Skeletal Muscle Heat Shock Protein Content and the Repeated Bout Effect.

The "Repeated Bout Effect" (RBE) occurs when a skeletal muscle is preconditioned with a few lengthening contractions (LC) prior to exposing the muscle to a greater number of LC. The preconditioning (PC) results in significantly less damage and preservation of force. Since it takes only a few LC to increase muscle heat shock protein (HSP) content, it was of interest to examine the relationship between HSPs and the RBE. To do this, one tibialis anterior (TA) muscle from Sprague-Dawley rats (n = 5/group) was preconditioned with either 0, 5, or 15 lengthening contractions (LC) and exposed to a treatment of 60 LC 48 h later. Preconditioning TA muscles with 15 LC, but not 5 LC, significantly elevated muscle αB-crystallin (p < 0.05), HSP25 (p < 0.05), and HSP72 content (p < 0.001). These preconditioned TA muscles also showed a significantly (p < 0.05) reduced loss of active torque throughout the subsequent 60 LC. While there was a trend for all preconditioned muscles to maintain higher peak torque levels throughout the 60 LC, no significant differences were detected between the groups. Morphologically, preconditioned muscles appeared to show less discernible muscle fiber damage. In conclusion, an elevated skeletal muscle HSP content from preconditioning may contribute to the RBE.

No impairment of contextual fear memory consolidation by oxytocin receptor antagonism in male rats.

Oxytocin is a peptide released into brain regions associated with the processing of aversive memory and threat responses. Given the expression of oxytocin receptors across this vigilance surveillance system of the brain, we investigated whether pharmacological antagonism of the receptor would impact contextual aversive conditioning and memory. Adult male rats were conditioned to form an aversive contextual memory. The effects of peripheral administration of either the competitive antagonist Atosiban or noncompetitive antagonist L-368,899 were compared to saline controls. Oxytocin receptor antagonism treatment did not significantly impact the consolidation of aversive contextual memory in any of the groups. We conclude that peripheral antagonism of oxytocin signalling did not impact the formation of aversive memory.

Intermittent hypoxia preconditioning can attenuate acute hypoxic injury after a sustained normobaric hypoxic exposure: A randomized clinical trial.

BACKGROUND: Intermittent hypoxia (IH) is emerging as a cost-effective nonpharmacological method for vital organ protection. We aimed to assess the effects of a short-term moderate intermittent hypoxia preconditioning protocol (four cycles of 13% hypoxia lasting for 10 min with 5-min normoxia intervals) on acute hypoxic injury induced by sustained hypoxic exposure (oxygen concentration of 11.8% for 6 h). METHODS: One hundred healthy volunteers were recruited and randomized to the IH group and the control group to receive IH or sham-IH preconditioning for 5 days, respectively, and then were sent to a hypoxic chamber for simulated acute high-altitude exposure (4500 m). RESULTS: The overall incidence of acute mountain sickness was 27% (27/100), with 14% (7/50) in the IH group and 40% (20/50) in the control group (p = 0.003). After 6-h simulated high-altitude exposure, the mean Lake Louise Score was lower in the IH group as compared to controls (1.30 ± 1.27 vs. 2.04 ± 1.89, p = 0.024). Mean peripheral oxygen saturations (SpO2 ) and intracranial pressure (ICP) measures after acute hypoxic exposure exhibited significant differences, with the IH group showing significantly greater SpO2 values (85.47 ± 5.14 vs. 83.10 ± 5.15%, p = 0.026) and lower ICP levels than the control group (115.59 ± 32.15 vs. 130.36 ± 33.83 mmH2 O, p = 0.028). IH preconditioning also showed greater effects on serum protein gene product 9.5 (3.89 vs. 29.16 pg/mL; p = 0.048) and C-reactive protein (-0.28 vs. 0.41 mg/L; p = 0.023). CONCLUSION: The short-term moderate IH improved the tolerance to hypoxia and exerted protection against acute hypoxic injury induced by exposure to sustained normobaric hypoxia, which provided a novel method and randomized controlled trial evidence to develop treatments for hypoxia-related disease.

Social buffering in rats reduces fear by oxytocin triggering sustained changes in central amygdala neuronal activity.

