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.

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.

BACKGROUND: Research has established natural recovery (NR) as an important pathway to substance use recovery. Studies investigating correlates of NR have mainly focused on demographic and substance use variables rather than life circumstances. This study seeks to better understand the phenomenon of natural recovery by (i) validating the international scientific literature concerning demographic and substance use indicators of NR in Flanders and (ii) assessing the additional explanatory power of recovery strengths and barriers during active addiction, controlling for demographic and substance use covariates.
METHODS: A total of 343 persons in recovery from alcohol or drug use problems (≥ 3 months) completed an online cross-sectional survey in Flanders. Participants in NR and in recovery after following treatment were compared using multivariate linear regression models. Reasons for not following treatment were analyzed using inductive thematic analysis.
RESULTS: Higher education level, lower severity of dependence, and cannabis use as the main problem substance (vs. alcohol) were statistically significant (p < 0.05) correlates of NR. When scores for the number of barriers and strengths associated with active addiction were added, barriers (but not strengths) were significantly associated with NR. When barrier items were individually tested, having untreated emotional or mental health problems, having a driver\'s license revoked and damaging property were statistically significant correlates. The most reported reason for not entering treatment was not experiencing any need to do so.
CONCLUSIONS: The results highlight the importance of a holistic approach to recovery support across multiple life domains. Limitations and opportunities for further research are discussed.

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.

Previous laboratory work has shown that induction of positive mood prior to fear extinction decreases the negative valence of the conditional stimulus (CS) and reduces reinstatement of fear. Before translating these insights to clinical practice, it is important to test this strategy in anxious individuals. Students with a high fear of public speaking (N = 62) were randomized to either a positive mood induction, a negative mood induction, or no induction control group. All participants performed two weekly sessions of virtual reality exposure and a 1-week follow-up test including a spontaneous recovery test and reinstatement test after a social rejection (unconditional stimulus). We used self-reported fear measures and skin conductance responses. We expected that the positive group, compared to the other groups, would evaluate the CS (i.e., speaking in front of an audience) as less negative following exposure and would show less spontaneous recovery and reinstatement of fear following a social rejection. Although mood was successfully manipulated, there were no group differences in CS valence following exposure. In all conditions, VR exposure successfully reduced public speaking fear, and these effects were stable at follow-up. In contrast with expectations, the positive group showed more spontaneous recovery of CS negative valence than the negative group. To conclude, we found no evidence that positive mood induction prior to exposure optimizes exposure effects for anxious individuals.

OBJECTIVE: Perinatal hypoxic-ischemic encephalopathy (HIE) is a condition that can lead to long-term cognitive, motor, and behavioral impairments in newborns. Although brain hypothermia therapy is currently the standard treatment for HIE, it does not provide complete neuroprotection. As a result, there is a need to explore additional therapies to enhance treatment outcomes. This study aims to investigate the potential role of Ginkgolide B (GB) in promoting neuroplasticity and facilitating spontaneous recovery after HIE.
METHODS: In this study, we employed a neonatal rat model of HIE to investigate the effects of GB on spontaneous recovery. GB treatment was initiated 24 h after hypoxia and administered continuously for a duration of 14 days. We evaluated several outcome measures after the treatment period, including spontaneous behavioral recovery and brain repair. Additionally, we quantified the levels of netrin-1 in both plasma and the peri-ischemic zone after the occurrence of HIE.
RESULTS: We found that GB treatment significantly facilitated spontaneous behavioral recovery in the HIE pups. Furthermore, cognitive function was restored, and brain tissue repair had a noticeable acceleration. We observed increased cell proliferation in the subventricular, stratum, and subgranular zones. Of particular interest, we observed elevated levels of netrin-1 in both plasma and the ischemic penumbra following GB treatment.
CONCLUSIONS: Our findings suggest that GB promotes neuroplasticity and enhances spontaneous recovery in newborns affected by HIE. The observed upregulation of netrin-1 may be crucial in mediating these effects. These results highlight the promising potential of GB as a post-HIE therapy, particularly in enhancing spontaneous recovery and improving long-term outcomes.

