Consolidation Of Extinction Research Articles

Aberrant Angiotensin Signaling in a Mouse Model of Post‐Traumatic Stress Disorder (PTSD)

Independent of their beneficial effects on hypertension and cardiovascular related disease, angiotensin receptor type 1 (AT1R) blockers can improve stress-related symptoms. AT1R receptor-mediated actions can be counteracted directly or indirectly by the angiotensin receptor type 2 receptor (AT2R). Our recent studies in a mouse model of PTSD have shown that AT1R blockade increases the extinction (learned inhibition) of a traumatic fear memory and that AT1R mRNA expression is reduced in fear related brain regions of losartan treated animals. These data imply that downstream AT1 signaling events maybe important in consolidation of fear memory extinction. Therefore we investigated the acute effects of AT2R inhibition on fear memory and baseline anxiety. We performed classical Pavlovian fear conditioning pairing auditory cues with foot shocks and examined fear extinction behavior and cardiovascular responses in the presence of the AT2R antagonist PD 123319. Twenty-four hours following fear conditioning, PD 123319 (15 mg/kg IP) was administered prior to fear memory extinction. The PD treated group exhibited significantly less freezing behavior (F10, 300 = 1.9; p<0.05) during fear expression and contrary to our previous results with the AT1 antagonist losartan, there was no effect during extinction retention, an index of long-term fear memory. These data indicate that AT1R and AT2R may have divergent effects on short and long-term fear memory formation. Further studies are required to understand the differential regulation of angiotensin receptor signaling in PTSD.

Acute tianeptine treatment selectively modulates neuronal activation in the central nucleus of the amygdala and attenuates fear extinction.

Antidepressant drugs are commonly prescribed treatments for anxiety disorders, and there is growing interest in understanding how these drugs impact fear extinction because extinction learning is pivotal to successful exposure-based therapy (EBT). A key objective within this domain is understanding how antidepressants alter the activation of specific elements of the limbic-based network that governs such fear processing. Chronic treatment with the antidepressant tianeptine has been shown to reduce the acquisition of extinction learning in rats, yet the drug's acute influence on activation in prefrontal and amygdalar regions, and on extinction learning are not well understood. To assess its influence on cellular activation, rats were injected with tianeptine and Fos immunoreactivity was measured in these regions. Acute tianeptine treatment selectively altered Fos expression within subdivisions of the central nucleus of the amygdala (CEA) in a bidirectional manner that varied in relation to ongoing activation within the capsular subdivision and its prefrontal and intra-amygdalar inputs. This pattern of results suggests that the drug can conditionally modulate the activation of CEA subdivisions, which contain microcircuits strongly implicated in fear processing. The effect of acute tianeptine was also examined with respect to the acquisition, consolidation and expression of fear extinction in rats. Acute tianeptine attenuated extinction learning as well as the recall of extinction memory, which underscores that acute dosing with the drug could alter learning during EBT. Together these findings provide a new perspective for understanding the mechanism supporting tianeptine's clinical efficacy, as well as its potential influence on CEA-based learning mechanisms.

Mice lacking TrkB in parvalbumin-positive cells exhibit sexually dimorphic behavioral phenotypes

Activity-dependent brain-derived neurotrophic factor (BDNF) signaling through receptor tyrosine kinase B (TrkB) is required for cued fear memory consolidation and extinction. Although BDNF is primarily secreted from glutamatergic neurons, TrkB is expressed by other genetically defined cells whose contributions to the behavioral effects of BDNF remain poorly understood. Parvalbumin (PV)-positive interneurons, which are highly enriched in TrkB, are emerging as key regulators of fear memory expression. We therefore hypothesized that activity-dependent BDNF signaling in PV-interneurons may modulate emotional learning. To test this hypothesis, we utilized the LoxP/Cre system for conditional deletion of TrkB in PV-positive cells to examine the impact of cell-autonomous BDNF signaling on Pavlovian fear conditioning and extinction. However, behavioral abnormalities indicative of vestibular dysfunction precluded the use of homozygous conditional knockouts in tests of higher cognitive functioning. While vestibular dysfunction was apparent in both sexes, female conditional knockouts exhibited an exacerbated phenotype, including extreme motor hyperactivity and circling behavior, compared to their male littermates. Heterozygous conditional knockouts were spared of vestibular dysfunction. While fear memory consolidation was unaffected in heterozygotes of both sexes, males exhibited impaired extinction consolidation compared to their littermate controls. Our findings complement evidence from human and rodent studies suggesting that BDNF signaling promotes consolidation of extinction and point to PV-positive neurons as a discrete population that mediates these effects in a sex-specific manner.

