Conditioning insulin effects.

It has previously been demonstrated that after a number of insulin injections in rats, an injection of a placebo leads to an elevation in blood sugar. It has been suggested that this apparent conditioned compensatory response is an artifact resulting from stressing the subject (when large doses of insulin are used) or represents a nonassociative phenomenon (when small doses of insulin are used). These two suggestions were rejected on the basis of the results of Experiments 1 and 2, respectively. Experiments 3 and 4 demonstrated that although the behavioral effects of insulin can be conditioned to the injection procedure, such conditioned insulinlike behaviors (contrary to suggestions of many investigators) are not mediated by a pypoglycemic state.     

Conditioning of successive adaptive responses to the initial effects of drugs

Data in the literature indicate that conditioned responses (CRs) generated by repeated pairing of conditional stimulus (CS) with administration of a neurotropic drug may resemble its unconditional effects or they may be opposite in direction; furthermore, the CRs may change as such pairings are continued. In explanation, it is hypothesized that as in conditioning of physiological reflexes, a CS repeatedly paired with administration of a neurotropic drug eventually comes to activate central“processing” events that are evoked by the“stimulus” properties of the drug,i.e., the effects of the drug at receptor sites inside or outside the pia mater which lie in the afferent arms of“reflex” neural circuits; or, the CS comes to activate central processing events that are evoked by centripetal feedback responses to the effects of the drug at receptor sites in the processing or efferent arms of reflex neural circuits. Depending on the receptor site action of the drug, the conditioned autonomic and/or neuromuscular responses that are observed may be in the same direction as, or opposite in direction to the unconditioned effects of the drug. With continued pairings of CS and drug, the unconditioned processing events evoked by the stimulus properties of the drug, and hence the CRs also, change in consequence of compensatory (sometimes“overshooting”) biochemical alterations proximal to the receptor site of action of the drug, induced by negative or positive neuronal feedback mechanisms. These concepts are utilized in a theory of opiate addiction and relapse.     

The mutual influence of insulin and environmentally-conditioned central nervous system performance on the regulation of carbohydrate metabolism

Investigating the effects of insulin on carbohydrate metabolism and on the central nervous system (C.N.S.) under conditions of rest and of stress in dogs and in rats, using the conditional reflex method and measuring the nitrogen and phosphate brain metabolites and the blood sugar differences, the author found that cerebral glucose metabolism is dependent upon insulin, and that if glucose supplies are adequate, insulin stimulates C.N.S. performance within 15–20 minutes. The C.N.S. and blood sugar reactivity depend upon the environmental situation: the conditional stimuli for stress increase glycemia. Animals under stress went into shock even though their glycemic levels were relatively high, whereas those at rest did not go into shock or sometimes reacted with slight symptoms of somnolence even at a lower glycemic level. In experimental hyperglycemia the level rises even more during stress, with ensuing coma, especially with larger doses of insulin. An increase of inhibition with reduced learning precedes the glycemic irregularities. Thus, insulin directly influences the central nervous system.     

Memory improvement by glucose, fructose, and two glucose analogs: a possible effect on peripheral glucose transport

The memory-improving action of post-training, noncontingent injections of glucose was investigated in a series of experiments which examined the effects of several substances that interact with glucose metabolism on the retention of a conditioned emotional response and on blood glucose levels in male hooded rats. Although post-training glucose injections of 1, 2, and 3 g/kg all produced similar increases in blood glucose, only 2 g/kg improved retention, suggesting that attainment of a particular blood glucose level is not critical for memory improvement. Post-training injections of a range of insulin doses (0.25-4 IU/kg) failed to affect retention. Post-training injection of fructose (the same doses as were used for glucose) had no effect on blood glucose levels and, as with glucose, only the 2 g/kg dose improved retention. This finding suggests that blood glucose levels are not critical for the memory-improving effect, that glucose and fructose may act on the same substrate and, because fructose does not act directly on the brain, it raises the possibility that both substances act peripherally. Post-training injections of 2-deoxyglucose and 3-O-methylglucose both improved retention. The fact that these mostly nonmetabolized glucose analogs were effective suggests that the memory-improving action of glucose may depend on the activation of a membrane glucose transport mechanism. The implications of the possible action of glucose on peripheral transport mechanisms for understanding the effect of reinforcers on memory are discussed.     

