Reconsolidation impairment of reward memory by stimulating stress response.

Research in memory reconsolidation has raised hope for new treatment options of persistent psychiatric disorders like substance dependence and post-traumatic stress disorder (PTSD). While animal research showed successful memory modification by interfering with reconsolidation, human research requires less invasive techniques. In our pilot study, we aimed to reduce appetitive memory reconsolidation of a newly acquired reward memory by exerting a stressor. Thirty healthy participants were randomly assigned to two groups performing a monetary reward paradigm at a personal computer. Day 1 was considered to allow for memory acquisition; on day 2, the experimental group was exposed to a frightening stimulus in the reconsolidation window; and day 3 again served to determine reward memory effects. Measures of reward memory were reaction times to reward announcing stimuli (ie, showing instrumental behavior), actual reward gained, and electrodermal response as a measure for reward anticipation. We found significantly smaller reaction time improvements to reward stimuli over time in the experimental group, as well as reduced achievements in monetary reward. Electrodermal response to reward announcing stimuli was lower in the experimental group after intervention, whereas it was higher in the untreated group. Thus, we argue in favor of the reconsolidation hypothesis, assuming our intervention had successfully interfered with the reconsolidation process. This points towards future treatment options that interfere with an addiction memory.

Fear Without Context: Acute Stress Modulates the Balance of Cue-Dependent and Contextual Fear Learning.

During a threatening encounter, people can learn to associate the aversive event with a discrete preceding cue or with the context in which the event took place, corresponding to cue-dependent and context-dependent fear conditioning, respectively. Which of these forms of fear learning prevails has critical implications for fear-related psychopathology. We tested here whether acute stress may modulate the balance of cue-dependent and contextual fear learning. Participants (N = 72) underwent a stress or control manipulation 30 min before they completed a fear-learning task in a virtual environment that allowed both cued and contextual fear learning. Results showed equally strong cue- and context-dependent fear conditioning in the control group. Stress, however, abolished contextual fear learning, which was directly correlated with the activity of the stress hormone cortisol, and made cue-dependent fear more resistant to extinction. These results are the first to show that stress favors cue-dependent over contextual fear learning.

Morphine Dependence is Attenuated by Treatment of 3,4,5-Trimethoxy Cinnamic Acid in Mice and Rats.

The effect of 3, 4, 5-trimethoxy cinnamic acid (TMCA) against morphine-induced dependence in mice and rats was investigated. Mice were pretreated with TMCA and then morphine was injected intraperitoneally; whereas rats were treated with TMCA (i.p.) and infused with morphine into the lateral ventricle of brain. Naloxone-induced morphine withdrawal syndrome and conditioned place preference test were performed. Moreover, western blotting and immunohistochemistry were used to measure protein expressions. Number of naloxone-precipitated jumps and conditioned place preference score in mice were attenuated by TMCA. Likewise, TMCA attenuated morphine dependent behavioral patterns such as diarrhea, grooming, penis licking, rearing, teeth chattering, and vocalization in rats. Moreover, the expression levels of pNR1and pERK in the frontal cortex of mice and cultured cortical neurons were diminished by TMCA. In the striatum, pERK expression was attenuated despite unaltered expression of pNR1 and NR1. Interestingly, morphine-induced elevations of FosB/ΔFosB+ cells were suppressed by TMCA (50, 100 mg/kg) in the nucleus accumbens sub-shell region of mice. In conclusion, TMCA could be considered as potential therapeutic agent against morphine-induced dependence.

Plastics and cardiovascular health: phthalates may disrupt heart rate variability and cardiovascular reactivity.

