The expression profile of brain-derived exosomal miRNAs reveals the key molecules responsible for spontaneous motor function recovery in a rat model with permanent middle cerebral artery occlusion.

The analysis of alterations in the expression and functionality of brain-derived exosomal miRNAs within ischemic stroke lesions provides significant insights into the mechanisms that contribute to disease recovery. We assessed spontaneous motor function in a rat model of permanent middle cerebral artery occlusion (pMCAO) using motor function scores and magnetic resonance imaging (MRI). Brain-derived exosomes from the infarcted brain tissue of the animal model were extracted and high-throughput sequencing of them was performed followed by bioinformatics analysis for differentially expressed miRNAs target genes. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to measure expression levels of differentially expressed miRNAs at various time points. The oxygen-glucose deprivation (OGD) model was established to investigate gene function through the assessment of cell proliferation and apoptosis using EdU proliferation and JC-1 apoptosis assay. The rat model demonstrated a spontaneous recovery of motor function and a reduction in cerebral infarction area from day 1 to day 14 post-operation. Over the course of the recovery period, miR-24-3p, miR-129-1-3p, and miR-212-5p maintained consistent expression levels, reaching their peak on the initial day following surgery. In the cell model, EdU detection indicated that miR-129-1-3p promoted cellular proliferation, while JC-1 detection revealed its suppressive impact on cellular apoptosis. The current research findings indicated the presence of spontaneous motor function restoration in a rat model of ischemic stroke. MiR-24-3p, miR-129-1-3p, and miR-212-5p were identified as pivotal genes in this recovery process, with miR-129-1-3p potentially influencing the restoration of spontaneous motor function in ischemic stroke through the regulation of neuronal proliferation and apoptosis.

How do animals weigh conflicting information about reward sources over time? Comparing dynamic averaging models.

Optimal foraging theory suggests that animals make decisions which maximize their food intake per unit time when foraging, but the mechanisms animals use to track the value of behavioral alternatives and choose between them remain unclear. Several models for how animals integrate past experience have been suggested. However, these models make differential predictions for the occurrence of spontaneous recovery of choice: a behavioral phenomenon in which a hiatus from the experimental environment results in animals reverting to a behavioral allocation consistent with a reward distribution from the more distant past, rather than one consistent with their most recently experienced distribution. To explore this phenomenon and compare these models, three free-operant experiments with rats were conducted using a serial reversal design. In Phase 1, two responses (A and B) were baited with pellets on concurrent variable interval schedules, favoring option A. In Phase 2, lever baiting was reversed to favor option B. Rats then entered a delay period, where they were maintained at weight in their home cages and no experimental sessions took place. Following this delay, preference was assessed using initial responding in test sessions where levers were presented, but not baited. Models were compared in performance, including an exponentially weighted moving average, the Temporal Weighting Rule, and variants of these models. While the data provided strong evidence of spontaneous recovery of choice, the form and extent of recovery was inconsistent with the models under investigation. Potential interpretations are discussed in relation to both the decision rule and valuation functions employed.

Role of the medial agranular cortex in unilateral spatial neglect.

Unilateral spatial neglect (USN) results from impaired attentional networks and can affect various sensory modalities, such as visual and somatosensory. The rodent medial agranular cortex (AGm), located in the medial part of the forebrain from rostral to caudal direction, is considered a region associated with spatial attention. The AGm selectively receives multisensory input with the rostral AGm receiving somatosensory input and caudal part receiving visual input. Our previous study showed slower recovery from neglect with anterior AGm lesion using the somatosensory neglect assessment. Conversely, the functional differences in spatial attention across the entire AGm locations (anterior, intermediate, and posterior parts) are unknown. Here, we investigated the relationship between the severity of neglect and various locations across the entire AGm in a mouse stroke model using a newly developed program-based analysis method that does not require human intervention. Among various positions of the lesions, the recovery from USN during recovery periods (postoperative day; POD 10-18) tended to be slower in cases with more rostral lesions in the AGm (r = - 0.302; p = 0.028). Moreover, the total number of arm entries and maximum moving speed did not significantly differ between before and after AGm infarction. According to these results, the anterior lesions may slowly recover from USN-like behavior, and there may be a weak association between the AGm infarct site and recovery rate. In addition, all unilateral focal infarctions in the AGm induced USN-like behavior without motor deficits.

Ca2+ -dependent activator protein for secretion 1 promotes spontaneous recovery in ischemic stroke by regulating BDNF secretion.