Repeated diazepam administration reversed working memory impairments and glucocorticoid alterations in the prefrontal cortex after short but not long alcohol-withdrawal periods

The study was designed to assess whether repeated administration of diazepam (Valium®, Roche)—a benzodiazepine exerting an agonist action on GABA_A receptors—may alleviate both the short (1 week, 1W) and long-term (6 weeks, 6W) deleterious effects of alcohol withdrawal occurring after chronic alcohol consumption (6 months; 12% v/v) in C57/BL6 male mice. More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels in the prefrontal cortex (PFC). In a subsequent experiment, diazepam was administered i.p. for 9 consecutive days (1 injection/day) during the alcohol withdrawal period at decreasing doses ranging from 1.0 mg/kg to 0.25 mg/kg. Diazepam was not detected in the blood of withdrawn mice at the time of memory testing, occurring 24 hours after the last diazepam injection. Repeated diazepam administration significantly improved alternation rates and normalized levels of glucocorticoids and pCREB activity in the PFC in 1W but not in 6W withdrawn mice. Thus, repeated diazepam administration during the alcohol-withdrawal period only transitorily canceled out the working memory impairments and glucocorticoid alterations in the PFC of alcohol-withdrawn animals.     

Old and new controversies in the alternative treatment of attention-deficit hyperactivity disorder

Use of complementary and alternative medicine (CAM) for treatment of attention-deficit hyperactivity disorder (ADHD) has become widespread in both referral and primary care populations. We review the purported mechanism of action and available evidence for selected CAM therapies for ADHD. Enduring controversies, such as elimination of artificial food additives, colors, and/or preservatives; the effect of sugar on behavior in children; and the use of EEG biofeedback, have been well studied but lack support as effective sole treatments for ADHD. The initial evidence for some emerging CAM therapies, such as essential fatty acid supplementation, yoga, massage, homeopathy, and green outdoor spaces, suggests potential benefits as part of an overall ADHD treatment plan. More rigorously designed studies are needed to evaluate their effectiveness as single therapy for ADHD.     

Classical conditioning of blood pressure inMacaca mulatta with cardiac rate controlled

The interaction of heart rate and blood pressure responses was studied in four male rhesus monkeys (M. mulatta) during classical delay conditioning and extinction. During initial conditioning sessions, heart rate was held constant by means of an external cardiac pacemaker; in follow-up conditioning sessions, the heart was free of constraint. Observations were made after these conditioning sessions, (a) during several sessions given over to continued training while different pacing rates were in effect; (b) during a series of extinction sessions in which the heart was paced and unpaced; and, (c) when a heart rate CR was simulated by manipulation of the pacer with no conditioned or unconditioned stimuli present. Throughout all sessions, systolic and diastolic pressures were measured at each heart beat. It was found that blood pressure conditioning was largely unaffected when heart rate changes were prevented during acquisition. Extinction of blood pressure responses was also seen to proceed relatively unimpeded when the heart was paced at a fixed frequency. During the postacquisition conditioning sessions, the several different pacing rates that were tested did not produce any significant differential effects in the blood pressure CRs. Simulated heart rate CRs were accompanied by small changes in pressures, sometimes opposite in direction from the pressure CRs observed during unpaced conditioning trials.     

Heart rate changes accompanying jaw movement Pavlovian conditioning in rabbits: Concomitant blood pressure adjustments and effects of peripheral autonomic blockade

