituitary adenylate cyclase activating peptide (PACAP) are also abundant in the BNST, further implicating an involvement of BNST in stress responses. Behaviorally, the BNST is critical for acquisition and expression of fear and is well positioned to regulate fear relapse after periods of extinction. Here, we consider the role of the BNST in stress and memory processes in the context of preclinical models of PTSD.

Over the years Pavlovian fear conditioning has proved to be a powerful model to investigate the neural underpinnings of aversive associative memory formation. Although it is well appreciated that plasticity occurring at excitatory synapses within the basolateral complex of the amygdala (BLA) plays a critical role in associative memory formation, recent evidence suggests that plasticity within the amygdala is more distributed than previously appreciated. In particular, studies demonstrate that plasticity in the central nucleus (CeA) is critical for the acquisition of conditioned fear. In addition, a variety of interneuron populations within the amygdala, defined by unique neurochemical markers, contribute to distinct aspects of stimulus processing and memory formation during fear conditioning. Here, we will review and summarize recent advances in our understanding of amygdala networks and how unique players within this network contribute to synaptic plasticity associated with the acquisition of conditioned fear.

The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. We found that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruited parvalbumin-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala-projecting pyramidal neurons in the IL was dominated by feed-forward inhibition. Selectively silencing parvalbumin-expressing, but not somatostatin-expressing, interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC→IL projections impaired extinction recall, whereas silencing IL projectors diminished fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, our findings describe a previously unknown circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse.

Surviving threats in the environment requires brain circuits for detecting (or anticipating) danger and for coordinating appropriate defensive responses (e.g., increased cardiac output, stress hormone release, and freezing behavior). The bed nucleus of the stria terminalis (BNST) is a critical interface between the “affective forebrain”—including the amygdala, ventral hippocampus, and medial prefrontal cortex—and the hypothalamic and brainstem areas that have been implicated in neuroendocrine, autonomic, and behavioral responses to actual or anticipated threats. However, the precise contribution of the BNST to defensive behavior is unclear, both in terms of the antecedent stimuli that mobilize BNST activity and the consequent defensive reactions. For example, it is well known that the BNST is essential for contextual fear conditioning, but dispensable for fear conditioning to discrete conditioned stimuli (CSs), at least as indexed by freezing behavior. However, recent evidence suggests that there are circumstances in which contextual freezing may persist independent of the BNST. Furthermore, the BNST is involved in the reinstatement (or relapse) of conditioned freezing to extinguished discrete CSs. As such, there are critical gaps in understanding how the BNST contributes to fundamental processes involved in Pavlovian fear conditioning. Here, we attempt to provide an integrative account of BNST function in fear conditioning. We discuss distinctions between unconditioned stress and conditioned fear and the role of BNST circuits in organizing behaviors associated with these states. We propose that the BNST mediates conditioned defensive responses—not based on the modality or duration of the antecedent threat or the duration of the behavioral response to the threat—but rather as consequence the ability of an antecedent stimulus to predict when an aversive outcome will occur (i.e., its temporal predictability). We argue that the BNST is not uniquely mobilized by sustained threats or uniquely involved in organizing sustained fear responses. In contrast, we argue that the BNST is involved in organizing fear responses to stimuli that poorly predictwhendanger will occur, no matter the duration, modality, or complexity of those stimuli. The concepts discussed in this review are critical to understanding the contribution of the human BNST to fear and anxiety disorders.

Gonadal steroids and their metabolites have been shown to be important modulators of emotional behavior. Allopregnanolone (ALLO), for example, is a metabolite of progesterone that has been linked to anxiety-related disorders such as posttraumatic stress disorder. In rodents, it has been shown to reduce anxiety in a number of behavioral paradigms including Pavlovian fear conditioning. We have recently found that expression of conditioned contextual (but not auditory) freezing in rats can be suppressed by infusion of ALLO into the bed nucleus of the stria terminalis (BNST). To further explore the nature of this effect, we infused ALLO into the BNST of male rats prior to both conditioning and testing. We found that suppression of contextual fear occurred when the hormone was present during either conditioning or testing but not during both procedures, suggesting that ALLO acts in a state-dependent manner within the BNST. A shift in interoceptive context during testing for animals conditioned under ALLO provided further support for this mechanism of hormonal action on contextual fear. Interestingly, infusions of ALLO into the basolateral amygdala produced a state-independent suppression of both conditioned contextual and auditory freezing. Altogether, these results suggest that ALLO can influence the acquisition and expression of fear memories by both state-dependent and state-independent mechanisms.