Plastics have revolutionized medical device technology, transformed hematological care, and facilitated modern cardiology procedures. Despite these advances, studies have shown that phthalate chemicals migrate out of plastic products and that these chemicals are bioactive. Recent epidemiological and research studies have suggested that phthalate exposure adversely affects cardiovascular function. Our objective was to assess the safety and biocompatibility of phthalate chemicals and resolve the impact on cardiovascular and autonomic physiology. Adult mice were implanted with radiofrequency transmitters to monitor heart rate variability, blood pressure, and autonomic regulation in response to di-2-ethylhexyl-phthalate (DEHP) exposure. DEHP-treated animals displayed a decrease in heart rate variability (-17% SD of normal beat-to-beat intervals and -36% high-frequency power) and an exaggerated mean arterial pressure response to ganglionic blockade (31.5% via chlorisondamine). In response to a conditioned stressor, DEHP-treated animals displayed enhanced cardiovascular reactivity (-56% SD major axis Poincarè plot) and prolonged blood pressure recovery. Alterations in cardiac gene expression of endothelin-1, angiotensin-converting enzyme, and nitric oxide synthase may partly explain these cardiovascular alterations. This is the first study to show an association between phthalate chemicals that are used in medical devices with alterations in autonomic regulation, heart rate variability, and cardiovascular reactivity. Because changes in autonomic balance often precede clinical manifestations of hypertension, atherosclerosis, and conduction abnormalities, future studies are warranted to assess the downstream impact of plastic chemical exposure on end-organ function in sensitive patient populations. This study also highlights the importance of adopting safer biomaterials, chemicals, and/or surface coatings for use in medical devices.NEW & NOTEWORTHY Phthalates are widely used in the manufacturing of consumer and medical products. In the present study, di-2-ethylhexyl-phthalate exposure was associated with alterations in heart rate variability and cardiovascular reactivity. This highlights the importance of investigating the impact of phthalates on health and identifying suitable alternatives for medical device manufacturing.

The Candy Crush Sweet Tooth: How 'Near-misses' in Candy Crush Increase Frustration, and the Urge to Continue Gameplay.

Like many gambling games, the exceedingly popular and lucrative smartphone game "Candy Crush" features near-miss outcomes. In slot machines, a near-miss involves getting two of the needed three high-paying symbols on the pay-line (i.e., just missing the big win). In Candy Crush, the game signals when you just miss getting to the next level by one or two moves. Because near-misses in gambling games have consistently been shown to invigorate play despite being frustrating outcomes, the goal of the present study was to examine whether such near-misses trigger increases in player arousal, frustration and urge to continue play in Candy Crush. Sixty avid Candy Crush players were recruited to play the game for 30 min while having their Heart Rate, Skin Conductance Level, subjective arousal, frustration and urge to play recorded for three types of outcomes: wins (where they level up), losses (where they don't come close to levelling up), and near-misses (where they just miss levelling up). Near-misses were more arousing than losses as indexed by increased heart rate and greater subjective arousal. Near-misses were also subjectively rated as the most frustrating of all outcomes. Most importantly, of any type of outcome, near-misses triggered the most substantial urge to continue play. These findings suggest that near-misses in Candy Crush play a role in player commitment to the game, and may contribute to players playing longer than intended.

Peripheral Administration of a Long-Acting Peptide Oxytocin Receptor Agonist Inhibits Fear-Induced Freezing.

Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non-brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response.

Oxytocin, social factors, and the expression of conditioned disgust (anticipatory nausea) in male rats.

Disgust has been proposed to have evolved as a means to rid the body and mouth of noxious substances and toxins, as well as to motivate and facilitate avoidance of contact with disease-causing organisms and infectious materials. Nonemetic species, such as the rat, show distinctive facial expressions, including the gaping reaction, indicative of nausea-based disgust. These conditioned disgust responses can be used to model anticipatory nausea in humans, which is a learned response observed following chemotherapy treatment. As social factors play a role in the modulation and expression of conditioned disgust responses in rats, and the nonapeptide, oxytocin (OT), is involved in the modulation of social behavior, the present study examined the effects of an OT antagonist, L-368 899, on the development and expression of socially mediated conditioned disgust in male rats. When administered 10 min before testing in a distinct context (different from the original conditioning context), L-368 899 (5 mg/kg) significantly decreased gaping behavior in rats that were conditioned with a social partner. LiCl-treated rats administered L-368 899 before testing also showed decreased social initiations toward their social partner. These findings suggest that OT may play a role in the modulation and expression of socially mediated conditioned disgust in rats.

