Neurocardiology shows that the central, not peripheral, action of propranolol reduces mortality following acute coronary artery occlusion in the conscious pig.

Neurocardiology emphasizes the role of the higher cerebral mechanisms in cardiovascular disorders. Several large clinical trials (BHAT, MIAMI, and ISIS) have consistently shown that treatment with a beta-receptor blocker (propranolol, metoprolol, or atenolol) will produce a 26% to 29% reduction in mortality in high-risk survivors of acute myocardial infarction. Because all beta-blockers cross the blood-brain barrier, it is not clear whether the salutary action is on the central or peripheral receptors. Therefore the effects of intracerebral versus intravenous propranolol were observed in 30 conscious pigs following complete occlusion of the left anterior descending coronary artery. Controls showed the propranolol to remain confined throughout the experiment to the central or peripheral compartment into which it was injected. To assure the occurrence of ventricular fibrillation (VF), each pig was psychologically stressed by being unconditioned to the laboratory. Intracerebral propranolol (0.05 mg/kg) prevented VF within a 20 min period of reversible ischemia in 6 of 9 pigs, whereas VF was prevented in 0 of 11 controls injected intravenously with either dextro-propranolol (2 pigs) or vehicle (9 pigs) (P less than .0006, binomial probability ratio). In some pigs in which VF was not manifested by 20 min, the ischemia was reversed and additional control observations were achieved; a total of 10 counter-balanced within-subjects experiments confirmed the between-subjects result (P less than .01, paired-t test). In contrast intravenous propranolol (0.2 to 2.0 mg/kg) in 7 pigs had no effect on VF latency compared to 7 vehicle controls. It is concluded that beta-receptor antagonists prevent VF in the ischemic myocardium by their effect on the brain and not the heart.     

Extinction of appetitive learning is disrupted by cycloheximide and propranolol in the sand maze in rats

The present study investigated whether memory for extinction in an appetitive task (the sand maze) could be attenuated by administration of cycloheximide (protein synthesis inhibitor) or propranolol (β-adrenergic receptor antagonist). Ninety-day-old male Long-Evans rats were trained to retrieve a sweet cereal reinforcer from an open container in the sand maze. One day following this non-spatial training, rats received three extinction trials in which they were placed in the maze with the reinforcer present, but unattainable. Thirty minutes prior to the first extinction trial, rats received an intraperitoneal injection of cycloheximide (1mg/kg), propranolol (25mg/kg), or vehicle (1mg/kg distilled water). Twenty-four hours later, rats were tested in the sand maze with the reinforcer again available. Results from the test trial showed that both cycloheximide and propranolol groups found the reinforcer more quickly than controls. Two weeks later, rats were trained on a spatial version of the sand maze in which they had to search for a buried reinforcer using extramaze cues. Cycloheximide and propranolol groups learned this task significantly faster than the control group, demonstrating the long-lasting effect of cycloheximide and propranolol on the blocking of memory for extinction.     

Progesterone to ovariectomized mice enhances cognitive performance in the spontaneous alternation, object recognition, but not placement, water maze, and contextual and cued conditioned fear tasks

Research on how steroid hormones mediate mnemonic processes have focused on effects of 17β-estradiol (E₂); yet, progesterone (P₄) co-varies with E₂ across endogenous hormonal milieu, and itself may influence cognitive processes. We investigated the hypothesis that acute P₄ treatment enhances cognitive performance compared to vehicle. Ovariectomized (OVX) c57/BL6J mice were randomly assigned to be subcutaneously injected with oil vehicle or P₄ (10 mg/kg). Mice were trained in the spontaneous alternation, object recognition, object placement, water maze, or fear conditioning tasks, and injected with vehicle or P₄ before training or immediately post-training, and then were tested 1, 4, or 24 h later. The data obtained from these experiments supported our hypothesis. P₄ increased the percentage of spontaneous alterations made in a T-maze more so than did vehicle. P₄, compared to vehicle, increased the percentage of time spent exploring the novel object in the object recognition task, but did not alter performance in the object placement task. P₄, compared to vehicle, decreased latencies to reach the location in the water maze where the platform had been during training in a probe trial, but did not alter performance in the control, cued trial. Compared to vehicle, P₄ treatment increased freezing in contextual and cued fear testing. Thus, acute P₄ treatment to OVX mice can improve cognitive performance across a variety of tasks.     