Anatomical disconnection of the ventral hippocampus (VH) and medial prefrontal cortex (mPFC) impairs the renewal of extinguished fear in rats. Here we examined whether subpopulations of neurons in the VH that project to the mPFC, including the prelimbic cortex (PL) and infralimbic cortex (IL), are selectively or differentially engaged by the renewal of fear to an extinguished auditory conditioned stimulus (CS). Rats were ipsilaterally injected with two distinct fluorescent retrograde tracers into the IL and PL and then underwent fear conditioning, extinction and retrieval in distinct contexts. Ventral hippocampal neurons were found to project to both IL and PL, and a small number of neurons projected to both regions. Fos expression was similarly elevated in each subpopulation of mPFC-projecting neuron in animals tested outside the extinction context relative to those tested in the extinction context or home controls. Interestingly, this pattern of results is not consistent with circuit models suggesting a differential role for VH projections to PL and IL in the bidirectional regulation of fear expression after extinction. Rather, these data suggest that projections from the VH to both PL and IL are uniquely involved in fear renewal, but not the suppression of fear after extinction. VH neurons may drive fear renewal by fostering fear expression by exciting PL while limiting fear suppression by inhibiting IL.

Once acquired, a fearful memory can persist for a lifetime. Although learned fear can be extinguished, extinction memories are fragile. The resilience of fear memories to extinction may contribute to the maintenance of disorders of fear and anxiety, including post-traumatic stress disorder (PTSD). As such, considerable effort has been placed on understanding the neural circuitry underlying the acquisition, expression, and extinction of emotional memories in rodent models as well as in humans. A triad of brain regions, including the prefrontal cortex, hippocampus, and amygdala, form an essential brain circuit involved in fear conditioning and extinction. Within this circuit, the prefrontal cortex is thought to exert top-down control over subcortical structures to regulate appropriate behavioral responses. Importantly, a division of labor has been proposed in which the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) regulate the expression and suppression of fear in rodents, respectively. Here we critically review the anatomical and physiological evidence that has led to this proposed dichotomy of function within mPFC. We propose that under some conditions, the PL and IL act in concert, exhibiting similar patterns of neural activity in response to aversive conditioned stimuli and during the expression or inhibition of conditioned fear. This may stem from common synaptic inputs, parallel downstream outputs, or cortico-cortical interactions. Despite this functional covariation, these mPFC subdivisions may still be coding for largely opposing behavioral outcomes, with PL biased towards fear expression and IL towards suppression.

Stress has a critical role in the development and expression of many psychiatric disorders, and is a defining feature of posttraumatic stress disorder (PTSD). Stress also limits the efficacy of behavioral therapies aimed at limiting pathological fear, such as exposure therapy. Here we examine emerging evidence that stress impairs recovery from trauma by impairing fear extinction, a form of learning thought to underlie the suppression of trauma-related fear memories. We describe the major structural and functional abnormalities in brain regions that are particularly vulnerable to stress, including the amygdala, prefrontal cortex, and hippocampus, which may underlie stress-induced impairments in extinction. We also discuss some of the stress-induced neurochemical and molecular alterations in these brain regions that are associated with extinction deficits, and the potential for targeting these changes to prevent or reverse impaired extinction. A better understanding of the neurobiological basis of stress effects on extinction promises to yield novel approaches to improving therapeutic outcomes for PTSD and other anxiety and trauma-related disorders.

Considerable research indicates that long-term synaptic plasticity in the amygdala underlies the acquisition of emotional memories, including those learned during Pavlovian fear conditioning. Much less is known about the synaptic mechanisms involved in other forms of associative learning, including extinction, that update fear memories. Extinction learning might reverse conditioning-related changes (e.g., depotentiation) or induce plasticity at inhibitory synapses (e.g., long-term potentiation) to suppress conditioned fear responses. Either mechanism must account for fear recovery phenomena after extinction, as well as savings of extinction after fear recovery. This article is part of a Special Issue entitled SI: Brain and Memory.