Ischemic stroke triggers a cascade of events that facilitates neural protection and spontaneous recovery, which accounts for a major part of functional recovery. Despite the cellular and molecular facilitations on neural protection, the molecular mechanisms of spontaneous recovery have not been fully understood. Ca2+ -dependent activator protein for secretion 1 (CAPS1), a member of CAPS family, plays a major role in synaptic transmission and synaptic effectiveness by regulating vesicle exocytosis. Here, the molecular mechanism of CAPS1 in spontaneous recovery after ischemic stroke was studied. In this study, transient left middle cerebral artery occlusion (MCAO) was used as the ischemic stroke model. The whole brain magnetic resonance imaging (MRI) and neurological score analysis showed decreased infarct volume and neurological scores at 7 days as compared with 1 day after MCAO, suggesting the spontaneous recovery. Elisa and Western blot analysis showed elevated BDNF and CAPS1 expression levels in bilateral hippocampus at both 1 day and 3 days after MCAO. Then, inhibition of CAPS1 by adeno-associated virus (AAV) microinjection in the hippocampus attenuated the spontaneous recovery of both motor and memory impairment induced by MCAO. In addition, elevated p-TrkB levels were detected after MCAO, which were reduced by CAPS1-AAV microinjection, indicating that CAPS1 could induce BDNF secretion after ischemic stroke. Moreover, we found elevated combination of CAPS1 with dense core vesicles (DCV) in the hippocampus at both 1 day and 3 days after MCAO, which could also be inhibited by CAPS1-AAV microinjection, indicating the potential mechanism of CAPS1 in regulating BDNF release after MCAO. Finally, we found that CAPS1/BDNF signaling could influence the neurogenesis in the hippocampus after MCAO. In conclusion, CAPS1 regulates neurogenesis by up-regulating BDNF release in the hippocampus, which finally facilitate spontaneous recovery after ischemic stroke.

Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles.

Spontaneous recovery after a stroke accounts for a significant part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used magnetic resonance imaging and confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance during 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.

A comparison of renewal, spontaneous recovery, and reacquisition after punishment and extinction.

Punishment and extinction are both effective methods of reducing instrumental responding and may involve similar learning mechanisms. To characterize the similarities and differences between them, we examined three well-established recovery or "relapse" effects -renewal, spontaneous recovery, and reacquisition - following either punishment or extinction of an instrumental response. In Experiment 1a, both punished and extinguished responses renewed to similar degrees following a context change at test (ABA renewal). In Experiment 1b, responding spontaneously recovered to similar degrees following punishment or extinction. In Experiment 2, responding was rapidly reacquired when the response was reinforced again following extinction but not following punishment, as predicted by the idea that the reinforcer delivered in reacquisition is part of the context of punishment, but not extinction. The results collectively suggest that both punishment and extinction produce similar context-dependent retroactive interference effects. More broadly, they also suggest that punished and extinguished responses may be equally likely to return following a change of context despite the intuition that punishment might provide a more extreme and effective means of suppressing behavior. To our knowledge, this is the first direct behavioral comparison of response recovery after punishment and extinction within individual experiments.

Spontaneous recovery rate of idiopathic sudden sensorineural hearing loss: A systematic review and meta-analysis.

PURPOSE: Steroids comprise the mainstay of treatment for idiopathic sudden sensorineural hearing loss (ISSNHL). Since steroidal treatment was integrated to clinical practice guidelines, newly published no-treatment or placebo arms in clinical trials are scarce. To evaluate the effectiveness of steroidal treatment ± hyperbaric oxygen therapy, the data should be compared to spontaneous recovery. The aim of this paper is to find the most accurate spontaneous recovery rate, in the light of which, other treatment modalities should be judged. MATERIALS AND METHODS: Eligible studies published until July 2021 were identified through systematic searches of 'PubMed', 'Web of Science' and 'Google Scholar'. Retrospective studies and randomised/non-randomised control trials involving only adult participants (≥18 years) with ISSNHL, and placebo/no treatment were included. Only articles that used the American Academy of Otolaryngology-Head and Neck Surgery's diagnostic criteria for ISSNHL were included. RESULTS: 942 records initially identified, 166 duplicates and 753 articles were excluded based on article subject, title, and abstract. The full texts of 13 articles were reviewed. Seven studies were included for qualitative synthesis, five papers included in quantitative synthesis. 180 ears were included in pooled statistics. The pooled spontaneous recovery was 60.28% (95% confidence interval [CI] = 38.88%-79.94%) with a heterogeneity of 86.0% (95% CI = 69.4%-93.6%). CONCLUSIONS: Spontaneous recovery of ISSNHL should not be over-looked, as it may be close to 60%. This may have both clinical and research implications.