The presence of a companion can reduce fear, but the neural mechanisms underlying this social buffering of fear are incompletely known. We studied social buffering of fear in male and female, and its encoding in the amygdala of male, auditory fear-conditioned rats. Pharmacological, opto,- and/or chemogenetic interventions showed that oxytocin signaling from hypothalamus-to-central amygdala projections underlied fear reduction acutely with a companion and social buffering retention 24 h later without a companion. Single-unit recordings with optetrodes in the central amygdala revealed fear-encoding neurons (showing increased conditioned stimulus-responses after fear conditioning) inhibited by social buffering and blue light-stimulated oxytocinergic hypothalamic projections. Other central amygdala neurons showed baseline activity enhanced by blue light and companion exposure, with increased conditioned stimulus responses that persisted without the companion. Social buffering of fear thus switches the conditioned stimulus from encoding "fear" to "safety" by oxytocin-mediated recruitment of a distinct group of central amygdala "buffer neurons".

Unlocking protein-based biomarker potential for graft-versus-host disease following allogenic hematopoietic stem cell transplants.

Despite the numerous advantages of allogeneic hematopoietic stem cell transplants (allo-HSCT), there exists a notable association with risks, particularly during the preconditioning period and predominantly post-intervention, exemplified by the occurrence of graft-versus-host disease (GVHD). Risk stratification prior to symptom manifestation, along with precise diagnosis and prognosis, relies heavily on clinical features. A critical imperative is the development of tools capable of early identification and effective management of patients undergoing allo-HSCT. A promising avenue in this pursuit is the utilization of proteomics-based biomarkers obtained from non-invasive biospecimens. This review comprehensively outlines the application of proteomics and proteomics-based biomarkers in GVHD patients. It delves into both single protein markers and protein panels, offering insights into their relevance in acute and chronic GVHD. Furthermore, the review provides a detailed examination of the site-specific involvement of GVHD. In summary, this article explores the potential of proteomics as a tool for timely and accurate intervention in the context of GVHD following allo-HSCT.

A search for effective reinforcers in appetitive conditioning for adult zebrafish: Ecologically relevant unconditioned stimuli.

Learning and memory related brain disorders represent a large unmet medical need. Laboratory studies with animals may model brain disorders and facilitate uncovering their mechanisms. The zebrafish has been proposed for such studies. However, numerous factors that influence performance in learning tasks have yet to be understood in zebrafish. One such factor is what motivates zebrafish. Here we introduce a novel reinforcer, an ecologically relevant unconditioned stimulus (US). We placed a photograph of gravel underneath quarter of the bottom of an experimental tank on one side and also positioned artificial plants there, the "natural" US. First, we showed that this stimulus was preferred by zebrafish. Next, we investigated whether this stimulus could serve as US for associative learning. We marked the walls of the tank on the side where the US was presented with red paper, the conditioned stimulus (CS+) we found neutral before, and we also marked the walls on the other side of the tank where no US was placed with blue paper (CS-). In addition to fish receiving this "paired" training, we also ran unpaired training with another group of zebrafish, in which the fish saw the US associated with blue and red in a random manner. After having trained the fish in this manner, we tested the performance of the paired and unpaired group of zebrafish in a memory probe trial during which no US was present, and only the CSs (blue and red walls) were shown. We found the paired group of zebrafish to show significant preference for the CS+, as they spent more time and swam closer to the red side compared to the unpaired group and compared to chance. We conclude that ecologically relevant stimuli can serve as efficient US in appetitive conditioning of zebrafish.

Aversive conditioning increases short-term wariness but does not change habitat use in black bears associated with conflict.

Conflict between humans and black bears (Ursus americanus) occurs throughout North America with increasing public demand to replace lethal management with non-lethal methods, such as aversive conditioning (AC). AC aims to teach animals to associate negative stimuli with humans or their infrastructure. We sought to test the efficacy of AC using radio-collared black bears in Whistler, British Columbia, by monitoring individuals and assigning those in conflict with people to control or treatment groups. We measured wariness using overt reaction distance, displacement distance, and reaction to researchers before, during and after executing 3-5-day AC programs that consisted of launching projectiles at bears in the treatment group. We also assessed predictors of successful AC events (i.e., leaving at a run), changes in bear use of human-dominated habitat during the day and at night, and the effects of including a sound stimulus to signal the beginning and end of AC events. Among treated bears, overt reaction distance increased by 46.5% and displacement distance increased by 69.0% following AC programs, whereas both overt reaction distance and displacement distance decreased over time among control group bears. Each additional AC event during the previous 30 days increased likelihood of bear departure in response to researcher presence by 4.5%. The success of AC events varied among individuals, declined with distance to cover, and increased with exposure to previous AC events. Projectiles launched from guns were slightly more effective at causing bears to displace compared to those launched from slingshots, and sound stimuli decreased the likelihood of a successful AC event. AC did not alter diurnal use by bears of human-dominated habitat. Our results suggest that AC effectively increases short-term wariness in black bears but does not alter bear use of human-dominated spaces, highlighting the importance of proactive attractant management and prevention of food conditioning.