Recent data in both rodents and humans suggests that the timing of extinction trials after conditioning influences the magnitude and duration of extinction. For example, administering extinction trials soon after Pavlovian fear conditioning in rats, mice, and humans results in minimal fear suppression – the so-called immediate extinction deficit. Here I review recent work examining the behavioral and neural substrates of the immediate extinction deficit. I suggest that extinction is most effective at some delay after conditioning, because brain systems involved in encoding and retrieving extinction memories function sub-optimally under stress.

Although fear directs adaptive behavioral responses, how aversive cues recruit motivational neural circuitry is poorly understood. Specifically, while it is known that dopamine (DA) transmission within the nucleus accumbens (NAc) is imperative for mediating appetitive motivated behaviors, its role in aversive behavior is controversial. It has been proposed that divergent phasic DA transmission following aversive events may correspond to segregated mesolimbic dopamine pathways; however, this prediction has never been tested. Here, we used fast-scan cyclic voltammetry to examine real-time DA transmission within NAc core and shell projection systems in response to a fear-evoking cue. In male Sprague Dawley rats, we first demonstrate that a fear cue results in decreased DA transmission within the NAc core, but increased transmission within the NAc shell. We examined whether these changes in DA transmission could be attributed to modulation of phasic transmission evoked by cue presentation. We found that cue presentation decreased the probability of phasic DA release in the core, while the same cue enhanced the amplitude of release events in the NAc shell. We further characterized the relationship between freezing and both changes in DA as well as local pH. Although we found that both analytes were significantly correlated with freezing in the NAc across the session, changes in DA were not strictly associated with freezing while basic pH shifts in the core more consistently followed behavioral expression. Together, these results provide the first real-time neurochemical evidence that aversive cues differentially modulate distinct DA projection systems.

It has been suggested that reduced infralimbic (IL) cortical activity contributes to impairments of fear extinction. We therefore explored whether pharmacological activation of the IL would facilitate extinction under conditions it normally fails (i.e., immediate extinction). Rats received auditory fear conditioning 1 h before extinction training. Immediately prior to extinction, rats received microinfusions into the IL of the GABAA receptor antagonist, picrotoxin, or the NMDA receptor partial agonist, D-cycloserine. Although neither drug facilitated extinction, they both facilitated the subsequent re-extinction of fear when animals were trained in a drug-free state, suggesting that activating the IL primes behavioral extinction.

The infralimbic division of the medial prefrontal cortex (IL) has been implicated in the consolidation and retention of extinction memories. However, the effects of IL lesions on the retention of extinction memory are inconsistent. In the present experiments, we examined whether rat strain influences the effects of IL lesions on extinction. In Experiment 1, Sprague-Dawley (SD) or Long-Evans (LE) rats received a standard auditory fear conditioning procedure, which was followed by an extinction session; freezing served as the index of conditional fear. Our results reveal that focal IL lesions impair the retention of extinction in SD, but not LE rats. In addition to the strain difference in sensitivity to IL lesions, LE rats exhibited significantly higher levels of contextual fear before the outset of extinction training than SD rats. In a second experiment we thus examined whether contextual fear influenced the sensitivity of extinction to IL lesions in LE rats. Long-Evans rats received the same conditioning as in Experiment 1, and then were either merely exposed to a novel context or administered unsignaled shocks in that context, followed by extinction and test sessions. Our results reveal that LE rats with IL lesions showed normal extinction regardless of the levels of contextual fear manifest before extinction. Thus, we conclude that rat strain is an important variable that influences the role of infralimbic cortex in fear extinction.

Pavlovian conditioning paradigms have become important model systems for understanding the neuroscience of behavior. In particular, studies of the extinction of Pavlovian fear responses are yielding important information about the neural substrates of anxiety disorders, such as phobias and post-traumatic stress disorder (PTSD) in humans. These studies are germane to understanding the neural mechanisms underlying behavioral interventions that suppress fear, including exposure therapy in anxiety disorders. This unit describes detailed behavioral protocols for examining the nature and properties of fear extinction in laboratory rodents.