Two experiments were conducted to ascertain the cardiovascular accompaniments of differential Pavlovian jaw movement (JM) conditioning. The first examined the blood pressure (BP) changes that accompany the tachycardiac conditioned responses (CRs) associated with JM conditioning. The BP response in all instances consisted of a depressor response that was greater to the reinforced CS+ than CS-, although the magnitude of the CR was quite small. The second experiment determined the effects of peripheral autonomic antagonists on the cardiac accelerations associated with JM conditioning. It was found that the peripheral vagal antagonist methyl scopolamine completely abolished responses to both CS+ and CS-, whereas atenolol, a beta adrenergic antagonist, augmented the response, compared to saline control injections. The JM responses were also affected by the autonomic blockades, with minimal responding occurring in the scopolamine group but slightly more JM CRs in the atenolol group, compared to saline control animals. These results suggest that the major cardiovascular response to an appetitive stimulus, which evokes JM conditioning, consists of cardiac accelerations with the BP depressor responses playing a minimal, if any, role. Moreover, these conditioned cardiac increases appear to be due solely to the release of vagal inhibition.     

Stimulus complexity, EEG abundance gradients, and detection efficiency in a visual recognition task.

Occipital EEG was monitored while subjects inspected 27 projected patterns. The number (N) and variety (V) of elements in the patterns were varied systematically. There were three levels of N (6, 12 or 24 elements) and three levels of V (circles, squares or hexagons occupying all, one half or one third of the element locations for all levels of N). Subjects were instructed that they would be required in a post-test to recognize the patterns, among patterns which had not appeared; they were also informed that the patterns had been constructed according to a set of simple rules, but the nature of these rules was not made fully explicit. The EEG was quantified by means of low-frequency analysis, yielding measures of abundance (theta, alpha and beta) and mean dominant frequency. For the recognition task, nine stimulus items were embedded among 45 items. Recognition efficiency was measured by means of the signal detection theory discrimination index (d'). The results were as follows: (i) Both N and V were inversely related to alpha abundance (P less than 0-01); (ii) the strongest relationship between stimulus parameters and the EEG held for N and EEG beta activity (13-5-19-5 Hz;P less than 0-001), where again the EEG and N were inversely related; (iii) there was a significant (P less than 0-05) direct relationship between N and theta activity; (iv) contrary to prediction, mean dominant alpha frequency decreased as N increased; (v) d' correlated significantly with a number of effects for N, i.e. subjects who exhibited greatest EEG discriminability of items during exposure of the patterns, subsequently obtained the higher detection scores in the recognition task. The work described therefore demonstrates that only only do stimulus parameters have systematic effects upon brain activity as measured by the EEG, but that such effects have functional value and reflect aspects of efficiency. The results are fully compatible with arousal theory constructs relating physiological reactivity and performance.     

Heart Rate Changes Accompanying Jaw Movement Pavlovian Conditioning in Rabbits: Concomitant Blood Pressure Adjustments and Effects of Peripheral Autonomic Blockade

Two experiments were conducted to ascertain the cardiovascular accompaniments of differential Pavlovian jaw movement (JM) conditioning. The first examined the blood pressure (BP) changes that accompany the tachycardiac conditioned responses (CRs) associated with JM conditioning. The BP response in all instances consisted of a depressor response that was greater to the reinforced CS+ than CS-, although the magnitude of the CR was quite small. The second experiment determined the effects of peripheral autonomic antagonists on the cardiac accelerations associated with JM conditioning. It was found that the peripheral vagal antagonist methyl scopolamine completely abolished responses to both CS+ and CS-, whereas atenolol, a beta adrenergic antagonist, augmented the response, compared to saline control injections. The JM responses were also affected by the autonomic blockades, with minimal responding occurring in the scopolamine group but slightly more JM CRs in the atenolol group, compared to saline control animals. These results suggest that the major cardiovascular response to an appetitive stimulus, which evokes JM conditioning, consists of cardiac accelerations with the BP depressor responses playing a minimal, if any, role. Moreover, these conditioned cardiac increases appear to be due solely to the release of vagal inhibition.     