Extinction learning is tremendously adaptive as it allows an animal to adjust their behavior in a changing environment. Yet, extinction is not without limitations and fear often reemerges over time (i.e. spontaneous recovery). Relative to adults, adolescent rodents and humans are particularly prone to spontaneous recovery following extinction. In this study, we aimed to address whether combining methods of fear regulation (extinction and conditioned inhibition) can facilitate extinction retention. Early adolescent (29 days old, n = 81) and adult (70 days old, n = 80) mice underwent extinction with or without a safety cue present. Safety cue presentations were systematically varied to overlap with or alternate with fear cue presentations. We found that initial safety learning was faster in adolescent mice. In addition, intermixing safety cues into extinction reduced spontaneous recovery during a test two weeks later. The decrease in spontaneous recovery relative to a standard extinction protocol was greater in adolescents than adults. Together, our findings provide initial evidence that safety learning may be inherently stronger during adolescence. These results inform the parameters by which conditioned safety and extinction learning may be merged to augment the inhibition of fear. While methods to enhance fear regulation are valuable for any age, the potential to do so during adolescence is particularly striking.

Deoxynivalenol (DON) is one of the most prevalent food-associated mycotoxins, and is known to cause a variety of adverse health effects on human and animals. Upon oral exposure, the intestine is the main target organ of DON. The current study unraveled that DON exposure (2 mg/kg bw/day or 5 mg/kg bw/day) can significantly reshape the gut microbiota in a mouse model. The study characterized the specific gut microbial strains and genes changed after DON exposure and also investigated the recovery of the microbiota upon either 2 weeks daily prebiotic inulin administration or 2 weeks recovery without intervention after termination of DON exposure (spontaneous recovery). The results obtained reveal that DON exposure causes a shift in gut microorganisms, increasing the relative abundance of Akkermansia muciniphila, Bacteroides vulgatus, Hungatella hathewayi, and Lachnospiraceae bacterium 28-4, while the relative abundance of Mucispirillum schaedleri, Pseudoflavonifractor sp. An85, Faecalibacterium prausnitzii, Firmicutes bacterium ASF500, Flavonifractor plautii, Oscillibacter sp. 1-3, and uncultured Flavonifractor sp. decreased. Notably, DON exposure enhanced the prevalence of A. muciniphila, a species considered as a potential prebiotic in previous studies. Most of the gut microbiome altered by DON in the low- and high-dose exposure groups recovered after 2 weeks of spontaneous recovery. Inulin administration appeared to promote the recovery of the gut microbiome and functional genes after low-dose DON exposure, but not after high-dose exposure, at which changes were exacerbated by inulin-supplemented recovery. The results obtained help to better understand the effect of DON on the gut microbiome, and the gut microbiota\'s recovery upon termination of DON exposure.

Home cage condition influences the central nervous system of experimental animals. However, little is known about the effect of home cage size and bedding material on fear-related behaviors. Thus, in this study, the effects of home cage size (large or small) and/or bedding material (paper or wood) on acquisition, retrieval, extinction, and spontaneous recovery of contextual fear memory were investigated in both male and female mice. The present study demonstrated that males housed in small cages with wood bedding showed a low fear response during fear extinction when compared to males housed in small or large cages with paper bedding. In females, mice housed in small cages with wood bedding showed low fear response during fear conditioning and extinction when compared to mice housed in large cages with paper bedding. Moreover, small cages with wood bedding, but not small or large cages with paper bedding, prevented the spontaneous recovery of fear memory in females. Thus, home cage conditions, and particularly bedding material, influence contextual fear extinction and spontaneous recovery. This finding may help to obtain reproducibility of results by researchers and explain discrepancies of results among research groups.

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.