Spontaneous recovery of fear reverses extinction-induced excitability of infralimbic neurons.

In rodents, the infralimbic (IL) region of the medial prefrontal cortex plays a key role in the recall of fear extinction. Previously we showed that fear conditioning decreases the intrinsic excitability of IL neurons, and that fear extinction reverses the depressed excitability. In the current study, we examined the time course of the extinction-induced changes in adolescent rats. Immediately after extinction, IL neurons continued to show depressed excitability. However 4 hours after extinction, IL neurons showed an increase in evoked spikes that correlated with a reduced fast afterhyperpolarizing potential. This suggests that acquisition of fear extinction induces an increase in spike firing 4 hours later, during the consolidation of extinction. We also examined IL excitability in a group of rats that showed spontaneous recovery of fear 17 days after extinction (SR group). Similar to neurons after fear conditioning, IL neurons from the SR group showed depressed intrinsic excitability compared to neurons 4 hours after extinction, suggesting that extinction-induced enhancement in intrinsic excitability decreases with time reverting back to a depressed state. These results suggest that plasticity in IL contributes to the spontaneous recovery of fear and preventing this depression of IL excitability could prolong fear extinction.

Fear extinction learning can be impaired or enhanced by modulation of the CRF system in the basolateral nucleus of the amygdala

The neuropeptide corticotropin-releasing factor (CRF) is released during periods of anxiety and modulates learning and memory formation. One region with particularly dense concentrations of CRF receptors is the basolateral nucleus of the amygdala (BLA), a critical structure for both Pavlovian fear conditioning and fear extinction. While CRF has the potential to modify amygdala-dependent learning, its effect on fear extinction has not yet been assessed. In the present study, we examined the modulatory role of CRF on within-session extinction and fear extinction consolidation. Intra-BLA infusions of the CRF binding protein ligand inhibitor CRF(6–33) which increases endogenous levels of free CRF, or intra-BLA infusions of exogenous CRF made prior to fear extinction learning did not affect either fear expression or within-session extinction learning. However, when these animals were tested twenty-four hours later, drug free, they showed impairments in extinction memory. Conversely, intra-BLA infusions of the CRF receptor antagonist α-helical CRF(9–41) enhanced memory of fear extinction. These results suggest that increased CRF levels within the BLA at the time of fear extinction learning actively impair the consolidation of long-term fear extinction.

Bidirectional effects of inhibiting or potentiating NMDA receptors on extinction after cocaine self-administration in rats.

Extinction of drug seeking is facilitated by NMDA receptor (NMDAr) agonists, but it remains unclear whether extinction is dependent on NMDAr activity. We investigated the necessity of NMDArs for extinction of cocaine seeking and whether extinction altered NMDAr expression within extinction-related neuroanatomical loci. Rats were trained to lever press for i.v. infusions of cocaine or sucrose reinforcement prior to extinction training or withdrawal. Administration of the NMDAr competitive antagonist CPP prior to four brief extinction sessions impaired subsequent extinction retention. In contrast, administration of the NMDAr coagonist D-serine after four brief extinction sessions attenuated lever pressing during subsequent extinction, indicative of facilitated consolidation of extinction. Furthermore, expression of the NMDAr subunits, GluN2A and GluN2B, was not altered in the ventromedial prefrontal cortex. However, both GluN2A and GluN2B subunit expression in the nucleus accumbens increased following cocaine self-administration, and this increased expression was relatively resistant to modulation by extinction. Our findings demonstrate that extinction of cocaine seeking is bidirectionally mediated by NMDArs and suggest that selective modulation of NMDAr activity could facilitate extinction-based therapies for treatment of cocaine abuse.

Angiotensin Type 1 Receptor Antagonists—A Novel Approach to Augmenting Posttraumatic Stress Disorder and Phobia Therapies?