Aversive conditioning is impaired in impulsive individuals: A study on learning asymmetries.

BACKGROUND AND OBJECTIVES: Appetitive and aversive conditioning are thought to be involved in the development and maintenance of mental disorders including anxiety, mood, eating, and substance use disorders. However, few studies measure the relative strength of appetitive and aversive associations, and their relevance to the risk of mental disorders. This study aims to address this gap. METHODS: We tested how readily healthy volunteers acquire appetitive vs. aversive associations. 150 participants associated complex 3D objects with either gain or loss and made decisions to gain or avoid losing points. We investigated the relationship of a learning asymmetry with neuroticism, impulsivity, and anhedonia, to test the hypothesis that a stronger learning asymmetry corresponds to more extreme scores on these traits. RESULTS: Impulsivity was positively associated with the learning asymmetry (R2 = .10). This resulted from an inverse relation with the strength of aversive associations, indicating that impulsive individuals are worse at aversive learning. However, appetitive associations did not differ significantly. No correlations with neuroticism or anhedonia were found. LIMITATIONS: Conditioning studies typically use primary reinforcers and a CS-. Lacking these may make these results less comparable to other studies. CONCLUSIONS: We demonstrate that the learning asymmetry can measure individual differences linked to personality traits, and that impulsivity, normally linked with appetitive learning, also influences aversive learning. These results enable additional studies of learning asymmetry in relation to mental disorders, which could include measurements of mental health symptoms to provide further insight into how appetitive and aversive learning interacts with mental disorders.

Explaining dual-action benefits: Inhibitory control and redundancy gains as complementary mechanisms.

Performing two actions at the same time usually results in performance costs. However, recent studies have also reported dual-action benefits: performing only one of two possible actions may necessitate the inhibition of the initially activated, but unwarranted second action, leading to single-action costs. Presumably, two preconditions determine the occurrence and strength of such inhibition-based dual-action benefits: (a) response set reductivity and (b) action prepotency. A nonreductive response set (given when all possible responses have to be kept in working memory) creates inhibitory action control demands in single-, but not in dual-action trials, and the ensuing inhibitory costs are proportional to the level of action prepotency (i.e., an action that is easy to initiate is hard to inhibit). Here, we set out to test this hypothesis by varying representational characteristics in working memory (namely response set reductivity and action prepotency) across four experiments. In Experiments 1 to 3, we compared (a) a randomized mode of trial presentation to (b) intermixed, but predictable fixed sequences of trial types and (c) a completely blocked mode of presentation. As expected, dual-action benefits were strongly present in Experiment 1, significantly reduced in Experiment 2, and absent in Experiment 3. This pattern of results matches our predictions derived from the assumption that differential inhibitory costs in single-action trials are the root cause of dual-action benefits. Crucially, however, the results of Experiment 4 (in which response conditions were only partially blocked) pointed to a secondary source of dual-action benefits that was inseparable from inhibition-based effects in previous experimental designs: semantic redundancy gains. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Two social minds in one brain? error-related negativity provides evidence for parallel processing pathways during social evaluation.

Several authors assume that evaluative conditioning (EC) relies on high-level propositional thinking. In contrast, the dual-process perspective proposes two processing pathways, one associative and the other propositional, contributing to EC. Dual-process theorists argue that attitudinal ambiguity resulting from these two pathways' conflicting evaluations demonstrate the involvement of both automatic and controlled processes in EC. Previously, we suggested that amplitude variations of error-related negativity and error-positivity, two well-researched event-related potentials of performance monitoring, allow for the detection of attitudinal ambiguity at the neural level. The present study utilises self-reported evaluation, categorisation performance, and neural correlates of performance monitoring to explore associative-propositional ambiguity during social attitude formation. Our results show that compared to associative-propositional harmony, attitudinal ambiguity correlates with more neutral subjective evaluations, longer response times, increased error commission, and diminished error-related negativity amplitudes. While our findings align with dual-process models, we aim to offer a propositional interpretation. We discuss dual-process theories in the context of evolutionary psychology, suggesting that associative processes may only represent a small piece of the EC puzzle.

Glia transmit negative valence information during aversive learning in Drosophila.

During Drosophila aversive olfactory conditioning, aversive shock information needs to be transmitted to the mushroom bodies (MBs) to associate with odor information. We report that aversive information is transmitted by ensheathing glia (EG) that surround the MBs. Shock induces vesicular exocytosis of glutamate from EG. Blocking exocytosis impairs aversive learning, whereas activation of EG can replace aversive stimuli during conditioning. Glutamate released from EG binds to N-methyl-d-aspartate receptors in the MBs, but because of Mg2+ block, Ca2+ influx occurs only when flies are simultaneously exposed to an odor. Vesicular exocytosis from EG also induces shock-associated dopamine release, which plays a role in preventing formation of inappropriate associations. These results demonstrate that vesicular glutamate released from EG transmits negative valence information required for associative learning.