Potentiation and overshadowing in odor-aversion learning: Role of method of odor presentation,the distal-proximal cue distinction,and the conditionability of odor

Four experiments with rat subjects examined interactions between odors and tastes in compound aversion conditioning. In Experiments 1 and 2, a saccharin taste potentiated the conditioning of an almond odorant presented on a cup near the location of the drinking spout, but overshadowed the same odorant when it was mixed in drinking water. This difference depended on the type of odor administered during conditioning rather than testing (Experiment 2). Experiments 3 and 4 examined implications of two other differences between the cup and drink odors: (1) while the cup odor was a distal cue that suppressed approach to the spout, the drink odor was primarily a proximal cue that suppressed consumption, and (2) the cup odor was less conditionable than the drink odor when the stimuli were conditioned alone. In Experiment 3, unlike the proximal saccharin taste, the proximal drink odor failed to potentiate the conditioning of a different distal odor. In Experiment 4, substantial dilution of the proximal drink's concentration resulted in both weaker conditioning of the stimulus alone, and potentiation of its conditioning by saccharin. The results suggest that the difference in the conditionability of the cup and drink odors, and not their status as distal and proximal cues, may be critical in the production of potentiation. Weakly conditionable target stimuli are uniquely potentiated by saccharin.     

Relations between infants’ emerging reach‐grasp competence and event‐related desynchronization in EEG

Recent reports of similar patterns of brain electrical activity (electroencephalogram: EEG) during action execution and observation, recorded from scalp locations over motor‐related regions in infants and adults, have raised the possibility that two foundational abilities – controlling one's own intentional actions and perceiving others’ actions – may be integrally related during ontogeny. However, to our knowledge, there are no published reports of the relations between developments in motor skill (i.e. recording actual motor skill performance) and EEG during both action execution and action observation. In the present study we collected EEG from 21 9‐month‐olds who were given opportunities to reach for toys and who also observed an experimenter reach for toys. Event‐related desynchronization (ERD) was computed from the EEG during the reaching events. We assessed infants’ reaching‐grasping competence, including reach latency, errors, preshaping of the hand, and bimanual reaches, and found that desynchronization recorded in scalp electrodes over motor‐related regions during action observation was associated with action competence during execution. Infants who were more competent reachers, compared to less competent reachers, exhibited greater ERD while observing reaching‐grasping. These results provide initial evidence for an early emerging neural system integrating one's own actions with the perception of others’ actions.     

Action effects in saccade control

According to the ideomotor principle, action preparation involves the activation of associations between actions and their effects. However, there is only sparse research on the role of action effects in saccade control. Here, participants responded to lateralized auditory stimuli with spatially compatible saccades toward peripheral targets (e.g., a rhombus in the left hemifield and a square in the right hemifield). Prior to the imperative auditory stimulus (e.g., a left tone), an irrelevant central visual stimulus was presented that was congruent (e.g., a rhombus), incongruent (e.g., a square), or unrelated (e.g., a circle) to the peripheral saccade target (i.e., the visual effect of the saccade). Saccade targets were present throughout a trial (Experiment 1) or appeared after saccade initiation (Experiment 2). Results showed shorter response times and fewer errors in congruent (vs. incongruent) conditions, suggesting that associations between oculomotor actions and their visual effects play an important role in saccade control.     

Electroencephalographic registration of low concentrations of isoamyl acetate

Previous research has demonstrated electroencephalogram (EEG) changes in response to low-odor concentrations, resulting in near-chance detection. Such findings have been taken as evidence for olfaction without awareness. We replicated and extended previous work by examining EEG responses to water-water control, 0.0001, 0. 001, 0.01, and 1 ppm isoamyl acetate (IAA) in water paired with water only. Detection was above chance (>50%) for.001 and above, and alpha decreased only to those concentrations, suggesting that EEG changes corresponded to IAA awareness. However, when correct trial EEGs were compared to incorrect trial EEGs during.001 ppm, right posterior/central alpha decreased during incorrect trials and alpha decreased more globally (including frontal sites) during correct trials. These data may not reflect awareness or unawareness per se. Instead, results are discussed regarding activation of perceptual systems in the posterior region during incorrect trials and the activation of frontal action systems during a subset of correct trials.     