Repair-related molecular changes during recovery phase of ischemic stroke in female rats.

BACKGROUND: Some degree of spontaneous recovery is usually observed after stroke. Experimental studies have provided information about molecular mechanisms underlying this recovery. However, the majority of pre-clinical stroke studies are performed in male rodents, and females are not well studied. This is a clear discrepancy when considering the clinical situation. Thus, it is important to include females in the evaluation of recovery mechanisms for future therapeutic strategies. This study aimed to evaluate spontaneous recovery and molecular mechanisms involved in the recovery phase two weeks after stroke in female rats. METHODS: Transient middle cerebral artery occlusion was induced in female Wistar rats using a filament model. Neurological functions were assessed up to day 14 after stroke. Protein expression of interleukin 10 (IL-10), transforming growth factor (TGF)-ß, neuronal specific nuclei protein (NeuN), nestin, tyrosine-protein kinase receptor Tie-2, extracellular signal-regulated kinase (ERK) 1/2, and Akt were evaluated in the peri-infarct and ischemic core compared to contralateral side of the brain at day 14 by western blot. Expression of TGF-ß in middle cerebral arteries was evaluated by immunohistochemistry. RESULTS: Spontaneous recovery after stroke was observed from day 2 to day 14 and was accompanied by a significantly higher expression of nestin, p-Akt, p-ERK1/2 and TGF-ß in ischemic regions compared to contralateral side at day 14. In addition, a significantly higher expression of TGF-ß was observed in occluded versus non-occluded middle cerebral arteries. The expression of Tie-2 and IL-10 did not differ between the ischemic and contralateral sides. CONCLUSION: Spontaneous recovery after ischemic stroke in female rats was coincided by a difference observed in the expression of molecular markers. The alteration of these markers might be of importance to address future therapeutic strategies.

Testing the memory reconsolidation hypothesis in a fear extinction paradigm: The effects of ecological and arbitrary stimuli.

Various studies demonstrated that extinction training taking place shortly after the activation of the acquired fear could weaken the conditioned fear. The procedure is called post-retrieval extinction (PRE). However, from the time it emerged, it has suffered from inconsistencies in the ability of researchers to replicate the seemingly established effects. Extant literature implies that conditioned fear might be differentially sensitive to the nature of conditioned stimuli (CS) used. The aim of the present study, therefore, is threefold. First, we aimed to replicate Schiller et al. (Nature, 463, 49-53. 2010) procedure in which the PRE had produced positive results with arbitrary CSs only. Also, we examined the PRE as a function of CS type (ecological-fear-relevant (images of spider and snake) vs. arbitrary (images of yellow and blue circles)). Finally, we aimed to investigate the long-term effects of the PRE (i.e., 24 h, 15 d, and 3 mo). The study consisted of acquisition, re-activation and extinction, and re-extinction phases. Dependent measure was the recovery of fear responses as indexed by the skin conductance responses (SCRs) and arousal ratings of the participants at the last trial of the extinction and the first trial of the re-extinction. All groups showed significant acquisition and extinction patterns, compared to the other two groups (i.e., 6 h after the activating CS and without an activating stimulus) only the group that undertook extinction trials 10 min after the activating CS showed a sustained extinction. Thus, our findings provided further evidence for the robustness of the PRE paradigm in preventing the recovery of extinguished fears behaviorally, both with ecological and arbitrary stimuli.

Habituation as an underlying mechanism for Sensory Specific Satiety: An assessment using flavor consumption and preference in rats.

Sensory specific satiety refers to a decline in the hedonic value of the sensory properties of a particular food as it is consumed. This phenomenon is characterized by a decrement in responding as a consequence of repeated exposure, is stimulus specific, and recovers after time. All these characteristics are shared with the habituation phenomenon and for this reason, habituation has been proposed as the underlying mechanism that explains this eating regulatory system. However, several studies conducted with human models have yielded mixed results. Using rats as experimental subjects, the present study tested the following three characteristics of habituation within a Sensory Specific Satiety (SSS) framework: spontaneous recovery, dishabituation and the distractor effect. Experiment 1 demonstrated the basic effect of SSS and its spontaneous recovery over time. In Experiment 2 we found that the presentation of a dishabituator after a pre-feeding procedure had no impact on the SSS effect. Finally, in Experiment 3 the presence of a distractor during a pre-feeding procedure did not alter the expression of SSS. These results challenge the idea that SSS constitutes a typical case of habituation, at least with the procedure used here.

