Chemogenetic modulation of the medial prefrontal cortex regulates resistance to acute stress-induced cognitive impairments.

The medial prefrontal cortex (mPFC) has been implicated in regulating resistance to the effects of acute uncontrollable stress. We previously showed that mPFC-lesioned animals exhibit impaired object recognition memory after acute exposure to a brief stress that had no effect in normal animals. Here, we used designer receptors exclusively activated by designer drugs to determine how modulating mPFC activity affects recognition-memory performance under stressful conditions. Specifically, animals with chemogenetic excitation or inhibition of the mPFC underwent either a brief ineffective stress (20-min restraint + 20 tail shocks) or a prolonged effective stress (60-min restraint + 60 tail shocks). Subsequent recognition memory tests showed that animals with chemogenetic mPFC inhibition exposed to brief stress showed impairment in an object recognition memory task, whereas those with chemogenetic mPFC excitation exposed to prolonged stress did not. Thus, the present findings the decreased mPFC activity exacerbates acute stress effects on memory function whereas increased mPFC activity counters these stress effects provide evidence that the mPFC bidirectionally modulates stress resistance.

Filtering distractors is costly.

To find a target in visual search, it is often necessary to filter out task-irrelevant distractors. People find the process of distractor filtering effortful, exerting physical effort to reduce the number of distractors that need to be filtered on a given search trial. Working memory demands are sufficiently costly that people are sometimes willing to accept aversive heat stimulation in exchange for the ability to avoid performing a working memory task. The present study examines whether filtering distractors in visual search is similarly costly. The findings reveal that individuals are sometimes willing to accept an electric shock in exchange for the ability to skip a single trial of visual search, increasingly so as the demands of distractor filtering increase. This was true even when acceptance of shock resulted in no overall time savings, although acceptance of shock was overall infrequent and influenced by a plurality of factors, including boredom and curiosity. These findings have implications for our understanding of the mental burden of distractor filtering and why people seek to avoid cognitive effort more broadly.

Effect of Exhaustive Training or Forced Immobilization on Physiological Condition and Main Metabolic and Stress Markers of Wistar Male Rats.

For correct and reliable experimental in vivo assessment of antistress effect of various bioactive substances, appropriate biomodels reproducing stress and organism response to stress in laboratory animals should be chosen. We chose treadmill test for simulating exhaustive physical load and forced immobilization accompanied by disorders of physiological and psychological condition. Verification of the models used indicates their wide applicability for testing certain biological manifestations under reproduced stress exposure.

Uncontrollable chronic stress affects eating behavior in rats.

The issue of whether the decrease in food intake induced by inescapable shock is due to the uncontrollability of the stressor or the shock per se has not yet been settled. Besides, whether food intake is differentially affected by an uncontrollable chronic stressor has been explored only by a few studies. Thus, we evaluated the effects of chronic escapable or inescapable electric shocks on eating behavior. Rats were exposed to shock sessions for 20 days in two occasions separated by baseline sessions with no shock in an ABAB design. Results showed a reduction in food and water intake and body weight gain during stress periods, especially with inescapable shocks. The findings support a close link between learned helplessness, chronic stress, and eating behavior.

Binding of Glyprolines to L-Arginine Inverts Its Analgesic and Antiagressogenic Effects.

We studied the effects of intraperitoneal administration of L-arginine in doses of 5, 15, and 50 µg/kg and peptides in doses containing equimolar amount of this amino acid on aggressive-defensive behavior of rats (footshock model). The peptides were synthesized by binding of Pro-Gly-Pro sequence to one or both ends of the L-arginine molecule. The analgesic and antiagressogenic effects of L-arginine and opposite effects of arginine-containing peptides (except Pro-Gly-Pro tripeptide) were demonstrated. The combination of arginine with glyprolines yielded peptides with intrinsic regulatory properties. This expands the possibilities of synthesis of drugs for correction of pain and aggression caused by pain.

Parameters of hormetic stress and resilience to trauma in rats.