The renin-angiotensin system system, which includes the renin and angiotensin-converting enzyme pathways, and its primary effector peptide angiotensin II (AII) acting through its two cognate receptors, AT1 and AT2 receptors, has been known for 70 years as a major regulator of vascular tone and fluid metabolism (1). Angiotensin receptor blockers (ARBs), consisting of a group of orally active drugs such as losartan (the group is often referred to as the “sartans”), and angiotensinconverting enzyme inhibitors are currently mainstream treatments for essential hypertension and some aspects of diabetes. In addition to these peripheral effects, AII and AT1 receptors are widely distributed in the brain and are being implicated in the regulation of many brain functions, including cerebral circulation, inflammation, neuroendocrine responses, learning, and memory (2). Because many ARBs are already on the market and have a good safety record with long-term use, they would be particularly attractive candidates to be used as novel treatments for central nervous system disorders where current therapies are inadequate. The article by Marvar et al. (3) in this issue of Biological Psychiatry may provide a strong impetus to consider testing ARBs, particularly as an adjunct therapy to augment cognitive-behavioral therapy, in posttraumatic stress disorder (PTSD) and phobias. The idea that ARBs may have some beneficial effects for patients with PTSD first arose from a correlational finding in an epidemiologic study, where veterans treated with ARBs for their medical conditions appeared to develop a less severe form of PTSD compared with veterans who were not taking ARBs (4). Although such correlations may turn out to be spurious, Marvar et al. decided to test whether the beneficial effect of ARBs is mechanistically demonstrable using preclinical models. There are robust animal models that can be used to study the basic circuits and phenotypes involved in PTSD symptoms. Using a standard auditory-cue paired conditioned fear model in mice, Marvar et al. tested the effects of single and multiple doses of selective AT1 antagonist losartan on fear extinction behavior, gene expression changes in the brain, and neuroendocrine and cardiovascular responses. They found that losartan treatment enhanced the consolidation of fear extinction without affecting acquisition, baseline anxiety, blood pressure, and neuroendocrine stress measures. Mice treated with losartan for 2 weeks also demonstrated reduced amygdala AT1 receptor messenger RNA (mRNA) levels. The authors concluded that AT1 receptor antagonism does have potential beneficial effects in a preclinical model of PTSD symptoms and could enhance the extinction of fear memories in PTSD.

Infralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine-conditioned place preference.

Brain-derived neurotrophic factor (BDNF) regulates synaptic activity and behavioral flexibility, and reduction of BDNF strongly predicts psychiatric disorders and cognitive dysfunction. Restoration of BDNF-dependent activity could alleviate these impairments, but BDNF has limited clinical utility due to its pharmacokinetics. Here we demonstrate that activation of a primary BDNF target, the tropomyosin-related kinase B (TrkB) receptor, enhances the amplitude and prolongs the decay kinetics of N-methyl-d-aspartate receptor (NMDAR) currents in male rat infralimbic prefrontal pyramidal neurons. Moreover, these effects were prevented and reversed by blockade of NMDARs containing the GluN2B subunit. Our results show that this signaling cascade bidirectionally regulates extinction of a cocaine-induced conditioned place preference (CPP), a task that requires behavioral flexibility. Blockade of infralimbic TrkB receptors or GluN2B-containing NMDARs disrupted consolidation of extinction of the CPP. In contrast, extinction was strengthened by potentiation of TrkB receptor activity with infralimbic infusions of BDNF or systemic injections of 7,8 dihydroxyflavone (7,8DHF), the newly synthesized TrkB receptor agonist. The 7,8DHF-induced enhancement of extinction was prevented by infralimbic infusions of a GluN2B-specific receptor antagonist, demonstrating that TrkB receptor activation enhances extinction of cocaine-CPP via GluN2B-containing NMDARs. Together, infralimbic TrkB receptor activation strengthens GluN2B-containing NMDAR currents to support extinction learning. TrkB receptor agonists would therefore be useful as pharmacological adjuncts for extinction-based therapies for treatment of psychiatric disorders associated with reduced BDNF activity.

Frontal Lobe Synaptic Plasticity in Development and Disease: Modulation by the Dopamine D1 Receptor

