Possible involvement of the vagus nerve in monitoring plasma catecholamine levels

In their article Miyashita and Williams (Neurobiology of Learning and Memory 2006, 85, 116-124) describe the effect of peripheral administration of epinephrine on neural discharge in vagal afferent fibers. It seems that described data supports the hypothesis of the vagus nerve participation in monitoring plasma catecholamine levels and consequently modifying brain functions. However, do these results indicate indeed that afferent vagus nerve pathways are activated by circulating epinephrine? Catecholamines influence virtually all tissues and many functions. Vagus nerve participates significantly in monitoring of those effects. Therefore epinephrine-induced increases of afferent vagus nerve activity described by Miyashita and Williams may reflect not only exclusive activation of beta-adrenergic receptors but also an activation of other types of receptors on vagal sensory nerve endings, e.g., mechanosensors, chemoreceptors, and osmosensors. Discussion is focused on the possibility that the increase in afferent vagus nerve activity may reflect activation of mechanoreceptors of the vagus nerve endings in the epinephrine-activated heart.     

Posttraining Electrical Stimulation of Vagal Afferents with Concomitant Vagal Efferent Inactivation Enhances Memory Storage Processes in the Rat

Peripherally administered or released substances that modulate memory storage, but do not freely enter the brain, may produce their effects on memory by activating peripheral receptors that send messages centrally through the vagus nerve. Indeed, vagus nerve stimulation enhances memory performance, although it is unclear whether this effect is due to the activation of vagal afferents or efferents. To eliminate the possible influence of descending fibers on memory storage processes, rats were implanted with cuff electrode/catheter systems along the left cervical vagus. Forty-eight hours following surgery, each animal received a 3.0-μl infusion (1.0 μl/min) of either lidocaine hydrochloride (75.0 mM) or isotonic saline below the point of stimulation. Animals were then trained 10 min later on an inhibitory-avoidance task with a 0.75-mA, 1.0-s foot shock. Sham stimulation or vagus nerve stimulation (0.5-ms biphasic pulses; 20.0 Hz; 30 s; 0.2, 0.4, or 0.8 mA) was administered immediately after training. Memory, tested 24 h later, was enhanced by stimulation whether descending vagus nerve fibers were inactivated or not. Both lidocaine- and saline-infused groups showed an intensity-dependent, inverted-U-shaped pattern of retention performance, with the greatest effect observed for 0.4 mA (U= 9,p< .05, andU= 7,p< .01, respectively). Additionally, animals that received lidocaine infusions, but no vagus nerve stimulation, showed impaired memory compared to the performance of saline-infused control animals (U= 11,p< .05). Together, these findings suggest that vagal afferents carry messages about peripheral states that lead to the modulation of memory storage and that the memory-enhancing effect produced by vagus nerve stimulation is not mediated via the activation of vagal efferents.     

Effects of hepatic denervation on the anorexic response to epinephrine, amphetamine, and lithium chloride: a behavioral identification of glucostatic afferents

Intraperitoneal injections of epinephrine (20, 40, 80, and 160 microgram/kg) and amphetamine (.1, .2, and .4 mg/kg) were administered to rats with various forms of hepatic denervation. In Experiment 1, destruction of the esophageal trunks of the vagus attenuated epinephrine and amphetamine anorexia, but destruction of the hepatic vagus did not. In Experiment 2, rats with celiac ganglionectomy, subdiaphragmatic vagotomy, or the combined operation all exhibited decreased epinephrine anorexia to the same extent. However, ganglionectomized rats were less responsive to amphetamine anorexia than were vagotomized ones. Vagotomized rats were significantly more reactive to lithium chloride (10, 20, and 30 mg/kg) than were controls. These results suggest that the major component of hepatic metabolic afferent fibers travels from the liver, through the celiac ganglion, and into the esophageal vagal trunks where they ascend to the brain. The anorexic action of amphetamine appears to result from a centrally induced sympathetic action on the liver.     