Hormesis is the process by which small stresses build resilience to large stresses. We pre-exposed rats to various parameters of mild-to-moderate stress prior to traumatic stress in the present experiments to assess the potential benefits of hormetic training on resilience to traumatic, uncontrollable stress. Rats underwent varying stress pre-training parameters prior to exposure to uncontrollable traumatic stress in the learned helplessness procedure. The ability to prevent the exaggerated fear responding and escape deficits that normally follow experience with traumatic stress were used as a measure of the benefits of hormetic training. Four experiments examined the effects of number of training sessions, stressor severity and pattern of rest between pre-training stress sessions. Repeated exposure to mild restraint stress or moderate shock stress eliminated both the enhanced fear conditioning and shuttle-escape deficits that result from exposure to traumatic, inescapable shock. The pattern of rest did not contribute to resilience when the pre-exposure stressor was mild, but was vital when the pre-exposure stressor was moderate, with an alternation of stress and rest being the most effective procedure. The data also suggest that the level of resilience may increase with the number of pre-exposure sessions.

Safety signals as instrumental reinforcers during free-operant avoidance.

Safety signals provide "relief" through predicting the absence of an aversive event. At issue is whether these signals also act as instrumental reinforcers. Four experiments were conducted using a free-operant lever-press avoidance paradigm in which each press avoided shock and was followed by the presentation of a 5-sec auditory safety signal. When given a choice between two levers in Experiment 1, both avoiding shock, rats preferentially responded on the lever that produced the safety signal as feedback, even when footshock was omitted. Following avoidance training with a single lever in Experiment 2, removal of the signal led to a decrease in avoidance responses and an increase in responses during the safety period normally denoted by the signal. These behavioral changes demonstrate the dual conditioned reinforcing and fear inhibiting properties of the safety signal. The associative processes that support the reinforcing properties of a safety signal were tested using a novel revaluation procedure. Prior experience of systemic morphine during safety signal presentations resulted in an increased rate of avoidance responses to produce the safety signal during a drug-free extinction test, a finding not seen with d-amphetamine in Experiment 3. Morphine revaluation of the safety signal was repeated in Experiment 4 followed by a drug-free extinction test in which responses did not produce the signal for the first 10 min of the session. Instrumental avoidance in the absence of the signal was shown to be insensitive to prior signal revaluation, suggesting that the signal reinforces free-operant avoidance behavior through a habit-like mechanism.

Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism.

OBJECTIVE: Intestinal permeability and psychological stress have been implicated in the pathophysiology of IBD and IBS. Studies in animals suggest that stress increases permeability via corticotropin-releasing hormone (CRH)-mediated mast cell activation. Our aim was to investigate the effect of stress on intestinal permeability in humans and its underlying mechanisms. DESIGN: Small intestinal permeability was quantified by a 2 h lactulose-mannitol urinary excretion test. In a first study, 23 healthy volunteers were subjected to four different conditions: control; indomethacin; public speech and anticipation of electroshocks. In a second study, five test conditions were investigated in 13 volunteers: control; after pretreatment with disodium cromoglycate (DSCG); administration of CRH; DSCG+CRH and DSCG+public speech. RESULTS: Indomethacin, as a positive comparator (0.071±0.040 vs 0.030±0.022; p<0.0001), and public speech (0.059±0.040; p<0.01), but not the shock protocol increased intestinal permeability. Similarly, salivary cortisol was only increased after public speech. Subgroup analysis demonstrated that the effect of public speech on permeability was only present in subjects with a significant elevation of cortisol. CRH increased the lactulose-mannitol ratio (0.042±0.021 vs 0.028±0.009; p=0.02), which was inhibited by the mast cell stabiliser DSCG. Finally, intestinal permeability was unaltered by public speech with DSCG pretreatment. CONCLUSIONS: Acute psychological stress increases small intestinal permeability in humans. Peripheral CRH reproduces the effect of stress and DSCG blocks the effect of both stress and CRH, suggesting the involvement of mast cells. These findings provide new insight into the complex interplay between the central nervous system and GI function in man.

The neurocognitive effects of simulated use-of-force scenarios.

While the physiologic effects of modern conducted electrical weapons (CEW) have been the subject of numerous studies, their effects on neurocognitive functioning, both short-term and long-term, are less well understood. It is also unclear how these effects compare to other use-of-force options or other arrest-related stressors. We compared the neurocognitive effects of an exposure to a TASER(®) (TASER International, Inc, Scottsdale, AZ) X26™ CEW to four other use-of-force scenarios during a training exercise using a well-established neurocognitive metric administered repeatedly over 1 h. Overall, we found that there was a decline in neurocognitive performance immediately post-scenario in all groups, but this effect was transient, of questionable clinical significance, and returned to baseline by 1 h post-scenario.

Role of amygdala central nucleus in aversive learning produced by shock or by unexpected omission of food.