Synaptic plasticity is now known to occur at glutamate synapses throughout the brain, including the neocortex, and to play a role in neurodevelopment as well as in a broad spectrum of adult neural functions. Here the hypothesis that synaptic plasticity, specifically long term depression, is the neural substrate that mediates adolescent synaptic pruning is re-examined in the context of its ramifications for neuropsychiatric illnesses. Stress, which in part is mediated by dopamine acting via the D1 receptor, may disrupt normal synaptic plasticity in adolescence resulting in excessive synaptic elimination. In this manner elevated dopamine levels due to stress could contribute to deficits in gray matter volume and reduced neural connectivity in diseases such as major depressive disorder and schizophrenia. Attention deficit hyperactivity disorder, another developmental illness associated with cortical gray matter volume deficits, may represent a state of diminished dopamine stimulation that is equally disruptive to normal mechanisms of synaptic plasticity. In post-traumatic stress disorder, long term potentiation necessary for conditioned fear extinction, is thought to be impaired. Recent evidence suggests that genotypes related to dopamine neurotransmission confer vulnerability to post-traumatic stress disorder, perhaps indicating that low dopamine levels are less permissive of the synaptic plasticity that underlies consolidation and retention of fear extinction. Further understanding of the role that dopamine-modulated synaptic plasticity plays in development and, when disrupted, in precipitating neuropsychiatric illness could lead to novel drug treatments, and ultimately to preventative pharmacotherapeutic interventions, for these disorders.

Blockade of Cav2.1-mediated NMDA receptor signaling disrupts conditioned fear extinction

Although fear extinction requires N-methyl-d-aspartate (NMDA) receptor signaling, Cav2.1-regulated synaptic function in extinction remains unknown. This study examined whether Cav2.1-mediated signaling plays role in consolidation of extinction. Wild-type mice received intracerebroventricular injection of Cav2.1 blocker (ω-agatoxin IVA, 4.0pg/side) showed impaired extinction behavior and increased expression of CREB-dependent gene Arc in medial prefrontal cortex (mPFC). Intra-mPFC injections of NMDA receptor antagonist (MK-801, 0.5μg/midline), which was ineffective in wild-type controls, blocked extinction in heterozygous rolling Nagoya (rol/+) mice carrying Cav2.1α1 gene mutation rol/+ mice. These results indicate that Cav2.1-mediated NMDA receptor signaling is functional pathway in mPFC-dependent fear extinction. Our results also indicate that the combination of pharmacological and genetic approaches can be used to study functional signaling pathways in neuronal circuits.

Double dissociation between the anterior cingulate cortex and nucleus accumbens core in encoding the context versus the content of pavlovian cocaine cue extinction.

One strategy proposed to treat addictive disorders is to extinguish the association between environmental stimuli (cues) and actions associated with drug use to reduce relapse. The context specificity of extinction learning, however, impairs the ability of addicts to generalize extinction training to the drug-taking context. We previously reported that the NMDA receptor partial agonist d-cycloserine administered after pavlovian extinction of cocaine cues in the nucleus accumbens core (NAc) reduced cue-induced renewal. Nevertheless, it was unclear whether this was due to disrupted contextual encoding of extinction or enhanced extinction consolidation. Thus, we examined the effect of the NMDA receptor antagonist d-AP5 on context encoding versus cue extinction learning. We also determined the role of the anterior cingulate cortex (ACC) in encoding the cue extinction memory or the context, due to its projections to NAc, and hypothesized the role in conflict monitoring and contextual modulation of decision making. Using rats, we observed that NMDA receptor antagonism in the NAc did not alter context encoding but did interfere with acquisition of the cue extinction memory, i.e., learning, conversely inactivation of the ACC reduced the contextual encoding of extinction but did not interfere with the acquisition or expression of extinction. The observed effects were not present in the absence of cue extinction training. Additionally, the contextual memory did not appear to be consolidated in the ACC as neither postsession inactivation nor protein synthesis inhibition impaired context-appropriate responding. These results have implications for overcoming the context specificity of extinction to treat psychiatric disorders including addiction.

Inhibition of the PI3 kinase cascade in corticolimbic circuit: temporal and differential effects on contextual fear and extinction

We studied the role of PI3K cascade in the basolateral amygdala (BLA) and the infralimbic region of the medial prefrontal cortex (IL-mPFC), in contextual fear learning and extinction in the rat. To that end, we micro-infused the phosphoinositide-3-kinase (PIK3) inhibitor LY294002 into either the mPFC or the BLA. Infusion of LY294002 into the BLA following fear conditioning was associated with enhanced freezing levels and impaired extinction in the subsequent sessions. Similarly, inhibition of PI3K in the BLA before the retrieval of fear memory was associated with impaired retrieval of the fear memory, which was expressed as reduced freezing levels that persisted over 2 d. In the IL-mPFC, only consolidation of fear extinction was impaired: micro-infusion of PI3K inhibitor following the retrieval of fear was associated with impaired extinction on the following days. These results indicate differences in the temporal parameters of the effects of PI3K inhibition in the IL-mPFC and in the BLA, which suggest differential involvement of these structures in long-term fear and in extinction of fear memory. Our findings provide additional evidence for the critical roles played by PI3K in intact formation of fear memory and in its extinction and add new evidence for a role of PI3K in consolidation of memory of extinction. Better understanding of the differential involvement of the PI3K cascade during acquisition and extinction of fear conditioning in the mPFC-amygdala circuit could potentially contribute to the understanding and treatment of anxiety disorders.