Salivary peptide tyrosine-tyrosine 3-36 modulates ingestive behavior without inducing taste aversion.

Hormone peptide tyrosine-tyrosine (PYY) is secreted into circulation from the gut L-endocrine cells in response to food intake, thus inducing satiation during interaction with its preferred receptor, Y2R. Clinical applications of systemically administered PYY for the purpose of reducing body weight were compromised as a result of the common side effect of visceral sickness. We describe here a novel approach of elevating PYY in saliva in mice, which, although reliably inducing strong anorexic responses, does not cause aversive reactions. The augmentation of salivary PYY activated forebrain areas known to mediate feeding, hunger, and satiation while minimally affecting brainstem chemoreceptor zones triggering nausea. By comparing neuronal pathways activated by systemic versus salivary PYY, we identified a metabolic circuit associated with Y2R-positive cells in the oral cavity and extending through brainstem nuclei into hypothalamic satiety centers. The discovery of this alternative circuit that regulates ingestive behavior without inducing taste aversion may open the possibility of a therapeutic application of PYY for the treatment of obesity via direct oral application.

Effects of overshadowing on conditioned and unconditioned nausea in a rotation paradigm with humans.

We examine whether overshadowing by salient stimuli is effective in reducing the ability of a certain environment (the putative conditioned stimulus) to evoke conditioned nausea in healthy humans that experience nausea-evoking rotation (as the unconditioned stimulus, US) in that environment. Twenty-four rotation-susceptible subjects (12 males, 12 females) were randomly assigned to receive either overshadowing by salient tasting beverages (OS+), or a control treatment (a familiar beverage, water; OS-) prior to rotation on three consecutive days (acquisition). To control for taste experiences, the alternative beverage was consumed 12 h later in the home environment (OS+: water, OS-: salient beverage). At Day 4 (test), all subjects drank the familiar beverage (water) prior to rotation (US). Rotation was standardized as 2 × 1-min rotation/day. Nausea was determined by a 7-item symptom scale measuring symptom number (SN) prior to (anticipatory), immediately after, and 15 and 30 min after rotation and by the Nausea Profile (NP) questionnaire immediately after rotation. Cortisol and tumour necrosis factor (TNF)-α in saliva were sampled at the same time-points. SN and cortisol were also measured at home. Overshadowing reduced anticipatory (conditioned) SN. Post-rotation nausea (i.e. the unconditioned response) measured by the NP decreased within the OS+ group only. Anticipatory cortisol and TNF-α were not affected by overshadowing. Treatment × gender interactions manifested for post-rotation cortisol and TNF-α. Groups did not differ in SN and cortisol at home. Overshadowing is effective in reducing symptoms of anticipatory nausea and rotation-induced unconditioned nausea; its effect on endocrine and immunological parameters is gender specific. Its application in alleviation of anticipatory nausea in cancer patients is considered.

Why are people afraid of the dentist? Observations and explanations.

OBJECTIVE: The aim of this review was to explore the peer-reviewed literature to answer the question: 'Why are people afraid of the dentist?' METHOD: Relevant literature was identified by searching the following on-line databases: PubMed, PsycInfo, the Cochrane Library and Google Scholar. Publications were extracted if they explored the causes and consequences of dental fear, dental anxiety or dental phobia. RESULTS: The research evidence suggests that the causes of dental fear, dental anxiety or dental phobia are related to exogenous factors such as direct learning from traumatic experiences, vicarious learning through significant others and the media, and endogenous factors such as inheritance and personality traits. Each individual aetiological factor is supported by the evidence provided. CONCLUSIONS: The evidence suggests that the aetiology of dental fear, anxiety or phobia is complex and multifactorial. The findings show that there are clear practical implications indicated by the existing research in this area: a better understanding of dental fear, anxiety and phobia may prevent treatment avoidance.

G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation.