Forgotten memory storage and retrieval in Drosophila.

Inaccessibility of stored memory in ensemble cells through the forgetting process causes animals to be unable to respond to natural recalling cues. While accumulating evidence has demonstrated that reactivating memory-stored cells can switch cells from an inaccessible state to an accessible form and lead to recall of previously learned information, the underlying cellular and molecular mechanisms remain elusive. The current study used Drosophila as a model to demonstrate that the memory of one-trial aversive olfactory conditioning, although inaccessible within a few hours after learning, is stored in KCαß and retrievable after mild retraining. One-trial aversive conditioning triggers protein synthesis to form a long-lasting cellular memory trace, approximately 20 days, via creb in KCαß, and a transient cellular memory trace, approximately one day, via orb in MBON-α3. PPL1-α3 negatively regulates forgotten one-trial conditioning memory retrieval. The current study demonstrated that KCαß, PPL1-α3, and MBON-α3 collaboratively regulate the formation of forgotten one-cycle aversive conditioning memory formation and retrieval.

Sex difference in the facilitation of fear learning by prior fear conditioning.

There is now ample evidence that the strength and underlying mechanisms of memory formation can be drastically altered by prior experience. However, the prior work using rodent models on this topic has used only males as subjects, and as a result, we do know whether or not the effects of prior experience on subsequent learning are similar in both sexes. As a first step towards addressing this shortcoming, rats of both sexes were given auditory fear conditioning, or fear conditioning with unsignaled shocks, followed an hour or a day later by a single pairing of light and shock. Fear memory for each experience was assessed by measuring freezing behavior to the auditory cue and fear-potentiated startle to the light. Results showed that males trained with auditory fear conditioning showed facilitated learning to the subsequent visual fear conditioning session when the two training sessions were separated by one hour or one day. Females showed evidence of facilitation in rats given auditory conditioning when they were spaced by an hour but not when they were spaced by one day. Contextual fear conditioning did not support the facilitation of subsequent learning under any conditions. These results indicate that the mechanism by which prior fear conditioning facilitates subsequent learning differs between sexes, and they set the stage for mechanistic studies to understand the neurobiological basis of this sex difference.

Aversive conditioning information transmission in Drosophila.

Animals rapidly acquire surrounding information to perform the appropriate behavior. Although social learning is more efficient and accessible than self-learning for animals, the detailed regulatory mechanism of social learning remains unknown, mainly because of the complicated information transfer between animals, especially for aversive conditioning information transmission. The current study revealed that, during social learning, the neural circuit in observer flies used to process acquired aversive conditioning information from demonstrator flies differs from the circuit used for self-learned classic aversive conditioning. This aversive information transfer is species dependent. Solitary flies cannot learn this information through social learning, suggesting that this ability is not an innate behavior. Neurons used to process and execute avoidance behavior to escape from electrically shocked flies are all in the same brain region, indicating that the fly brain has a common center for integrating external stimuli with internal states to generate flight behavior.

Intermixed safety cues facilitate extinction retention in adult and adolescent mice.

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.

Social buffering reduces fear expression in Wistar rats when tested in pairs, but not when retested alone.

Social buffering is a phenomenon in which the stress response of an individual can be reduced by the presence of another individual. However, little is known about the effect of social buffering on aversive after memory extinction, especially when animals are tested alone afterwards. The aim of this study was to verify the social buffering effect in rats during the extinction session of the contextual fear conditioning model and the fear response when animals are tested alone in the following day. Animals were divided into subjects and associates, with the subjects undergoing the fear conditioning protocol and the associates paired with the subjects during the fear extinction session. Across five different experiments, we tested moderate and high intensity contextual fear conditioning protocols, as well four variations of pairs: (i) two conditioned subjects, (ii) a conditioned subject and a non-conditioned associate, (iii) a conditioned subject and an associate who observed the conditioning of the partner and (iv) two conditioned subjects, with one treated with diazepam. The social buffering effect was found efficient to reduce the fear memory expression during the fear extinction session. In the moderate intensity protocol, the reduction in freezing time occurred only in subjects accompanied by non-conditioned associates and observer associates. In the high intensity protocol, the social buffering effect occurred in subjects accompanied by either conditioned or non-conditioned associates, although the effect was more evident in the presence of non-conditioned subjects. Treatment of the conditioned associates with diazepam did not improve the social buffering effect. Moreover, social buffering effects were not correlated with self-grooming or prosocial behaviors, which indicates that the presence of another animal might decrease freezing by promotion of exploratory activity. Finally, the social buffering effect was not observed in the extinction test, either because the extinction was too effective in the moderate intensity protocol or because the extinction was equally ineffective in the high intensity protocol. Our results suggest that social buffering does not improve fear extinction consolidation.