In recent studies, inactivation of the dorsal hippocampus before the retrieval of extinguished fear memories disrupted the context-dependent expression of these memories. In the present experiments, we examined the role of the dorsal hippocampus in the acquisition of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock [unconditional stimulus (US)], rats received an extinction session in which the CS was presented without the US. In experiment 1, infusion of muscimol, a GABAAreceptor agonist, into the dorsal hippocampus before the extinction training session decreased the rate of extinction. Moreover, when later tested for fear to the extinguished CS, all rats that had received hippocampal inactivation before extinction training demonstrated renewed fear regardless of the context in which testing took place. This suggests a role for the dorsal hippocampus in both acquiring the extinction memory and encoding the CS–context relationship that yields the context dependence of extinction. In experiment 2, inactivation of the dorsal hippocampus before testing also disrupted the context dependence of fear to the extinguished CS. In experiment 3, quantitative autoradiography revealed the boundaries of muscimol diffusion after infusion into the dorsal hippocampus. Together, these results reveal that the dorsal hippocampus is involved in the acquisition, contextual encoding, and context-dependent retrieval of fear extinction. Learning and remembering when and where aversive events occur is essential for adaptive emotional regulation.

We have shown previously that electrolytic lesions of the dorsal hippocampus (DH) produce a severe deficit in contextual fear if made 1 d, but not 28 d, after fear conditioning (Kim and Fanselow, 1992). As such, the hippocampus seems to play a time-limited role in the consolidation of contextual fear conditioning. Here, we examine retrograde amnesia of contextual fear produced by DH lesions in a within-subjects design. Unlike our previous reports, rats had both a remote and recent memory at the time of the lesion. Rats were given 10 tone–shock pairings in one context (remote memory) and 10 tone–shock pairings in a distinct context (with a different tone) 50 d later (recent memory), followed by DH or sham lesions 1 d later. Relative to controls, DH-lesioned rats exhibited no deficit in remote contextual fear, but recent contextual fear memory was severely impaired. They also did not exhibit deficits in tone freezing. This highly specific deficit in recent contextual memory demonstrated in a within-subjects design favors mnemonic over performance accounts of hippocampal involvement in fear. These findings also provide further support for a time-limited role of the hippocampus in memory storage.

In fear conditioning, a rat is placed in a distinct environment and delivered footshock. The response to the footshock itself is called an activity burst and includes running, jumping, and vocalization. The fear conditioned to the distinct environment by the footshock elicits complete immobility termed freezing. Lesions of the ventral periaqueductal gray (vPAG) strongly attenuate freezing. However, lesions of the dorsolateral periaqueductal gray (dlPAG) increase the amount of freezing seen to conditional fear cues acquired under conditions in which intact rats do not demonstrate much fear conditioning. To examine the necessity of these regions in the acquisition and expression of fear, we performed five experiments that examined the effects of electrolytic lesions of the dlPAG and the vPAG in learned and unlearned fear. In experiment 1, lesions of the vPAG strongly attenuated, whereas lesions of the dlPAG enhanced, unconditional freezing to a cat. In experiment 2, lesions of the dlPAG made before but not after training enhanced the amount of freezing shown to conditional fear cues acquired via immediate footshock delivery. In experiment 3, vPAG lesions made either before or after training with footshock decreased the level of freezing to conditional fear cues. Neither dlPAG lesions nor vPAG lesions affected footshock sensitivity (experiment 4) or consumption on a conditioned taste aversion test that does not elicit antipredator responses (experiment 5). On the basis of these results, it is proposed that activation of the dlPAG produces inhibition of the vPAG and forebrain structures involved with defense. In contrast, the vPAG seems to be necessary for postencounter freezing defensive behavior.

The influence of overtraining on the magnitude of fear-conditioning deficits produced by neurotoxic lesions of the basolateral amygdala (BLA) was examined. Either 1 d before or 1 week after the administration of neurotoxic BLA lesions, rats received either 1 or 25 conditioning trials consisting of the delivery of unsignaled foot shock in a novel observation chamber; freezing served as the measure of conditional fear. In this conditioning paradigm, asymptotic performance is reached in five conditioning trials, and 25 conditioning trials constitutes an overtraining procedure. The results revealed that overtraining does not affect the magnitude of the contextual freezing deficits produced by post-training BLA lesions. Similarly, overtraining did not influence the level of reacquisition obtained by rats with post-training BLA lesions after 10 reacquisition trials. A similar pattern of results was observed in rats with pretraining BLA lesions. Neurotoxic BLA lesions did not alter either motor activity or shock reactivity. These results indicate that overtraining does not limit the important role of the BLA in the acquisition and expression of contextual fear conditioning.