Effect of stress induced by electrical stimulation of the hypothalamus on the electrical stability of the heart in rabbits

The influence of stress on cardiac electrical stability (CES) and chaotic dynamics of the electrical activity of the heart was studied in acute and chronic experiments in rabbits. Stress was caused by 2-3 h daily immobilization of the animals with electrical stimulation of emotiogenic centers of the hypothalamus through implanted electrodes. CES was estimated by the thresholds for ventricular arrhythmia: paroxysmal ventricular tachycardia, repeated ventricular extrasystoles and ventricular fibrillation (VF). The results showed: (i) CES in stressed rabbits was decreased significantly compared with controls; (ii) the level of chaos at the onset of VF in stressed rabbits was increased significantly compared with controls; (iii) heart rate of stressed rabbits was significantly greater than in controls; (iv) changes in CES parameters depended on whether stress was acute or chronic; (v) acute stress promoted transition of spontaneously reversible VF into spontaneously irreversible VF. Thus, stress increased the degree of disorganization of heart electrical activity and also decreased its electrical stability. The experiments indicate that stress is a destabilizing factor influencing the reversibility of heart rate disorders. The probability of such reversibility depends on whether stress is acute or chronic: acute stress is more likely to lead to irreversible spontaneous VF.     

Deficits in the endogenous control of covert visuospatial attention in children with developmental coordination disorder

Deficits in the covert orienting of visuospatial attention have been reported in children with Developmental Coordination Disorder (DCD). Using two new versions of the covert orienting of visuospatial attention task (COVAT), the study presented here sought to investigate how generalised deficits are in this domain by using longer time intervals between cue and imperative stimulus. Twenty children with DCD and 20 controls were tested on two different COVATs with the interval between cue and peripheral imperative stimulus (or stimulus onset asynchrony, SOA) of 150 and 850 ms presented in a random sequence: the first used peripheral cues and no probability information (exogenous mode) and the second used central cues and an 80% probability that imperative stimuli would appear at the cued location (endogenous mode). Results showed that the time course of covert orienting to peripheral cues was normal in both groups. For central cues, however, children with DCD were more disadvantaged by invalid cues compared with controls, regardless of SOA; this finding was consistent with a deficit in the disengage operation of directing covert attention. These results confirm and extend our earlier finding that impairments in the endogenous control of covert visuospatial attention exist in children with DCD.PsycINFO classification: 2820; 2330; 2346; 3250     

The role of central and peripheral vision in perceiving the direction of self-motion

Three experiments were performed to examine the role that central and peripheral vision play in the perception of the direction of translational self-motion, or heading, from optical flow. When the focus of radial outflow was in central vision, heading accuracy was slightly higher with central circular displays (10°–25° diameter) than with peripheral annular displays (40° diameter), indicating that central vision is somewhat more sensitive to this information. Performance dropped rapidly as the eccentricity of the focus of outflow increased, indicating that the periphery does not accurately extract radial flow patterns. Together with recent research on vection and postural adjustments, these results contradict theperipheral dominance hypothesis that peripheral vision is specialized for perception of self-motion. We propose afunctional sensitivity hypothesis—that. self-motion is perceived on the basis of optical information rather than the retinal locus of stimulation, but that central and peripheral vision are differentially sensitive to the information characteristic of each retinal region.     

Administration of corticosterone after memory reactivation disrupts subsequent retrieval of a contextual conditioned fear memory: dependence upon training intensity

Reactivation of stabilized memories returns them to a labile state and causes them to undergo extinction or reconsolidation processes. Although it is well established that administration of glucocorticoids after training enhance consolidation of contextual fear memories, but their effects on post-retrieval processes are not known. In this study, we first asked whether administration of corticosterone after memory reactivation would modulate subsequent expression of memory in rats. Additionally, we examined whether this modulatory action would depend upon the strength of the memory. We also tested the effect of propranolol after memory reactivation. Adult male Wistar rats were trained in a fear conditioning system using moderate (0.4 mA) or high shock (1.5 mA) intensities. For reactivation, rats were returned to the chamber for 90 s 24h later. Immediately after reactivation, rats were injected with corticosterone (1, 3 or 10mg/kg) or vehicle. One, 7 and 14 days after memory reactivation, rats were returned to the context for 5 min, and freezing behavior was scored. The findings indicated that corticosterone when injected after memory reactivation had no significant effect on recall of a moderate memory, but it impaired recall of a strong memory at a dose of 3mg/kg. Propranolol (5mg/kg) given after the reactivation treatment produced a modest impairment that persisted over three test sessions. Further, the results showed that corticosterone, but not propranolol deficit was reversed by a reminder shock. These findings provide evidence that administration of glucocorticoids following memory reactivation reduces subsequent retrieval of strong, but not moderate, contextual conditioned fear memory likely via acceleration of memory extinction. On the other hand, propranolol-induced amnesia may result from blockade of reconsolidation process. Further studies are needed to determine the underlying mechanisms.     