Fear extinction induces mGluR5-mediated synaptic and intrinsic plasticity in infralimbic neurons.

Studies suggest that plasticity in the infralimbic prefrontal cortex (IL) in rodents and its homolog in humans is necessary for inhibition of fear during the recall of fear extinction. The recall of extinction is impaired by locally blocking metabotropic glutamate receptor type 5 (mGluR5) activation in IL during extinction training. This finding suggests that mGluR5 stimulation may lead to IL plasticity needed for fear extinction. To test this hypothesis, we recorded AMPA and NMDA currents, AMPA receptor (AMPAR) rectification, and intrinsic excitability in IL pyramidal neurons in slices from trained rats using whole-cell patch-clamp recording. We observed that fear extinction increases the AMPA/NMDA ratio, consistent with insertion of AMPARs into IL synapses. In addition, extinction training increased inward rectification, suggesting that extinction induces the insertion of calcium-permeable (GluA2-lacking) AMPARs into IL synapses. Consistent with this, selectively blocking calcium-permeable AMPARs with Naspm reduced the AMPA EPSCs in IL neurons to a larger degree after extinction. Extinction-induced changes in AMPA/NMDA ratio, rectification, and intrinsic excitability were blocked with an mGluR5 antagonist. These findings suggest that mGluR5 activation leads to consolidation of fear extinction by regulating the intrinsic excitability of IL neurons and modifying the composition of AMPARs in IL synapses. Therefore, impaired mGluR5 activity in IL synapses could be one factor that causes inappropriate modulation of fear expression leading to anxiety disorders.

Myocardial infarction increases noradrenergic activity in medial prefrontal cortex and impairs consolidation of fear extinction more in female rats

Anxiety often develops after myocardial infarction (MI), particularly in women. Patients with anxiety often show a deficit in the ability to recall that a fearful cue no longer predicts danger (extinction recall), a process that requires adrenergic receptor activation in the infralimbic medial prefrontal cortex (ILmPFC). Here, we assessed noradrenergic activity in the ILmPFC and extinction recall after MI. Rats were subjected to fear conditioning with footshock, and sham or real coronary artery ligation. 8 weeks after surgery, male MI rats (n=4) had larger fear responses to the conditioned cue compared to male controls (n=6, P&lt;0.05). Fear could be extinguished in both groups, and both readily recalled extinction 24 hrs later. Female MI rats (n=6) showed similar fear to the cue and fear extinction as female controls (n=6), but they did not recall extinction 24hrs later (P&lt;0.05). Tyrosine hydroxylase expression was increased in noradrenergic nerve terminals of the ILmPFC after MI (P&lt;0.05) and the effect was exaggerated in female rats (P&lt;0.05). We conclude that chronic increases in noradrenergic activity in the ILmPFC may contribute to deficits in consolidation of extinction memories after MI in females

Opening the genome to reduce cocaine-seeking behavior

Since the discovery of specific mechanisms regulating gene transcription, studies have explored therapeutic avenues in the treatment of disease through such epigenetic targets, including the mechanisms of histone acetylation/deacetylation. Indeed, compounds that inhibit histone deacetylation [i.e., histone deacetylase (HDAC) inhibitors] have been investigated as treatments for a variety of diseases, including cancer (1), Alzheimer’s disease, and Parkinson disease (2). Considering the role that transcription plays in learning and memory (3), it is not surprising that memory-related diseases and disorders are particularly ripe for treatments based on epigenetic targets. In PNAS, Malvaez et al. (4) report that systemic administration of a selective HDAC3 inhibitor to rats enhances the extinction of cocaine-seeking, consistent with previous work (5, 6). Crucially, they demonstrate that the enhanced extinction is rapid and persistent and even appears to eliminate the reinstatement of cocaine-seeking, suggesting the potential for targeting this mechanism as an adjunctive therapy. Moreover, the authors use a unique behavioral design that enables them to distinguish the effects of the HDAC inhibitor on extinction consolidation from effects on reconsolidation and performance.

HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner.

Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.