Opioid peptidergic systems modulate the activity of beta-adrenergic mechanisms during memory consolidation processes

Post-training administration of the opioid receptor antagonist naloxone (0.1 mg/kg) facilitated 48-hr retention, in mice, of a one-trial step-through inhibitory avoidance response. The naloxone-induced memory facilitation was blocked in animals given the selective brain-noradrenergic neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) (50.0 mg/kg, ip) 7 days before training. Pretreatment with the norepinephrine-uptake inhibitor desmethylimipramine (10.0 mg/kg, ip, 30 min), but not with the serotonin-uptake inhibitor fluoxetine (5.0 mg/kg, ip, 30 min), prevented this antagonism. The simultaneous administration of the central beta-adrenoceptor blocker l-propranolol (2.0 mg/kg, ip), also blocked the effects of naloxone on memory. The effects of naloxone were not blocked by d-propranolol (2.0 mg/kg, ip), the peripheral beta-adrenoceptor blocker sotalol (2.0 mg/kg, ip), the alpha-adrenoceptor blocker phenoxybenzamine (10.0 mg/kg, ip), or the predominantly peripheral alpha-adrenoceptor blocker phentolamine (10.0 mg/kg, ip). These findings suggest that central beta-adrenergic mechanisms are involved in the effects of naloxone on memory. Naloxone (0.1 mg/kg, ip) potentiated the effects of the central beta-adrenoceptor agonist clenbuterol (0.001-1.00 mg/kg, ip), which, when administered alone, facilitates or impairs retention as a function of the dose injected. The simultaneous administration of beta-endorphin (0.1 micrograms/kg, ip) exerted effects opposite to those elicited by naloxone, that is, shifted the dose-response curve of clenbuterol to the right. Considered together, these findings are consistent with the view that the facilitatory action of naloxone on memory results from the release of central beta-adrenergic mechanisms from an inhibition induced by opioid peptides released during or immediately after training.     

Emotionally arousing pictures increase blood glucose levels and enhance recall

Arousal enhances memory in human participants and this enhancing effect is likely due to the release of peripheral epinephrine. As epinephrine does not readily enter the brain, one way that peripheral epinephrine may enhance memory is by increasing circulating blood glucose levels. The present study investigated the possibility that emotionally arousing color pictures would improve memory and elevate blood glucose levels in human participants. Blood glucose levels were measured before, 15 min, and 30 min after male university students viewed 60 emotionally arousing or relatively neutral pictures. Participants viewed each picture for 6 s and then had 10 s to rate the arousal (emotional intensity) and valence (pleasantness) of each picture. A free-recall memory test was given 30 min after the last picture was viewed. Although the emotionally arousing and neutral picture sets were given comparable valence ratings, participants who viewed the emotionally arousing pictures rated the pictures as being more arousing, recalled more pictures, and had higher blood glucose levels after viewing the pictures than did participants who viewed the neutral pictures. These findings indicate that emotionally arousing pictures increase blood glucose levels and enhance memory, and that this effect is not due to differences in the degree of pleasantness of the stimuli. These findings support the possibility that increases in circulating blood glucose levels in response to emotional arousal may be part of the biological mechanism that allows emotional arousal to enhance memory.     

Epinephrine Effects on Memory Are Not Dependent on Hepatic Glucose Release

Epinephrine released or administered soon after a given training task modulates memory processes. Since epinephrine does not readily cross the blood–brain barrier, studies have suggested that some of the central effects of epinephrine might be mediated by peripheral release of glucose. These experiments examined the involvement of blood glucose levels in the posttraining effects of peripherally administered epinephrine. The effects of the administration of epinephrine (25 and 625 mg/kg) on memory of an inhibitory avoidance task were evaluated in fed and fasted rats (depleted glycogen stores in liver). Blood glucose levels after the task in each group were also measured. Female Wistar rats were divided in two groups. Fed and 48-h-fasted animals were submitted to the inhibitory avoidance task and received ip epinephrine or saline immediately after training. The test session was carried out 48 h after training. Epinephrine (25 or 625 mg/kg) caused an increased glycemia in fed rats, but no effect was observed in fasted animals. Administration of epinephrine 25 mg/kg induced a facilitation of memory, while epinephrine 625 mg/kg impaired retention (either in fasted or in fed animals). There was no relation between increased glycemia induced by epinephrine and its effects on memory, since this drug presented its classical effects independently of the previous state of the animal (fed or fasted). The results of the present study suggest that the effects of systemic released or administered epinephrine on memory processes are not dependent on hepatic glucose release.     