Chronic propranolol induces deficits in retention but not acquisition performance in the water maze in mice

Agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, reports suggest that beta-adrenergic receptor antagonists, such as propranolol, have conflicting behavioral effects with acute vs chronic dosing. This study was designed to evaluate the effects of chronic propranolol on retention for a spatial learning task. Adult male ICR mice were given daily injections of propranolol (2, 4, 8, or 12 mg/kg ip) or 0. 9% NaCl for 15 days prior to, and during, trials in a Morris water maze. Mice received five massed acquisition (escape) trials in each of three daily sessions, followed by a single 60-s probe trial on the fourth day. The location of the submerged platform was constant for each animal over acquisition trials, but varied across animals; starting position varied across trials. A 5 (dose) x 3 (trial blocks) mixed factorial ANOVA for escape time yielded a significant trial blocks effect only (p <.001), showing performance improving over sessions. Time spent in the target quadrant on the probe trial was shorter under all doses of propranolol when compared to vehicle group (all p <.001), indicating poorer retention of prior platform location. This effect, however, was not dose-related. Swim speed was not significantly affected by propranolol. These data demonstrate that chronic dosing with propranolol can impair retention of spatial learning, which cannot be attributed to reduced arousal or motor function.     

Cholinergic blockade, septal lesions, and DRL performance in the rat.

Four experiments describing the effects of cholinergic blockade produced by systemic injection of either atropine sulfate or atropine methyl nitrate on the differential reinforcement of low rate (DRL) responding of rats are reported. It was shown that atropine sulfate injected either chronically or at high dosage suppressed DRL responding. Injected acutely, atropine sulfate produced disinhibitory effects. When atropine was injected either chronically or acutely into animals with septal lesions, there was suppression of responding. It was suggested that the specific behavioral outcome resulting from cholinergic blockade depends on the balance resulting from the competing peripheral and central effects of such blockade.     

Organisational effects of neonatal and pubertal testosterone on sexually differentiated behaviours in the open-field and head-dip apparatus

On days 1 and 4 after birth rats were injected with 100 μg of testosterone propionate (TP) or vehicle, and at 35 days of age they were injected intramuscularly with 400 μg of testosterone oenanthate (TO), a long acting androgen, or the vehicle. There were four groups (oil-oil, TP-oil, oil-TO, TP-TO), each group subdivided by sex. Females treated with testosterone neonatally or at puberty were masculinised or defeminised on adult open-field behaviours, being less active and rearing less than oil-oil females; the oil-TO group also defaecated significantly more than controls. The TP-TO female group was indistinguishable from the oil-TO group. In a second experiment, sex differences were found in head-dipping behaviour as well as in activity and rearing. Females treated with TP or TO reared less and defaecated more than controls, and TP also decreased activity, but neither hormone treatment affected head-dipping behaviour. There is thus a peripubertal as well as a neonatal period when testosterone can act organisationally to masculinise or defeminise female rats. Potentiation between effects of neonatal and pubertal androgens was found on female body weights. TO alone had no effect, but TP-TO females were significantly heavier than controls at 90 days of age and by 130 days of age the TP-oil group was also heavier than controls.     

Facilitation of inhibitory avoidance by hypertonic saline is reversed by a vasopressin and a nicotinic antagonist

Hypertonic saline (1 ml of 0.25, 0.50, and 1.00 M NaCl, ip) facilitated retention of a one-trial, step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. A similar result was obtained after a subcutaneous injection of lysine vasopressin (LVP, 0.03 microgram/kg). Neither hypertonic saline nor LVP modified latencies to step-through of mice that had not received a footshock during training. The enhancement of retention produced both by hypertonic saline and by LVP was prevented by the vasopressin receptor antagonist AAVP (0.01 microgram/kg, sc) given after training, but 10 min before the treatments. The effect of hypertonic saline was also prevented by the central acting cholinergic nicotinic receptor antagonist mecamylamine (5 mg/kg, sc). On the contrary, neither hexamethonium (5 mg/kg, sc), a peripheral acting nicotinic receptor blocker, nor atropine (0.5 mg/kg, sc) or methylatropine (0.5 mg/kg, sc), two anticholinergic drugs which are known to act on cholinergic muscarinic receptors, prevented the effect of post-training hypertonic saline. These results suggest that a peripheral osmotic stimulus, probably through an endogenous release of vasopressin, may be behaviorally significant, and are consistent with the view that vasopressin may modulate the activity of central cholinergic nicotinic mechanisms which are critical for the behavioral change observed.     