Learning triggers alterations in gene transcription in brain regions such as the hippocampus and the entorhinal cortex (EC) that are necessary for long-term memory (LTM) formation. Here, we identify an essential role for the G9a/G9a-like protein (GLP) lysine dimethyltransferase complex and the histone H3 lysine 9 dimethylation (H3K9me2) marks it catalyzes, in the transcriptional regulation of genes in area CA1 of the rat hippocampus and the EC during memory consolidation. Contextual fear learning increased global levels of H3K9me2 in area CA1 and the EC, with observable changes at the Zif268, DNMT3a, BDNF exon IV, and cFOS gene promoters, which occurred in concert with mRNA expression. Inhibition of G9a/GLP in the EC, but not in the hippocampus, enhanced contextual fear conditioning relative to control animals. The inhibition of G9a/GLP in the EC induced several histone modifications that include not only methylation but also acetylation. Surprisingly, we found that downregulation of G9a/GLP activity in the EC enhanced H3K9me2 in area CA1, resulting in transcriptional silencing of the non-memory permissive gene COMT in the hippocampus. In addition, synaptic plasticity studies at two distinct EC-CA1 cellular pathways revealed that G9a/GLP activity is critical for hippocampus-dependent long-term potentiation initiated in the EC via the perforant pathway, but not the temporoammonic pathway. Together, these data demonstrate that G9a/GLP differentially regulates gene transcription in the hippocampus and the EC during memory consolidation. Furthermore, these findings support the possibility of a role for G9a/GLP in the regulation of cellular and molecular cross talk between these two brain regions during LTM formation.

Fluoxetine reduces periodontal disease progression in a conditioned fear stress model in rats.

BACKGROUND AND OBJECTIVE: Recent evidence suggests that the use of fluoxetine could reduce periodontal disease severity. However, the effect of fluoxetine on periodontal disease has not been tested in the context of conditioned fear stress (CFS). We hypothesized that inhibition of chronic stress by fluoxetine might decrease the levels of bone loss in periodontal disease. The aim of the present study was to analyze the effect of fluoxetine on bone loss in chronic periodontitis. MATERIAL AND METHODS: Fourteen Wistar rats were submitted to ligature-induced periodontal disease and divided into four groups (A-D). Groups A (n = 3) and B (n = 4) were not stressed, while Groups C (n = 3) and D (n = 4) were submitted to a CFS paradigm for 38 d. Daily fluoxetine (20 mg/kg) was administered to Groups B and D from day 20 to day 39, at which point the rats were submitted to an open field test and killed on day 40. Mandibles were removed for histological and immunohistochemical analyses. RESULTS: Stress was associated with a higher level of bone loss in Group C compared with Group A. Additionally, no differences in bone loss were observed among Groups A, B and D. CONCLUSION: We showed that stress is associated with the progression of bone loss in a CFS model in rats and that fluoxetine treatment reduces the bone loss.

Noradrenergic enhancement of associative fear memory in humans.

Ample evidence in animals and humans supports the noradrenergic modulation in the formation of emotional memory. However, in humans the effects of stress on emotional memory are traditionally investigated by declarative memory tests (e.g., recall, recognition) for non-associative emotional stimuli (e.g., stories, pictures). Given that anxiety disorders are thought to originate from associative learning processes and are characterized by distressing emotional responses, the existing literature seems to be inconclusive for the understanding of these disorders. Here, we tested whether noradrenaline strengthens the emotional expression of associative fear memory by using a differential fear conditioning procedure in humans. Stimulation of the noradrenergic system by the administration of yohimbine HCl (20mg) during memory formation did not directly augment the differential startle fear response 48 h later. Yet, the other retention tests uncovered that the administration of yohimbine HCl contrary to placebo pill extensively delayed the process of extinction learning and generated a superior recovery of fear (i.e., reinstatement and reacquisition). Conversely, the yohimbine HCl manipulation did not affect the skin conductance responding and the US expectancy ratings, emphasizing the concept of multiple memory systems. To our knowledge this is the first demonstration in humans that increased noradrenaline release during or shortly after a stressful event strengthens the formation of associative fear memory traces. The present findings suggest that noradrenaline may play an important role in the etiology and maintenance of anxiety disorders.