Hippocampal lesions and pavlovian cardiovascular conditioning

New Zealand albino rabbits received either sham, cortical control, or hippocampal lesions and were subjected to differential Pavlovian conditioning in which tones of different frequencies served as conditional stimuli (CSs), and a brief paraorbital electric shock train served as the unconditional stimulus. Heart rate (HR), blood pressure (BP), and electromyographic (EMG) conditional responses (CRs) were recorded. Animals with cortical and hippocampal damage or animals with cortical damage alone revealed attenuated bradycardiac CRs, but HR CRs of the former two groups did not significantly differ. BP changes were minimal; reliable differences were not obtained between CS+ and CS?. However, these changes consisted of small but reliable depressor responses, which were not affected by either cortical or hippocampal lesions. Few EMG CRs were obtained. These data, combined with those of previous experiments, suggest that forebrain structures may modulate higher level processing of stimulus information, perhaps in terms of assessing the biological significance of such stimulation.     

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.     

Brain mechanisms in fatal cardiac arrhythmia.

Intravenous injection of histamine to rabbits was used as a prototype in an investigation of the mechanism of sudden death due to anaphylaxis and other causes. The "dive" reflex, bradycardia due to activation of the ophthalmic branch of the fifth cranial nerve, was induced in thirty-seven of the animals while they inhaled a very small amount of cigarette smoke. Associated with the resulting bradycardia were lowered blood pH and increased serum content of lactic acid and potassium and increased peripheral arterial constriction with elevation of diastolic blood pressure. Intravenous injection of 1 ml of histamine in the presence of the dive reflex induced potentially fatal ventricular arrhythmia, but no cardiac disturbance when administered while the dive reflex was inactive, thereby strongly suggesting that sudden death in anaphylaxis may involve an overzealous response to a normally protective neural reflex.     

Brain mechanisms in fatal cardiac arrhythmia

Intravenous injection of histamine to rabbits was used as a prototype in an investigation of the mechanism of sudden death due to anaphylaxis and other causes. The “dive” reflex, bradycardia due to activation of the ophthalmic branch of the fifth cranial nerve, was induced in thirty-seven of the animals while they inhaled a very small amount of cigarette smoke. Associated with the resulting bradycadia were lowered blood pH and increased serum content of lactic acid and potassium and increased peripheral arterial constriction with elevation of diastolic blood pressure. Intravenous injection of 1 ml of histamine in the presence of the dive reflex induced potentially fatal ventricular arrhythmia, but no cardiac disturbance when administered while the dive reflex was inactive, thereby strongly suggesting that sudden death in anaphylaxis may involve an overzealous response to a normally protective neural reflex.     

Classical conditioning of the nictitating membrane response of the lemon shark (Negaprion brevirostris)

An experimental group of lemon sharks received 100 daily presentations of light flash as the conditioned stimulus (CS) and electric shock as the unconditioned stimulus (US) in a classical conditioning situation. The conditioned responses (CRs) and unconditioned responses (URs) under observation consisted of extensions of the nictitating membrane. Separate control groups received either (a) no CS or US, (b) CS-alone, or (c) completely random presentations of CS and US. Few CRs occurred in the experimental group at the outset of conditioning, but the percentage of CRs during the second half of the first acquisition session exceeded 95%. Conditioning stabilized above 95% CRs during Acquisition Sessions 3 through 7. These responses could not be attributed to pseudoconditioning, sensitization, or other nonassociative factors. When the experimental group was subsequently given six CS-alone sessions, the course of extinction was gradual. Most results seemed similar to those previously obtained during classical conditioning of the nictitating membrane in rabbits.     

Selective autonomic blockade of conditioned and unconditioned cardiovascular changes in rhesus monkeys (Macaca mulatta).

Changes in heart rate and in systolic and diastolic blood pressures were examined in eight rhesus monkeys during six sessions of differential classical conditioning. The conditioned stimuli consisted of tones differing in frequency and the unconditioned stimuli consisted of tail shock. Both the conditioned responses (CRS) and unconditioned responses (UCRs) consisted of increases in heart rate and in systolic and diastolic pressures, but blood pressure CRs sometimes occurred in the absence of heart rate CRs. Graded doses of the selective blocking agents propranolol, phentolamine, and atropine methylnitrate were systemically administered to four of the monkeys prior to additional conditioning sessions. The results suggested that the CRs and UCRs were mediated by both sympathetic and parasympathetic influences.