Many psychological learning theories have noted commonalities between aversive states produced by presentation of negative reinforcers, such as electric shock, and the omission of expected positive reinforcers, such as food. Here, three groups of rats received training with one auditory cue paired with shock and another with the omission of expected food, a shock-paired cue and a food-omission control cue, or a food-omission cue and a shock control cue. Food-omission cues were established by contrast with food delivery; after extensive light-food pairings, the light was followed by the food-omission cue instead of food. Aversiveness of the food-omission cue was assessed with a conditioned punishment procedure, in which presentation of that cue was made contingent on performance of one previously trained instrumental response, whereas a second response had no consequences. We found that rats with lesions of amygdala central nucleus (CeA) showed impaired acquisition of freezing to the cue paired with shock and no evidence for acquisition of aversive properties by the cue that accompanied the omission of expected food. Furthermore, analyses of Arc and Homer1a mRNAs after rats were exposed to a two-epoch test procedure that allowed assessment of gene expression produced by two different test stimuli showed that both food-omission and shock-paired cues generated more neuronal activity in CeA than appropriate control cues. However, the number of neurons that were activated by both shock and food-omission cues was not significantly greater than expected by chance. Thus, under these test conditions, different subsets of CeA neurons represented these two aversive states.

Phantom shocks in patients with implantable cardioverter defibrillator: results from a randomized rehabilitation trial (COPE-ICD).

AIMS: The aim of this trial was to assess a combined rehabilitation intervention including an exercise training component and a psycho-educational component in patients treated with implantable cardioverter defibrillator (ICD). The hypothesis was that the intervention would reduce the occurrence of phantom shocks. METHODS AND RESULTS: The design was secondary explorative analyses of data from a randomized controlled trial. One hundred and ninety-six patients with first-time ICD implantation (79% male, mean age 58 years) were randomized (1 : 1) to either combined rehabilitation or a control group receiving 'treatment as usual'. A total of 144 participants completed the 12-month follow-up. Intervention consisted of 12 weeks of exercise training and 1 year of psycho-educational follow-up focusing on modifiable factors associated with poor outcomes, e.g. phantom shocks. Outcome measures were ancillary questions regarding the experience of phantom shocks, date, time, and place. Twelve patients (9.4%) experienced a phantom shock, 7 in the intervention group and 5 in the control group (NS). Neither age, sex, quality of life nor perceived health at baseline was significantly related to the probability of occurrence of phantom shock. CONCLUSION: Phantom shocks were experienced by about one in ten ICD patients, with no interventional effect found and no significant difference found regarding receiving an actual shock therapy among phantom shock patients. : TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT00569478).

Differential effects of psychopathy and antisocial personality disorder symptoms on cognitive and fear processing in female offenders.

Psychopathy and antisocial personality disorder (APD) have long been considered important risk factors for criminal behavior and incarceration. However, little is known about the psychobiological underpinnings that give rise to the disinhibited behavior of female offenders. Using an instructed fear-conditioning paradigm and a sample of incarcerated female offenders, we manipulated attentional focus and cognitive load to characterize and differentiate between the dysfunctional cognitive and affective processes associated with these syndromes. We used fear-potentiated startle (FPS) and event-related potentials as measures of affective and cognitive processing, respectively. After controlling for APD symptoms, psychopathic women displayed greater FPS while attending directly to threat-relevant stimuli and displayed less FPS while performing a demanding task that directed attention to threat-irrelevant information. Conversely, controlling for psychopathy, women with high APD symptoms displayed less overall FPS, especially when instructed to focus on threat-relevant stimuli. However, as the demands on cognitive resources increased, they displayed greater FPS. For both psychopathy and APD, analysis of the event-related potentials qualified these findings and further specified the abnormal cognitive processes associated with these two syndromes. Overall, simultaneous analysis of psychopathy and APD revealed distinct patterns of cognitive processing and fear reactivity.

Contextual fear conditioning predicts subsequent avoidance behaviour in a virtual reality environment.