Assessment of sleep parameters during contingent electrical stimulation in subjects with jaw muscle activity during sleep: a polysomnographic study.

There is emerging evidence that feedback techniques based on contingent electrical stimulation (CES) have an inhibitory effect on the electromyogram (EMG) activity of jaw-closing muscles and therefore could be useful in the management of sleep bruxism. This polysomnographic (PSG) study was designed to investigate the effect of CES on PSG parameters in subjects with self-reported bruxism. Fourteen subjects underwent a full PSG investigation in the laboratory for three consecutive nights - one night of adaptation, one night without CES, and one night with CES - in a randomized order. During all sessions the EMG activity was recorded by a portable feedback device from the temporalis muscle. An electrical pulse, which was adjusted to a moderate, but non-painful, intensity, was applied to subjects during the session with CES, if jaw-muscle activity was detected. The total sleep time, the number of micro-arousals per hour of sleep, the time spent in sleep stages 3 and 4 and in rapid eye movement (REM) sleep, and the number of periodic limb movements, were not influenced by CES. The number of EMG episodes per hour of sleep during the nights with and without CES was not significantly different. The present study suggests that CES at non-painful intensities does not cause major arousal responses in any of the sleep parameters assessed in this study.

Methods for Assessing Willingness to Try and Vegetable Consumption among Children in Indigenous Early Childcare Settings: The FRESH Study.

Food preferences begin in early childhood, and a child's willingness to try (WTT) new vegetables is an important determinant of vegetable intake. Young children living in rural communities are at increased risk for food insecurity, which may limit exposure to and consumption opportunities for vegetables. This manuscript describes the validation of the Farfan-Ramirez WTT (FR-WTT) measure using baseline data from the FRESH study, a gardening intervention for Native American families with preschool-aged children in Osage Nation, Oklahoma. Individually weighed vegetable containers were prepared with six types of vegetables and ranch dip. Researchers presented children (n = 164; M = 4.3 years, SD = 0.8) with these vegetables preceding a snack- or lunch time and recorded the child's FR-WTT for each vegetable using a 5-point scale, ranging from "did not remove food (0)" to "put food in mouth and swallowed (4)". After the presentation period, contents were re-weighed to calculate vegetable consumption. Household parents/guardians completed the Child Food Neophobia Scale (CFNS) for their child. FR-WTT scores were positively correlated with consumption weights of all vegetables (r = 0.7613, p < 0.0001) and each vegetable individually (r = 0.2016-0.7664). The total FR-WTT score was inversely correlated with the CFNS score (r = 0.3268, p < 0.0001). Sensitivity analyses demonstrated similar relationships by BMI, food security, and age. In conclusion, the FR-WTT is a valid method for assessing young children's vegetable eating behavior and intake.

Heterotopic CO2 laser stimulation inhibits tooth-related somatosensory evoked potentials.

BACKGROUND: The diffuse noxious inhibitory control (DNIC) effect is the neurophysiological basis for the phenomenon that heterotopic "pain inhibits pain" in remote areas of the body. The effect of DNIC is mediated by spino-bulbo-spinal loops and a final postsynaptic inhibitory mechanism. The DNIC effect depends on intensity, duration, quality, and application site of conditioning stimulation and stimulated nerve fiber-type. DNIC induced by CO(2) laser conditioning stimulation has, however, not yet been investigated, and the present study was designed to examine this. METHODS: As the indicator of test stimulation, the late component of somatosensory evoked potentials (SEPs) induced by electrical tooth stimulation and pain intensity were examined under CO(2) laser conditioning stimulation. As the conditioning stimuli, CO(2) laser energy (lambda = 10.6 microm, spot size Ø = 2 mm) was applied to the dorsum of the left hand. RESULTS: The maximum reductions in SEP amplitude and pain intensity evaluated using a visual analog scale were 34.7% and 28.7%, respectively during CO(2) laser conditioning stimulation. No aftereffect was observed. CONCLUSION: The present study revealed that CO(2) laser radiation attenuated the late component of SEPs induced by electrical tooth stimulation, triggering the DNIC effect but with no aftereffect.