Glucose modulation of memory storage processing

Epinephrine, derived from the adrenal medulla, enhances memory storage for several forms of learning. One physiological action of this hormone is to liberate hepatic glucose stores. This experiment tested the possibility that glucose could itself enhance memory. Rats were water deprived, pretrained to drink, pretrained to drink in the behavioral apparatus, and then trained in a one-trial inhibitory (passive) avoidance task. Immediately after the training footshock, the animals each received an injection of glucose (1.0-500 mg/kg). When tested for retention 24 h later, the animals which received 10 or 100 mg/kg doses of glucose exhibited enhanced retention performance; higher and lower doses had no significant effect on the memory tests. Also, glucose injections (100 mg/kg) delayed by 1 h after training had no effect on the retention tests. These findings suggest that the increase in plasma glucose levels subsequent to epinephrine injection may contribute to the effects of epinephrine on memory. In addition, the results suggest that peripheral glucose levels may exert important influences on memory storage.     

Post-training Unilateral Vagal Stimulation Enhances Retention Performance in the Rat

Many peripherally administered substances which modulate memory do not freely enter the brain. Such compounds may act through peripheral receptors that send messages centrally through vagal afferents. To explore this hypothesis, rats were chronically implanted with cuff electrodes on the left cervical vagus nerve. Each animal was trained 48 h after surgery on a one-trial inhibitory-avoidance task with a 0.75-mA, 1.0-s footshock. Immediately following training, each animal received either no stimulation or vagal stimulation (0.5-ms biphasic pulses; 20 Hz, 30 s) at one of three intensities (0.2, 0.4, 0.8 mA; eight animals per group). Retention was tested 24 h later. Neither the 0.2-in or 0.8-mA groups (22.1-s; 53.7-s median latency) showed altered retention performances, whereas the 0.4-mA group showed significantly improved retention (881.0 s) compared to unstimulated controls (21.1 s; U = 6, p < .01). This inverted-U shaped function indicates that vagal activation during memory consolidation modulates retention for memory tasks.     

经皮迷走神经刺激对抑制控制的调节机制

近年众多研究表明,经皮迷走神经刺激(tVNS)作为一种新型、非侵入式的神经调控技术对个体的抑制控制功能具有积极的调节作用。已有研究发现, tVNS对抑制控制的调节作用可能是通过调控蓝斑核-去甲肾上腺素系统(LC-NE)的活动和神经递质GABA的浓度来实现的。然而,目前对tVNS调控抑制控制的神经机制仍存在诸多尚未明确的问题。未来研究在进一步优化tVNS的刺激参数后,可以从tVNS对抑制控制能力受损群体的调控作用及机制、如何实现和增强tVNS长期积极效应等方面进行深入探索。     

Enhanced human memory consolidation with post-learning stress: interaction with the degree of arousal at encoding

Abundant evidence indicates that endogenous stress hormones such as epinephrine and corticosterone modulate memory consolidation in animals. We recently provided the first demonstration that an endogenous stress hormone (epinephrine) can enhance human memory consolidation. However, these findings also suggested that post-learning stress hormone activation does not uniformly enhance memory for all recently acquired information; rather, that it interacts with the degree of arousal at initial encoding of material in modulating memory for the material. Here we tested this hypothesis by administering cold pressor stress (CPS) or a control procedure to subjects after they viewed slides of varying emotional content, and assessing memory for the slides 1 wk later. CPS, which significantly elevated salivary cortisol levels, enhanced memory for emotionally arousing slides compared with the controls, but did not affect memory for relatively neutral slides. These findings further support the view that post-learning stress hormone-related activity interacts with arousal at initial encoding to modulate memory consolidation.     