Avoidance behaviour is a crucial component of fear and is importantly involved in the maintenance of anxiety disorders. Presumably, fear conditioning leads to avoidance of the feared object or context. A virtual reality contextual fear conditioning paradigm was used to investigate the association between explicit conditioning effects and subsequent avoidance behaviour. Mild electric shocks were administered in one context (anxiety context), but never in a second context (safety context). Subsequent avoidance behaviour was assessed by asking participants to choose two out of three contexts (a neutral context was added) to visit again. Participants avoided the anxiety context, but did not prefer the safety over the neutral context. Participants with substantial conditioning effects, as reflected in differential valence, arousal and anxiety ratings, avoided the anxiety context but not the safety context. In sum, we demonstrated an association between context conditioning effects on an explicit level and later avoidance behaviour.

The effect of induced anxiety on cognition: threat of shock enhances aversive processing in healthy individuals.

Individuals with anxiety disorders demonstrate altered cognitive performance including (1) cognitive biases towards negative stimuli (affective biases) and (2) increased cognitive rigidity (e.g., impaired conflict adaptation) on affective Stroop tasks. Threat of electric shock is frequently used to induce anxiety in healthy individuals, but the extent to which this manipulation mimics the cognitive impairment seen in anxiety disorders is unclear. In this study, 31 healthy individuals completed an affective Stroop task under safe and threat-of-shock conditions. We showed that threat (1) enhanced aversive processing and abolished a positive affective bias but (2) had no effect on conflict adaptation. Threat of shock thus partially models the effects of anxiety disorders on affective Stroop tasks. We suggest that the affective state of anxiety-which is common to both threat and anxiety disorders-modulates the neural inhibition of subcortical aversive processing, whilst pathologies unique to anxiety disorders modulate conflict adaptation.

Importance of associative learning processes for one-trial behavioral sensitization of preweanling rats.

During adulthood, associative learning is necessary for the expression of one-trial behavioral sensitization; however, it is uncertain whether the same associative processes are operative during the preweanling period. Two strategies were used to assess the importance of associative learning for one-trial behavioral sensitization of preweanling rats. In the initial experiments, we varied both the sequence and time interval between presentation of the conditioned stimulus (CS, novel environment) and unconditioned stimulus (US, cocaine). In the final experiment, we determined whether electroconvulsive shock-induced retrograde amnesia would disrupt one-trial behavioral sensitization. Results showed that robust-sensitized responding was apparent regardless of the sequence in which cocaine and the novel environment (the presumptive CS) were presented. Varying the time between CS and US presentation (0, 3, or 6 h) was also without effect. Results from experiment 3 showed that single or multiple electroconvulsive shock treatments did not alter the expression of the sensitized response. Therefore, these data indicated that one-trial behavioral sensitization of preweanling rats was exclusively mediated by nonassociative mechanisms and that associative processes did not modulate sensitized responding. These findings are in contrast to what is observed during adulthood, as adult rats exhibit one-trial behavioral sensitization only when associative processes are operative.

Functional emergence of the hippocampus in context fear learning in infant rats.

The hippocampus is a part of the limbic system and is important for the formation of associative memories, such as acquiring information about the context (e.g., the place where an experience occurred) during emotional learning (e.g., fear conditioning). Here, we assess whether the hippocampus is responsible for pups' newly emerging context learning. In all experiments, postnatal day (PN) 21 and PN24 rat pups received 10 pairings of odor-0.5 mA shock or control unpaired odor-shock, odor only, or shock only. Some pups were used for context, cue or odor avoidance tests, while the remaining pups were used for c-Fos immunohistochemistry to assess hippocampal activity during acquisition. Our results show that cue and odor avoidance learning were similar at both ages, while contextual fear learning and learning-associated hippocampal (CA1, CA3, and dentate gyrus) activity (c-Fos) only occurred in PN24 paired pups. To assess a causal relationship between the hippocampus and context conditioning, we infused muscimol into the hippocampus, which blocked acquisition of context fear learning in the PN24 pups. Muscimol or vehicle infusions did not affect cue learning or aversion to the odor at PN21 or PN24. The results suggest that the newly emerging contextual learning exhibited by PN24 pups is supported by the hippocampus.

Differential effects of controllable and uncontrollable footshock stress on sleep in mice.