Rapid Remission of Conditioned Fear Expression with Extinction Training Paired with Vagus Nerve Stimulation

Fearful experiences can produce long-lasting and debilitating memories. Extinction of conditioned fear requires consolidation of new memories that compete with fearful associations. In human subjects, as well as rats, posttraining stimulation of the vagus nerve enhances memory consolidation. Subjects with posttraumatic stress disorder show impaired extinction of conditioned fear. The objective of this study was to determine whether vagus nerve stimulation (VNS) can enhance the consolidation of extinction of conditioned fear. Male Sprague-Dawley rats were trained on an auditory fear conditioning task followed by 1 to 10 days of extinction training. Treatment with vagus nerve or sham stimulation was administered concurrently with exposure to the fear conditioned stimulus. Another group was given VNS and extinction training but the VNS was not paired with exposure to conditioned cues. Retention of fear conditioning was tested 24 hours after each treatment. Vagus nerve stimulation paired with exposure to conditioned cues enhanced the extinction of conditioned fear. After a single extinction trial, rats given VNS stimulation demonstrated a significantly lower level of freezing, compared with that of sham control rats. When extinction trials were extended to 10 days, paired VNS accelerated extinction of the conditioned response. Extinction paired with VNS is more rapid than extinction paired with sham stimulation. As it is currently approved by the Federal Food and Drug Administration for depression and seizure prevention, VNS is a readily available and promising adjunct to exposure therapy for the treatment of severe anxiety disorders.

Blockade of Estrogen by Hormonal Contraceptives Impairs Fear Extinction in Female Rats and Women

Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production; yet, their effects on fear extinction are unknown. We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women (n=76) and female rats (n = 140). Women using HCs exhibited significantly poorer extinction recall compared with naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists before fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories. Together, these findings suggest that HCs may impact women's ability to inhibit fear but that this impairment is not permanent and could potentially be alleviated with estrogen treatment.

Neural regulation of the time course for cocaine‐cue extinction consolidation in rats

Sites within the hippocampus, amygdala and prefrontal cortex may regulate how responses maintained by cues associated with cocaine are extinguished. To test the role of various brain sites in the consolidation of cocaine-cue extinction learning, the dorsal subiculum (dSUB), rostral basolateral amygdala (rBLA) and infralimbic prefrontal cortex (IL) were manipulated in rats. Following cocaine self-administration training (cues present, cocaine available), responding was assessed during 1-h extinction tests (cues present, no cocaine available). To study extinction consolidation specifically, the protein synthesis inhibitor anisomycin or vehicle was infused bilaterally into the dSUB, rBLA or IL either immediately following or 6 h after the first two of three extinction training sessions. With manipulations made immediately after extinction sessions, infusions of anisomycin into the dSUB or the rBLA deterred extinction. Rats maintained elevated levels of cocaine seeking relative to vehicle despite the absence of cocaine delivery. Manipulations of IL had no effect. Control studies showed that bilateral protein synthesis inhibition in dSUB and rBLA 6 h after the extinction sessions ended was unable to deter extinction. Rats reduced cocaine seeking in the usual manner in the absence of cocaine delivery. Collectively, these findings suggest that the dSUB and rBLA are neural substrates important for consolidation of cocaine-cue extinction learning and have time-dependent roles. Understanding the contribution of individual neural substrates for cocaine-cue extinction consolidation may help guide treatment strategies aimed at enhancing cue exposure therapy in cocaine-dependent people.

L-type voltage-gated calcium channels in the basolateral amygdala are necessary for fear extinction.

L-type voltage-gated calcium channels (L-VGCCs) in the basolateral nucleus of the amygdala (BLA) are necessary for long-term memory of fear conditioning, where they are thought to drive the activation of protein kinases and to initiate gene transcription. However, their role in fear extinction learning is unclear given that systemic injections of VGCC antagonists induce a protracted stress response. Here we tested the effects of local infusions of the L-VGCC antagonists verapamil and nifedipine on both within-session extinction and fear extinction consolidation. Intra-BLA infusions of verapamil or nifedipine did not affect the expression of fear conditioning or the amount of within-session extinction but impaired extinction memory when rats were tested 24 h later drug-free. L-VGCC antagonists also prevented the increase in phosphorylated mitogen-activated protein kinase (MAPK) normally seen in the BLA following extinction learning. These results suggest that activation of L-VGCCs in the BLA at the time of fear extinction learning is necessary for the long-term retention of fear extinction via the MAPK pathway.