Cannabidiol Prevents Spontaneous Fear Recovery after Extinction and Ameliorates Stress-Induced Extinction Resistance.

Cannabidiol, the main non-psychotropic constituent of cannabis, has potential as a treatment for anxiety-related disorders since it reduces learned fear expression and enhances fear extinction. The return of fear over time after successful extinction and stress-induced extinction resistance are potential barriers to the treatment of these disorders with extinction-based psychological therapy. In two experiments using rats subjected to auditory fear conditioning, we determined the effects of systemic cannabidiol treatment on (1) delayed extinction and later spontaneous fear recovery, and (2) extinction resistance caused by immediate extinction (the immediate extinction deficit (IED)). In Experiment 1, cannabidiol was given before delayed extinction occurring 24 h after conditioning, with extinction recall and spontaneous fear recovery tested drug-free 1 and 21 days after extinction, respectively. We found that cannabidiol had no effect on extinction recall but it prevented spontaneous fear recovery. In Experiment 2, the IED procedure was first validated, with immediate extinction occurring 30 min after conditioning. We confirmed that immediate extinction impaired extinction recall, compared to delayed extinction. Next, cannabidiol was given before immediate or no extinction, with extinction recall tested drug-free the next day. We found that cannabidiol rescued the IED, which did not involve effects on fear memory consolidation. In summary, cannabidiol prevented spontaneous fear recovery after delayed extinction and ameliorated extinction resistance caused by immediate extinction. Although the pharmacological mechanisms underlying these effects remain to be determined, our results add to evidence indicating that cannabidiol might prove useful as an adjunct for potentiating the psychological treatment of anxiety-related disorders.

Another look at the extinction of conditioned flavor preferences: Amount of training and tests for spontaneous recovery.

A conditioned flavor preference develops when hungry or thirsty rats experience a neutral flavor mixed in solution with a nutrient. In two sets of studies, we previously demonstrated that this learned preference is highly sensitive to flavor nonreinforcement (i.e., exposure to the flavor without the nutrient) either prior to (latent inhibition), during (partial reinforcement), or following (extinction) flavor-nutrient pairings. In each of these studies we employed a nutrient devaluation procedure to assess the integrity of specific flavor-nutrient associations following extinction, but more recently Gonzalez, Morillas, and Hall (Journal of Experimental Psychology: Animal Learning & Cognition, 42, 380-390, 2016) observed that sensitivity to extinction in thirsty rats in this preparation may depend upon use of a post-conditioning nutrient devaluation procedure. To assess the generality of our earlier results, but without including a post-conditioning nutrient devaluation phase, we assessed in three experiments the role of the number of flavor-nutrient pairings given prior to extinction and the possibility of spontaneous recovery following a 3-week delay. We observed that extinction consistently weakened the flavor preference in thirsty rats (in spite of the absence of a nutrient devaluation procedure) and also found no evidence for spontaneous recovery. These results establish that our prior findings that conditioned flavor preferences are weakened by extinction are quite robust in thirsty rats and that these extinction effects may be fairly permanent.

Additive Behavioral Improvement after Combined Cell Therapy and Rehabilitation Despite Long-Term Microglia Presence in Stroke Rats.

Microglia are involved in the post-stroke immunomodulation of brain plasticity, repair, and reorganization. Here, we evaluated whether adipose-tissue-derived mesenchymal stem cells (ADMSCs) and/or rehabilitation improve behavioral recovery by modulating long-term perilesional inflammation and creating a recovery-permissive environment in a rat model of ischemic stroke. METHODS: A two-way mixed lymphocyte reaction was used to assess the immunomodulatory capacity of ADMSCs in vitro. Two or 7 days after permanent middle cerebral artery occlusion (pMCAO), rats were intravenously administered ADMSCs or vehicle and housed in a standard or enriched environment (EE). Behavioral performance was assessed with a cylinder test, then we performed stereological and ImageJ/Fiji quantifications of ionized calcium-binding adaptor molecule 1 (Iba1) cells and blood-brain barrier (BBB) leakage. RESULTS: Human ADMSCs were immunosuppressive in vitro. The cylinder test showed partial spontaneous behavioral recovery of pMCAO rats, which was further improved by combined ADMSCs and housing in EE on days 21 and 42 (p < 0.05). We detected an ischemia-induced increase in numbers, staining intensity, and branch length of Iba1+ microglia/macrophages as well as BBB leakage in the perilesional cortex. However, these were not different among pMCAO groups. CONCLUSION: Combined cell therapy and rehabilitation additively improved behavioral outcome despite long-term perilesional microglia presence in stroke rats.

The CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity after stroke.

BACKGROUND: Spontaneous functional recovery occurs during the acute phase after stroke onset, but this intrinsic recovery remains limited. Therefore, exploring the mechanism underlying spontaneous recovery and identifying potential strategies to promote functional rehabilitation after stroke are very important. The CD200/CD200R signaling pathway plays an important role in neurological recovery by modulating synaptic plasticity during multiple brain disorders. However, the effect and mechanism of action of the CD200/CD200R pathway in spontaneous functional recovery after stroke are unclear. METHODS: In this study, we used a transient middle cerebral artery occlusion (MCAO) model in rats to investigate the function of CD200/CD200R signaling in spontaneous functional recovery after stroke. We performed a battery of behavioral tests (Longa test, adhesive removal test, limb-use asymmetry test, and the modified grip-traction test) to evaluate sensorimotor function after intracerebroventricular (i.c.v.) injection with CD200 fusion protein (CD200Fc) or CD200R blocking antibody (CD200R Ab) post-stroke. Density and morphology of dendritic spines were analyzed by Golgi staining. Microglia activation was evaluated by immunofluorescence staining. Western blot was used to detect the levels of protein and the levels of mRNA were measured by qPCR. RESULTS: Our study demonstrated that sensorimotor function, synaptic proteins, and structures were gradually recovered and CD200R was transiently upregulated in ipsilateral cortex after stroke. Synapse-related proteins and dendritic spines were preserved, accompanied by sensorimotor functional recovery, after stereotaxic CD200Fc injection post-stroke. In addition, CD200Fc restrained microglia activation and pro-inflammatory factor release (such as Il-1, Tnf-α, and Il-6) after MCAO. On the contrary, CD200R Ab aggravated sensory function recovery in adhesive removal test and further promoted microglia activation and pro-inflammatory factor release (such as Il-1) after MCAO. The immune-modulatory effect of CD200/CD200R signaling might be exerted partly by its inhibition of the MAPK pathway. CONCLUSIONS: This study provides evidence that the CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity via inhibition of microglia activation and inflammatory factor release.

Alchemy-Inspired Green Paper for Spontaneous Recovery of Noble Metals.

Recycling of noble metal from waste materials, namely from electronic wastes (e-waste), spent catalyst, and industrial wastewater, is attracting growing attention due to the scarcity, economic importance, and criticality of those noble metals. Traditional techniques reported to date require toxic reagent and strict extraction conditions, which deeply hinders the development of precious metal recovery in complex environments. Here, an approach is proposed that uses flexible metallic transition metal dichalcogenide (TMD) paper, which provides abundant active sites for spontaneous adsorption and reduction of noble metal ions, as an Alchemy-inspired template to recover noble metal in an efficient and green way without the aid of reductant and heating. The metallic TMD (MoS2 , WS2 ) paper is shown to rapidly extract five noble metal ions (Au, Pd, Pt, Ag, and Ru) from complex samples containing various interferents. This unique property endows the metallic TMD paper with gifted ability in extracting gold from e-waste, and recovering platinum group metals (palladium and platinum) from spent catalysts, which provides a blueprint for the design of next-generation green platforms for noble metal regeneration.

Should We Care About Early Post-Stroke Rehabilitation? Not Yet, but Soon.

PURPOSE OF REVIEW: Studies in humans and animal models show that most recovery from impairment occurs in the first 1-3 months after stroke as a result of both spontaneous recovery as well as increased responsiveness to enriched environments and training. Improvement from impairment is attributable to a short-lived "sensitive period" of post-stroke plasticity defined by unique genetic, physiological, and structural events. Unfortunately, rehabilitative interventions in humans have not been able to exploit this sensitive period similar to that seen in animal models. Here, we review these data and suggest a path forward. RECENT FINDINGS: Pre-clinical data reveal underlying mechanisms that define the post-stroke sensitive period. These data are then discussed in the context of the spontaneous post-stroke recovery described in humans. Future work will need to capitalize on unique interactions between the sensitive period, spontaneous recovery, and novel types of rehabilitative interventions.

The incidence and recovery rate of idiopathic vocal fold paralysis: a population-based study.