A limited range of vagus nerve stimulation intensities produce motor cortex reorganization when delivered during training.

Pairing vagus nerve stimulation (VNS) with rehabilitation has emerged as a potential strategy to improve recovery after neurological injury, an effect ascribed to VNS-dependent enhancement of synaptic plasticity. Previous studies demonstrate that pairing VNS with forelimb training increases forelimb movement representations in motor cortex. However, it is not known whether VNS-dependent enhancement of plasticity is restricted to forelimb training or whether VNS paired with other movements could induce plasticity of other motor representations. We tested the hypothesis that VNS paired with orofacial movements associated with chewing during an unskilled task would drive a specific increase in jaw representation in motor cortex compared to equivalent behavioral experience without VNS. Rats performed a behavioral task in which VNS at a specified intensity between 0 and 1.2 mA was paired with chewing 200 times per day for five days. Intracortical microstimulation (ICMS) was then used to document movement representations in motor cortex. VNS paired with chewing at 0.8 mA significantly increased motor cortex jaw representation compared to equivalent behavioral training without stimulation (Bonferroni-corrected unpaired t-test, p < 0.01). Higher and lower intensities failed to alter cortical plasticity. No changes in other movement representations or total motor cortex area were observed between groups. These results demonstrate that 0.8 mA VNS paired with training drives robust plasticity specific to the paired movement, is not restricted to forelimb representations, and occurs with training on an unskilled task. This suggests that moderate intensity VNS may be a useful adjuvant to enhance plasticity and support benefits of rehabilitative therapies targeting functions beyond upper limb movement.

Does training method matter? Evidence for the negative impact of aversive-based methods on companion dog welfare.

Dog training methods range broadly from those using mostly positive punishment and negative reinforcement (aversive-based) to those using primarily positive reinforcement (reward-based). Although aversive-based training has been strongly criticized for negatively affecting dog welfare, there is no comprehensive research focusing on companion dogs and mainstream techniques, and most studies rely on owner-reported assessment of training methods and dog behavior. The aim of the present study was to evaluate the effects of aversive- and reward-based training methods on companion dog welfare within and outside the training context. Ninety-two companion dogs were recruited from three reward-based schools (Group Reward, n = 42), and from four aversive-based schools, two using low proportions of aversive-based methods (Group Mixed, n = 22) and two using high proportions of aversive-based methods (Group Aversive, n = 28). For evaluating welfare during training, dogs were video recorded for three sessions and six saliva samples were collected, three at home (baseline levels) and three after training (post-training levels). Video recordings were used to examine the frequency of stress-related behaviors (e.g., lip lick, yawn) and the overall behavioral state of the dog (e.g., tense, relaxed), and saliva samples were analyzed for cortisol concentration. For evaluating welfare outside the training context, dogs participated in a cognitive bias task. Results showed that dogs from Group Aversive displayed more stress-related behaviors, were more frequently in tense and low behavioral states and panted more during training, and exhibited higher post-training increases in cortisol levels than dogs from Group Reward. Additionally, dogs from Group Aversive were more 'pessimistic' in the cognitive bias task than dogs from Group Reward. Dogs from Group Mixed displayed more stress-related behaviors, were more frequently in tense states and panted more during training than dogs from Group Reward. Finally, although Groups Mixed and Aversive did not differ in their performance in the cognitive bias task nor in cortisol levels, the former displayed more stress-related behaviors and was more frequently in tense and low behavioral states. These findings indicate that aversive-based training methods, especially if used in high proportions, compromise the welfare of companion dogs both within and outside the training context.

Stress impairs acquisition of delay eyeblink conditioning in men and women.