Mesenchymal Stem Cells for Treating Alzheimer's Disease: Cell Therapy and Chemical Reagent Pretreatment.

As the size of the population aged 65 and older continues to grow, the incidence and mortality rates of Alzheimer's disease (AD) are increasing annually. Unfortunately, current treatments only treat symptoms temporarily and do not alter the patients' life expectancy or course of AD. Mesenchymal stem cells (MSCs) have shown a certain therapeutic potential in neurodegenerative diseases including AD due to their neuroinflammatory regulation and neuroprotective effects. However, the low survival and homing rates of MSCs after transplantation seriously affect their therapeutic effectiveness. Therefore, appropriate in vitro preconditioning is necessary to increase the survival and homing rates of MSCs to improve their effectiveness in treating AD. Here we summarize the therapeutic mechanisms of MSCs in AD and the chemical reagents used for the pretreatment of MSCs.

Acan downregulation in parvalbumin GABAergic cells reduces spontaneous recovery of fear memories.

While persistence of fear memories is essential for survival, a failure to inhibit fear in response to harmless stimuli is a feature of anxiety disorders. Extinction training only temporarily suppresses fear memory recovery in adults, but it is highly effective in juvenile rodents. Maturation of GABAergic circuits, in particular of parvalbumin-positive (PV+) cells, restricts plasticity in the adult brain, thus reducing PV+ cell maturation could promote the suppression of fear memories following extinction training in adults. Epigenetic modifications such as histone acetylation control gene accessibility for transcription and help couple synaptic activity to changes in gene expression. Histone deacetylase 2 (Hdac2), in particular, restrains both structural and functional synaptic plasticity. However, whether and how Hdac2 controls the maturation of postnatal PV+ cells is not well understood. Here, we show that PV+- cell specific Hdac2 deletion limits spontaneous fear memory recovery in adult mice, while enhancing PV+ cell bouton remodeling and reducing perineuronal net aggregation around PV+ cells in prefrontal cortex and basolateral amygdala. Prefrontal cortex PV+ cells lacking Hdac2, show reduced expression of Acan, a critical perineuronal net component, which is rescued by Hdac2 re-expression. Pharmacological inhibition of Hdac2 before extinction training is sufficient to reduce both spontaneous fear memory recovery and Acan expression in wild-type adult mice, while these effects are occluded in PV+-cell specific Hdac2 conditional knockout mice. Finally, a brief knock-down of Acan expression mediated by intravenous siRNA delivery before extinction training but after fear memory acquisition is sufficient to reduce spontaneous fear recovery in wild-type mice. Altogether, these data suggest that controlled manipulation of PV+ cells by targeting Hdac2 activity, or the expression of its downstream effector Acan, promotes the long-term efficacy of extinction training in adults.

Male and female C57BL/6 mice display drug-induced aversion and reward in the combined conditioned taste avoidance/conditioned place preference procedure.

BACKGROUND: Drugs of abuse have rewarding and aversive effects that, in balance, impact abuse potential. Although such effects are generally examined in independent assays (e.g., CPP and CTA, respectively), a number of studies have examined these effects concurrently in rats in a combined CTA/CPP design. The present study assessed if similar effects can be produced in mice which would allow for determining how each is affected by subject and experiential factors relevant to drug use and abuse and the relationship between these affective properties. METHODS: Male and female C57BL/6 mice were exposed to a novel saccharin solution, injected (IP) with saline or 5.6, 10 or 18 mg/kg of the synthetic cathinone, methylone, and placed on one side of the place conditioning apparatus. The following day, they were injected with saline, given access to water and placed on the other side of the apparatus. After four conditioning cycles, saccharin avoidance and place preferences were assessed in a final two-bottle CTA test and a CPP Post-Test, respectively. RESULTS: In the combined CTA/CPP design, mice acquired a significant dose-dependent CTA (p = 0.003) and a significant CPP (p = 0.002). These effects were independent of sex (all ps > 0.05). Further, there was no significant relationship between the degree of taste avoidance and place preference (p > 0.05). CONCLUSIONS: Similar to rats, mice displayed significant CTA and CPP in the combined design. It will be important to extend this design in mice to other drugs and to examine the impact of different subject and experiential factors on these effects to facilitate predictions of abuse liability.