Visual disengagement in young infants in relation to age,sex, SES,developmental level and adaptive functioning

Visual attention plays a key role in infants’ interaction with the environment, and shapes their behavioral and brain development. As such, early problems with flexibly switching gaze from one stimulus to another (visual disengagement) have been hypothesized to lead to developmental difficulties (e.g. joint attention and social skills) over time. This study aimed to identify cross-sectional associations between performance in the Gap task (gaze shift latencies and visual attention disengagement) and measures of development and adaptive behavior in conjunction to any sex or socioeconomic status effects in infancy. We measured visual attention disengagement in 436 5-month-old infants and calculated its association with cognitive developmental level, adaptive behaviours, socioeconomic status (SES) and biological sex. In the Gap task, participants must redirect their gaze from a central stimulus to an appearing peripheral stimulus. The three experimental conditions of the task (Gap, Baseline and Overlap) differ on the timepoint when the central stimuli disappears in relation to the appearance of the peripheral stimulus: 200 ms before the peripheral stimulus appears (Gap), simultaneously to its appearance (Baseline), or with peripheral stimulus offset (Overlap). The data from the experimental conditions showed the expected pattern, with average latencies being the shortest in the Gap and longest in the Overlap condition. Females were faster (p = .004) than males in the Gap condition, which could indicate that arousal-related effects differ as a function of biological sex. Infants from higher SES were slower (p = .031) in the Overlap condition compared to lower SES infants. This suggests that basic visual attention may differ by socio-cultural background, and should be considered when studying visual attention and its developmental correlates. We observed no significant association to concurrent developmental level or adaptive function. Given its large sample size, this study provides a useful reference for future studies of visual disengagement in early infancy.     

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.     

Apparent shift in visual field preference after unilateral stroke

Patients with either a left- or a right-hemisphere stroke lesion scored higher in tasks of word-picture matching and of nonverbal shape matching when information was presented tachistoscopically (120 msec) to the visual field (VF) projecting to their undamaged hemisphere. Left-hemisphere stroke patients (n = 13) were dissociated from right-hemisphere stroke patients (n = 15) by low word recognition from memory and by low right VF but nearly normal left VF accuracy in word-picture matching or shape matching; the former appeared to rely upon processing of word meaning by the right hemisphere. In contrast, right-stroke patients had higher right than left VF scores in both tasks, and their discrimination of nonverbal shapes via the right VF was not different from that of controls (n = 15). Preferred processing by the VF projecting to the undamaged hemisphere appeared as a shift in perceptual asymmetry but may indicate, in support of a "direct access" model, that each hemisphere responds more or less efficiently to word and to nonverbal shape discriminations.     

Bacterial Melanin Improves Cognitive Impairment Induced by Cerebral Hypoperfusion in Rats

The effect of bacterial melanin (BM) solution on learning and memory impairment induced by chronic cerebral hypoperfusion in rats was studied. Male rats were injected intramuscularly with BM solution on the second day after bilateral permanent occlusion of the common carotid artery. Rats received 6 mg/ml (170 mg/kg) BM and performed significantly better in cognition tests compared with controls. The present findings demonstrate that the beneficial effects of BM injection on cognitive functions may be due to preventing neuropathological alterations, suppressing the inflammation process, stimulating vascularization and inhibiting oxidative damage. Obtained data suggest that BM has therapeutic potential for the treatment of neurodegeneration caused by ischemia.     

Form symbolism, analogy, and metaphor

Simple forms, such as a square and a circle, can be symbolic; for example, a square can be deemed to behard and a circle to besoft. The relation between form symbolism and the comprehension of metaphors and analogies was studied in three experiments. Subjects were asked to rate matches between terms such assoft andhard andcircle andsquare as symbols (Experiment 1), metaphors (Experiment 2), and analogies (Experiment 3). The results show that a highly rated symbolic relation could be a poorly rated metaphorical relation. Ratings of analogies were similar to ratings of symbols. We argue that apt metaphors, analogies, and symbolic forms claim that the vehicle and the topic of the comparisons have common features, but that metaphoric representation entails more common features than does either symbolism or analogy, because metaphor requires that the vehicle be an especially apt example of a superordinate class. Thus, metaphor is a particularly strong claim about common features shared by the topic and the vehicle.     