Capsaicin-sensitive afferent vagal fibers are involved in concurrent taste aversion learning

Taste aversion learning (TAL) is a type of learning characterized by rejection of a gustatory/flavor stimulus as a consequence of its pairing with visceral discomfort and malaise. TAL can be established in the laboratory by two different behavioral procedures, concurrent or sequential. Neural mechanisms of these learning modalities remain to be elucidated, but several studies have discussed the implication of various anatomical structures, including the vagus nerve. The aim of this study was to examine the role of capsaicin-sensitive vagal afferent fibers in concurrent (Experiment 1) and sequential (Experiment 2) TAL in Wistar rats. Results showed that perivagal administration of capsaicin (1mg of capsaicin dissolved in 1ml of vehicle (10% Tween 80 in oil)) blocked acquisition of concurrent but not sequential TAL. These data support the hypothesis of two different modalities of TAL mediated by distinct neurobiological systems, with vagal nerve participation only being essential in concurrent TAL.     

The Impairment of Retention Induced by Insulin in Mice May Be Mediated by a Reduction in Central Cholinergic Activity

Immediate posttraining intraperitoneal injection of nonconvulsive doses of insulin (2-20 IU/kg) significantly impaired retention of male Swiss mice tested 24 h after training in a one-trial step-through inhibitory avoidance task. The dose-response curve showed a U-shaped form. However, of the doses tested, only 8 IU/kg was effective. Insulin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of insulin on retention performance were not due to nonspecific proactive effects on response latencies. The impairing effects of insulin (8 IU/kg) on retention were time-dependent, which suggests that insulin impaired memory storage. The simultaneous administration of glucose (10-1000 mg/kg) antagonized, in a dose-related manner, the actions of insulin (8 IU/kg) on retention, suggesting that the hormone may have produced a hypoglycemic response leading to a decrease in CNS glucose availability with a subsequent memory impairment. Low subeffective doses of atropine (0.5 mg/kg) or mecamylamine (5 mg/kg), but not methylatropine (0.5 mg/kg) or hexamethonium (5 mg/kg), given immediately after training but 10 min before an ineffective dose of insulin (4 IU/kg), interacted with and impaired retention. The central anticholinesterase physostigmine (35 or 70 μg/kg), but not its quaternary analog neostigmine (35 or 70 μg/kg), prevented the memory impairment induced by insulin (8 IU/kg). Considered together, these findings are consistent with the view that a decrease in the CNS glucose availability impairs the synthesis and/or release of acetylcholine in brain regions critically involved in memory storage.     

Sex-related impairment of memory for emotional events with beta-adrenergic blockade

On the basis of recent evidence indicating a sex-related lateralization of amygdala function in memory for emotional events, together with substantial evidence suggesting hemispheric specialization in processing global (central) versus local (detail) aspects of a situation, and the established dependence of the amygdala's memory modulating function on beta-adrenergic receptor activation, we predicted differential effects of a beta-adrenergic receptor antagonist (propranolol) on long-term memory for an emotionally arousing story in men and women. Specifically, we predicted that, relative to placebo, propranolol would impair memory for information central to the story line, but not memory for peripheral story details in men. Conversely, propranolol would impair memory for peripheral details, but not for central information in women. Here we confirm this prediction with a novel analysis of data from our two published studies of propranolol's effect on memory for an emotionally arousing story. These findings demonstrate a sex-related impairment of memory for emotional information by beta-adrenergic blockade. Additionally, they provide support for the hypothesis that, in this paradigm, emotional arousal enhances long-term memory for central information in men via activation of right amygdala/hemisphere function, and enhances long-term memory for peripheral details in women via activation of left amygdala/hemisphere function.     