STUDY OBJECTIVES: Inescapable shock (IS), an uncontrollable stressor, and presentation of fearful contexts associated with IS produce prominent reductions in REM sleep. We compared sleep in animals trained with IS to that in animals trained with escapable shock (ES), a controllable stressor, in a paradigm in which animals always received shock but could terminate it by their actions. DESIGN: Male BALB/cJ mice were implanted with telemetry transmitters for recording EEG and activity. After recovery from surgery, baseline sleep recordings were obtained for 2 days. The mice were then randomly assigned to receive ES (n=9) or IS (n=9). ES mice could escape a footshock (20 trials; 0.5 mA; 5.0 sec maximum duration; 1.0 min intervals) by moving to the unoccupied chamber in a shuttlebox. Yoked-control IS mice in a separate shuttlebox received identical footshock. The mice received 2 days of shock training (ST1; ST2) and were re-exposed to the shuttlebox without footshock (context alone). SETTING: NA. PATIENTS OR PARTICIPANTS: NA. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: On each training and test day, the mice were returned to their home cages, and EEG and activity were recorded for 20 h. Freezing was scored in the context alone. Compared to baseline, ES mice showed significantly increased REM, and IS mice showed significantly decreased REM after ST1, ST2, and context alone. Total NREM was decreased after shock training only in IS mice. Contextual freezing was enhanced in both ES and IS mice. CONCLUSIONS: The directionally opposite changes in REM suggest that stressor controllability is an important factor in the effects of stress and stressful memories on sleep.

Pain relativity in motor control.

Motivational theories of pain highlight its role in people's choices of actions that avoid bodily damage. By contrast, little is known regarding how pain influences action implementation. To explore this less-understood area, we conducted a study in which participants had to rapidly point to a target area to win money while avoiding an overlapping penalty area that would cause pain in their contralateral hand. We found that pain intensity and target-penalty proximity repelled participants' movement away from pain and that motor execution was influenced not by absolute pain magnitudes but by relative pain differences. Our results indicate that the magnitude and probability of pain have a precise role in guiding motor control and that representations of pain that guide action are, at least in part, relative rather than absolute. Additionally, our study shows that the implicit monetary valuation of pain, like many explicit valuations (e.g., patients' use of rating scales in medical contexts), is unstable, a finding that has implications for pain treatment in clinical contexts.

Mandibular bone density and calcium content affected by different kind of stress in mice.

OBJECTIVES: Stress is considered to affect many body and mental functions. This leads to activation of the hypothalamic-pituitary-adrenal axis and the adrenomedullary sympathetic system resulting to increased glucocorticoid release. Corticosteroids are known to cause systemic bone loss. The aim of the study was to investigate the role of different kinds of stress on the mandible bone mass of Wistar mice. METHODS: 75 male Wistar mice were divided into three groups (n=25 each). The animals of group C were submitted to stress by electroshock with 22-45 volts for a duration of 4 seconds each minute for one hour each day. Group B was submitted to isolation stress and group A was the control group. The duration of the experiment was 137 days. RESULTS: The adrenals weight was increased (group C vs group A, p<0.001; group B vs group A p<0.05), while urine hydroxyproline was reduced under stress. The calcium content of the mandible and the ratio between calcium content and mandible volume was decreased (p<0.05 for both groups). CONCLUSIONS: Mandibular bone mass was affected by different kinds of stress and may represent a considerable parameter for the diagnosis, prevention and treatment of bone mass deficiency.

Early life sleep disruption is a risk factor for increased ethanol drinking after acute footshock stress in prairie voles.

Early postnatal experiences are important for shaping the development of the stress response and may contribute to the later emergence of alcohol use disorders. We have previously found that early life sleep disruption impairs social development and alters GABA neurons in the brain of adult prairie voles, a socially monogamous rodent that displays natural ethanol preference in the laboratory. However, it is unclear whether these effects on social behavior are due, in part, to overall anhedonia and/or altered behavioral response to stress. To address this question, litters containing prairie vole pups were sleep disrupted by gentle cage agitation for 7 consecutive days from postnatal days (P) 14 to 21 (early life sleep disruption, or ELSD group) or allowed to sleep undisturbed (Control). Adult voles underwent a 2-bottle choice ethanol drinking procedure integrated with a single session of footshocks. Ethanol intake after footshock was measured as well as c-Fos immunoreactivity in the lateral and central amygdala. ELSD animals showed increased ethanol consumption and increased neural activity in these amygdala regions after footshock compared to control animals. There were no differences in baseline ethanol drinking prior to exposure to a stressor. These results suggest that early life sleep disruption in prairie voles does not produce anhedonia but can have long-lasting effects on stress reactivity. In addition to shaping species-typical social behavior, early life sleep may be important in the development of stress induced ethanol consumption and the activation of limbic pathways associated with stress. (PsycInfo Database Record (c) 2020 APA, all rights reserved).