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.     

Substance P is involved in terminating the hypothalamo- pituitary-adrenal axis response to acute stress through centrally located neurokinin-1 receptors

The neurokinin substance P (SP) has been previously shown to inhibit basal hypothalamo-pituitary-adrenal (HPA) axis activity. This study was designed to investigate the effects of central injection of the specific neurokinin-1 receptor antagonist RP67580 on the HPA axis response to acute restraint stress. In non-restrained rats injected with RP67580, plasma ACTH and corticosterone levels were elevated at 30 and 60 min compared to rats injected with vehicle, but there were no differences between vehicle and RP67580 groups at 4h. In restrained rats injected with vehicle, plasma ACTH and corticosterone levels were significantly elevated at 30 min and 60 min following initiation of the stress but had returned to basal levels at 4h. In restrained rats injected icv with RP67580, plasma corticosterone and ACTH levels were significantly elevated at 30 min and 60 min, with no significant differences compared to the restraint stressed vehicle-injected group. However, in the RP67580-injected group, corticosterone and ACTH levels remained significantly elevated at 4h following onset of restraint compared to those in the restraint stressed vehicle-injected group. Corticotrophin-releasing factor mRNA levels in the parvocellular subdivision of the paraventricular nucleus of the hypothalamus and POMC mRNA levels in the anterior pituitary were significantly increased in the stressed group 4h following injection with RP67580 compared to the stressed group injected with vehicle alone. These data show that endogenous SP does not inhibit the initial magnitude of the HPA axis response to restraint stress, but does act through neurokinin-1 receptors at a central level to reduce the duration of the response to stress. This suggests that SP may be an important central agent controlling the transition between acute and chronic stress.     

The effects of beta-noradrenergic receptor blockade on acquisition of eyeblink conditioning in 3-month-old F344 rats

There is evidence that blocking beta-noradrenergic receptors will cause deficits in some forms of learning. We investigated the effects of systemic injections of 1, 5, and 10 mg/kg doses of propranolol on acquisition of delay eyeblink conditioning in 3-month-old Fischer 344 rats. We presented a 3-kHz, 90-dB tone as a conditioning stimulus and a 6 psi airpuff as our unconditioned stimulus to freely moving rats. We monitored eyelid activity using EMG signals. The treatment subjects were injected with either propranolol or saline 0.5 h prior to daily training sessions. Two groups of control subjects, one receiving injections of saline and one receiving injections of 5 mg/kg propranolol, received daily training sessions with unpaired and randomized presentation of the tone and airpuff. Each daily training session for the treatment groups consisted of 27 paired training trials and 3 conditioned stimulus-alone training trials. Rats injected with saline vehicle or with 1 mg/kg propranolol achieved a 60% or better learned response rate within two training sessions. Rats injected with 5 or 10 mg/kg propranolol never achieved a response rate significantly different from animals that received unpaired, random presentations of the tone and airpuff stimuli. These results agree with prior studies from our lab that have shown a dose-dependent effect of beta-noradrenergic receptor blockade on learning in rabbit eyeblink conditioning as well as in a runway, motor learning paradigm. We believe that the beta-noradrenergic system plays an important role in learning and memory in more than one cerebellar-dependent learning paradigm.     

Perceptual order and the effect of vocalic context on fricative perception

This three-part study demonstrates that perceptual order can influence the integration of acoustic speech cues. In Experiment 1, the subjects labeled the [s] and [∫] in natural FV and VF syllables in which the frication was replaced with synthetic stimuli. Responses to these “hybrid” stimuli were influenced by cues in the vocalic segment as well as by the synthetic frication. However, the influence of the preceding vocalic cues was considerably weaker than was that of the following vocalic cues. Experiment 2 examined the acoustic bases for this asymmetry and consisted of analyses revealing that FV and VF syllables are similar in terms of the acoustic structures thought to underlie the vocalic context effects. Experiment 3 examined the perceptual bases for the asymmetry. A subset of the hybrid FV and VF stimuli were presented inreverse, such that the acoustic and perceptual bases for the asymmetry were pitted against each other in the listening task. The perceptual bases (i.e., the perceived order of the frication and vocalic cues) proved to be the determining factor. Current auditory processing models, such as backward recognition masking, preperceptual auditory storage, or models based on linguistic factors, do not adequately account for the observed asymmetries.