Epilepsy, consciousness and neurostimulation

Consciousness is often disrupted in epilepsy. This may involve altered responsiveness or changes in awareness of self and subjective experiences. Subcortical arousal systems and paralimbic fronto-parietal association cortices are thought to underpin current concepts of consciousness. The Network Inhibition Hypothesis proposes a common neuroanatomical substrate for impaired consciousness during absence, complex partial and tonic-clonic seizures. Neurostimulation in epilepsy remains in its infancy with vagal nerve stimulation (VNS) as the only firmly established technique and a series of other methods under investigation including deep brain stimulation (DBS), intracranial cortical stimulation and repetitive transcranial magnetic stimulation (rTMS). Many of these systems impact on the neural systems thought to be involved in consciousness as a continuous duty cycle although some adaptive (seizure triggered) techniques have been developed. Theoretically, fixed duty cycle neurostimulation could have profound effects on responsiveness, awareness of self and subjective experience. Animal studies suggest vagal nerve stimulation positively influences hippocampal long term potentiation. In humans, a chronic effect of increased alertness in VNS implanted subjects and acute effect on memory consolidation have been reported but convincing data on either improvements or deterioration in attention and memory is lacking. Thalamic deep brain stimulation (DBS) is perhaps the most interesting neurostimulation technique in the context of consciousness. Neither bilateral anterior or centromedian thalamic nucleus DBS seem to affect cognition. Unilateral globus pallidus internus DBS caused transient wakefulness in an anaesthetised individual. As intracranial neurostimulation, particularly thalamic DBS, becomes more established as a clinical intervention, the effects on consciousness and cognition with variations in stimulus parameters will need to be studied to understand whether these secondary effects of neurostimulation make a significant positive (or adverse) contribution to quality of life.     

Epinephrine enhancement of human memory consolidation: interaction with arousal at encoding

Abundant evidence indicates that endogenous stress hormones like epinephrine and cortisol modulate memory consolidation in animals. Despite this evidence, there has been no demonstration that endogenous stress hormones modulate memory consolidation in humans. In the present study, healthy subjects viewed a series of 21 slides, and immediately after received an intravenous infusion of either saline or epinephrine (40 or 80 ng/kg/min). Memory for the first three (primacy) and last three (recency) slides viewed was assessed with an incidental free recall test one week later. Epinephrine dose-dependently increased memory for the primacy slides, but did not affect memory of the recency slides. A subsequent experiment involving new subjects revealed significantly higher electrodermal responses to the primacy compared with recency slides. These findings support the view (Gold & McGaugh, 1975) that endogenous stress hormones modulate memory consolidation for experiences that induce their release. Additionally, they suggest that in humans these hormones may interact with the degree of arousal at initial encoding of information to modulate memory consolidation processes for that information.     

Noradrenergic receptor blockade of the NTS attenuates the mnemonic effects of epinephrine in an appetitive light-dark discrimination learning task

These experiments examined the contribution of noradrenergic neurons in the nucleus of the solitary tract (NTS) in mediating the memory-facilitating effects of epinephrine. In Experiment 1, saline or 0.05 or 0.1 mg/kg of epinephrine was given intraperitoneally (ip) to rats after the second day of training in a light-dark Y-maze discrimination task. On a 20-trial retention test given 2 and 7 days later, the 0.1 mg/kg epinephrine group made significantly more correct responses than controls and required fewer trials to reach criterion. In Experiment 2, phosphate-buffered saline or the noradrenergic antagonist dl-propranolol (0.3 or 1.0 microg/0.5 microl) was infused into the NTS prior to an ip injection of saline or 0.1 mg/kg of epinephrine. The memory-enhancing effects of epinephrine were attenuated by the infusion of 0.3 microg/0.5 microl of dl-propranolol into the NTS. These findings indicate an involvement of NTS noradrenergic neurons in mediating the effects of peripheral epinephrine on memory storage processes.     