PURPOSE: To determine the incidence and spontaneous recovery rate of idiopathic vocal fold paralysis (IVFP) and paresis (IVFp), and the impact of steroid treatment on rates of recovery. METHODS: This retrospective cohort study included all patients with IVFP or IVFp within a large integrated health-care system between January 1, 2008 and December 31, 2014. Patient demographics and clinical characteristics, including time to diagnosis, spontaneous recovery status, time to recovery, and treatment, were examined. RESULTS: A total of 264 patients were identified, 183 (69.3%) with IVFP and 81 (30.7%) with IVFp. Nearly all cases (96.6%) were unilateral and 89.8% of patients were over the age of 45. The combined (IVFP and IVFp) 7-year mean incidence was 1.04 cases per 100,000 persons each year with the highest 7-year mean annual incidence in white patients (1.60 per 100,000). The total rate of spontaneous recovery was 29.5%, where 21.2% had endoscopic evidence of resolution and 8.3% had clinical improvement in their voice without endoscopic confirmation. The median time to symptom resolution was 4.0 months. Use of steroids was not linked with spontaneous recovery in multivariable analyses. CONCLUSION: The annual incidence of VFP (IVFP and IVFp) was 1.04 cases per 100,000 persons, with spontaneous recovery occurring in nearly a third of patients, regardless of steroid use.

Spontaneous recovery of fear differs among early - late adolescent and adult male mice.

Adolescence is a vulnerable period for developing anxiety-related mental disorders such as post-traumatic stress disorder (PTSD), which requires a long-term course of therapy when a traumatic event has been experienced during childhood. However, the biological mechanism underlying these age-dependent characteristics remains unclear. In the present study, we used early adolescent, late adolescent and adult (4-, 8-, and 15-week old) male mice to examine age differences in fear memory, fear extinction, and spontaneous recovery of fear. We also measured the activation of extracellular signal-regulated kinase (ERK) 2 in the dorsal hippocampus (dHip) and the basolateral amygdala (BLA) following a spontaneous recovery test. Our major findings were as follows: (1) early adolescent and adult mice did not recover the fear response; only late adolescent mice recovered the fear response. (2) The ERK2 in the dHip was more activated after the spontaneous recovery test in late adolescent mice than in adult mice, and the ERK2 in the BLA was more activated after the spontaneous recovery test in adult mice than in late adolescent mice. These results suggest that there exists a unique period in which spontaneous recovery occurs and that these late adolescent behavioral signatures may be related to alteration in the ERK2 phosphorylation in the dHip and BLA.

Discrimination between safe and unsafe stimuli mediates the relationship between trait anxiety and return of fear.

Individuals with anxiety disorders show deficits in the discrimination between a cue that predicts an aversive outcome and a safe stimulus that predicts the absence of that outcome. This impairment has been linked to increased spontaneous recovery of fear following extinction, however it is unknown if there is a link between discrimination and return of fear in a novel context (i.e. context renewal). It is also unknown if impaired discrimination mediates the relationship between trait anxiety and either spontaneous recovery or context renewal. The present study used a differential fear conditioning paradigm to examine the relationships between trait anxiety, discrimination learning, spontaneous recovery and context renewal in healthy volunteers. Fear learning was assessed using continuous ratings of US expectancy and subjective ratings of fear. Discrimination mediated the relationships between trait anxiety and both spontaneous recovery and context renewal such that elevated trait anxiety was associated with poorer discrimination, which in turn was associated with increased fear at test phases. Results are discussed in terms of the genesis and maintenance of anxiety disorders.

Extinction of relapsed fear does not require the basolateral amygdala.

It is well established that extinguished fears are restored with the passage of time or a change in physical context. These fear restoration phenomena are believed to mimic the conditions under which relapse occurs in patients that have been treated for anxiety disorders by means of cue-exposure therapy. Here, we used a rodent model to extinguish relapsed fear and assess whether this new extinction prevents further relapse. We found that activity in the basolateral amygdala (BLA) is required to initially extinguish conditioned fear, but this activity was not necessary to subsequently extinguish relapsed fear. That is, extinction of spontaneously recovered or renewed fear was spared by BLA inactivation. Yet, this BLA-independent learning of extinction did not protect against further relapse: extinction of relapsed fear conducted without BLA activity was still likely to return after the passage of time or a shift in physical context. These findings have important clinical implications. They indicate that pharmacological agents with anxiolytic properties may disrupt initial cue-exposure therapy but may be useful when therapy is again needed due to relapse. However, they also suggest that these agents will not protect against further relapse, implying the need for developing drugs that target other brain regions involved in fear inhibition.