In rodents stress impairs delay as well as trace eyelid conditioning in females, but enhances it in males. The present study tested the effects of acute psychosocial stress exposure on classical delay eyeblink conditioning in healthy men and women. In a between subject design, participants were exposed to psychosocial stress using the Trier Social Stress Test (TSST) or a control condition which was followed by a delay eyeblink classical conditioning procedure. Stress exposure led to a significant increase in salivary cortisol and impaired acquisition of conditioned eyeblink responses (CRs). This was evident by a later first CR and an overall lower CR rate of the stress group. The stress-induced acquisition impairment was observed in both women and men. Subjects failing to show a stress-induced cortisol increase (cortisol non-responder) were not impaired in acquisition. Our findings indicate that acute stress, possibly via activation of the hypothalamus-pituitary-adrenal (HPA) axis, reduces the ability to acquire a simple conditioned motor response in humans.

Behavioral regulation of the milieu interne in man and rat.

In regulating the internal homeostatic environment mammals, by necessity, employ behavioral strategies that differ from the tactics used in coping with contingencies in the external environment. When an animal consumes a meal, the palatability of that meal is automatically adjusted in accordance with the ultimate internal effects of that meal. If the meal causes toxicosis, the animal acquires an aversion for the taste of the meal; conversely, if recuperation follows ingestion of the meal, the taste of that meal is enhanced. Unlike the learning that occurs when externally referred visual and auditory signals are followed by punishment in the form of peripheral pain or reward in the form of food in the mouth, conditioning to the homeostatic effects of food can occur in a single trial and rarely requires more than three to five trials, even though the ultimate effects of the meal are delayed for hours. Paradoxically, the animal need not be aware of the ultimate internal effect in the same sense that it is aware of external contingencies. For example, an aversion can be acquired even if the animal is unconscious when the agent of illness is administered. Thus, the way in which food-effects are stored in memory may be fundamentally different from the way in which memories of specific time-space strategies devised for external contingencies are stored. This separation of function is indicated by limbic lesions which disrupt conditioning to a buzzer that is followed by shock and facilitate conditioning to a taste that is followed by illness. Operationally speaking, one can describe both aversion conditioning and buzzer-shock conditioning in the spacetime associationistic terms of classical conditioning. However, psychologically speaking, one must realize that in aversion conditioning the animal does not act as if it were acquiring an "if-then" strategy. It acts as if a hedonic shift, or a change in the incentive value of the flavor were taking place. Such hedonic shifts are critical in regulation of the internal milieu. When an animal is in need of calories, food tends to be more palatable; as the caloric deficit is restored, food becomes less palatable. If the animal's body temperature is below optimum, a warm stimulus applied to the skin is pleasant. When body temperature is too high, the converse is true. In this way, homeostatic states monitored by internal receptors produce changes in the incentive values of external stimuli sensed by the peripheral receptors, and guide feeding behavior. In mammals at least, the gustatory system, which provides sensory control of feeding, sends fibers to the nucleus solitarius. This brainstem relay station also receives fibers from the viscera and the internal monitors of the area postrema. Ascending fibers bifurcate at the level of the pons and project toward the feeding areas of the hypothalamus and the cortex. The olfactory system which primarily projects to the limbic system does not play a primary role in adjusting food incentives. Rather, it plays a secondary role in the activation of feeding, as do other external sensory systems. This specialized conditioning mechanism, which specifically adjusts gustatory hedonic values through delayed visceral feedback, is widespread among animals, including man and rat. These two species are remarkably similar in their thresholds and preferences for gustatory stimuli. The behavioral similarities are based on the animals' having similar gustatory systems, similar convergence of gustatory and internal afferents to the nucleus solitarius, and similar midbrain regulatory mechanisms. Thus, it is not surprising that the feeding of obese rats with internal hypothalamic damage resembles the feeding of obese human beings insensitive to the internal signs of this caloric state. Obviously, man has a highly specialized form of symbolic communication and the rat does not, yet man's cognitive specialization does not prevent him from developing aversions to food consumed before illness even when he knows that his illness was not caused by food (43).