Centrifugal acceleration to 3Gz is related to increased release of stress hormones and decreased mood in men and women

It has been suggested that the central and peripheral neural processes (CPNP) are affected by gravitational changes. Based on the previous experiments during parabolic flights, central and peripheral changes may not only be due to the changed gravitational forces but also due to neuroendocrine reactions related to the psycho-physiological consequences of gravitational changes. The present study focuses on the interaction of neuroendocrine changes and the physical and mental states after acceleration to three-time terrestrial gravity (3Gz). Eleven participants (29.4+/-5.1 [SD] years (male (n=8): 30+/-5.1 years; female (n=3): 27.7+/-2.1 years) underwent a 15 min acceleration to 3Gz in a human centrifuge. Before and after the acceleration to 3Gz circulating stress hormone concentrations (cortisol, adrenocorticotropic hormone (ACTH), prolactin, epinephrine, norepinephrine) and perceived physical and mental states were recorded. A second control group of 11 participants underwent the same testing procedure in a laboratory session. Serum cortisol concentration during exposure to the centrifugal acceleration increased by 70%, plasma concentration of ACTH increased threefold, prolactin twofold, epinephrine by 70% and norepinephrine by 45%, whereas the perceived physical well-being decreased. These findings demonstrate that psycho-physiological changes have to be regarded as a relevant factor for the changes in CPNP during phases of hypergravity exposure.     

Epinephrine facilitation of appetitive learning: attenuation with adrenergic receptor antagonists

Previous studies using aversive training tasks have reported that retention is enhanced by post-training administration of epinephrine. This study investigated the effects of post-training administration of epinephrine on retention of an appetitive task. The results indicate that epinephrine can enhance retention performance in an appetitive task of both rats and mice. Pretraining injections of propranolol and phenoxybenzamine, alpha- and beta-adrenergic receptor antagonists, attenuate the memory-enhancing effects of epinephrine. These results are consistent with the view that release of peripheral epinephrine may regulate storage of new information and may mediate memory modulation produced by a variety of treatments.     

The effects of training, epinephrine, and glucose injections on plasma glucose levels in rats

Recent findings indicate that a post-training injection of glucose enhances memory storage, suggesting that release of glucose into plasma may mediate the effects of epinephrine and perhaps other treatments on memory. The present experiment examined the effects of handling, inhibitory (passive) avoidance training, epinephrine and glucose injections on plasma glucose levels in Sprague-Dawley rats. Handling produced a small, but significant, transient increase in plasma glucose above basal levels. Saline injections caused a similar increase in circulating glucose levels. Inhibitory avoidance training with high footshock (2.0 mA, 2.0 s) resulted in significant increases in plasma glucose levels above those of low (0.5 mA, 0.75 s) and unshocked animals suggesting that glucose release is responsive to inhibitory avoidance training. Subcutaneous injections of epinephrine (0.01-1.0 mg/kg), or glucose (10-1000 mg/kg) significantly elevated glucose levels above those of saline-injected animals in a dose-dependent manner. Memory facilitating doses of epinephrine and glucose resulted in increases in plasma glucose levels similar to those seen in rats trained with high footshock. Higher doses of epinephrine and glucose resulted in further increases in circulating glucose, to levels significantly greater than those of memory facilitating doses. These results suggest that memory modulation, both endogenous and in response to epinephrine injections, may be mediated in part by circulating glucose levels. Thus, the findings of these experiments support the view that circulating glucose levels regulate the efficacy of neural memory storage processes.     

Differential effects of subdiaphragmatic vagotomy on NaCl-induced aversion learning

The vagus nerve has been proposed in numerous studies as one of the peripheral mechanisms involved in drug-induced taste aversion learning, although available data have been controversial. The differential results obtained in the present series of experiments with vagotomy and NaCl-induced short-term and long-term aversion learning suggest that the vagal system plays a decisive role in tasks requiring the rapid detection of an aversive substance in the gastrointestinal tract (short-term tasks). In contrast, this mechanism appears to be unnecessary in long-term tasks, where learning may be mediated by alternative slower-acting peripheral mechanisms such as the humoral system.