Pain-reducing properties of rewarding electrical brain stimulation in the rat.

In 4 experiments with 13 male Charles River rats, electrodes implanted along the medial forebrain bundle were screened for self-stimulation and stimulation-induced analgesia. Analgesia was defined by changes in unconditioned or escape responses to footshock. Almost all electrodes produced both self-stimulation and analgesia or neither. Thresholds for the 2 effects were highly correlated. Brain stimulation produced an analgesic aftereffect comparable in duration with the poststimulation enhancement of performance in self-stimulation (the priming effect). The refractory period of neurons underlying analgesia, assessed by behavioral means, was similar to that previously found for the priming effect in self-stimulation (.8-1.2 msec). Results suggest a common neural system mediating electrical analgesia and the priming effect of self-stimulation. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Refractory periods of neurons directly excited in stimulus-bound eating and drinking in the rat.

Studied male hooded rats to determine whether the amygdaloid, or the brainstem, or neither population of neurons is involved in eating and drinking. Latency to the onset of eating or drinking became short when the intrapair interval of twice-threshold stimulating pulse pairs was increased beyond .50-.65 msec. This indicates that the absolute refractory periods of neurons directly excited in eating and in drinking elicited by lateral hypothalamic stimulation are between .50-.70 msec. The previous finding that the absolute refractory period characteristic of basolateral amygdaloid neurons directly excited by the same lateral hypothalamic stimulation is also in this range is considered evidence that the amygdaloid neurons are involved in the eating and drinking. Results also indicate either that the eating and drinking are elicited through different neurons with similar characteristics, or through the same neurons. (17 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

"Temporal summation decay" in hypothalamic self-stimulation: Threshold changes at long intrapair intervals due to axonal subnormal periods.

Rats were trained to bar press for trains of conditioning (C) and test (T) pulses delivered via lateral hypothalamic electrodes. As intrapair (C–T) intervals increased from 10 msec to 100 msec, the frequency of pulses required for self-stimulation increased, similar to results of N. S. Smith and E. E. Coons (1970). This effect was observed only for electrode placements where self-stimulation was obtained at frequencies below 16 Hz and currents of 600 μA and higher. The effect was larger when the train duration was increased from 0.5 sec to 2.0 sec. The threshold increase was abolished when the T pulses were greater in current than the C pulses but not when C pulses were larger than T pulses. The larger T pulses also removed relative refractory period effects at a C–T interval of 1.0 msec. Therefore, the increase in required current or frequency at long C–T intervals appears to be due to a decline in axonal excitability (i.e., the subnormal period) rather than a decay in synaptic temporal summation. Possible flaws in other reports of paired-pulse "temporal summation decay" at long C–T intervals using 2 electrodes are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rapid synaptic transmission in the avian ciliary ganglion is mediated by two distinct classes of nicotinic receptors

We analyzed the kinetics and pharmacology of EPSCs in two kinds of neurons in the embryonic avian ciliary ganglion. Whole-cell voltage-clamp recordings revealed that the singly innervated ciliary neurons had large-amplitude (1.5-8.0 nA) EPSCs that could be classified according to the kinetics of their falling phases. Most of the neurons responded with an EPSC the falling phase of which followed a double exponential time course with time constants of approximately 1 and 10 msec. The EPSCs of the remaining ciliary neurons followed a single time constant ( approximately 8 msec). Multiple innervated choroid neurons had smaller-amplitude responses (0.2-1.5 nA when all inputs were activated) that appeared to contain only a slowly decaying component (tau = 12 msec). The fast and slow components of EPSC decay seen in most ciliary neurons could be pharmacologically isolated with two toxins against nicotinic acetylcholine receptors (AChRs). The fast component was blocked by 50 nM alpha-bungarotoxin (alpha-BuTx), which binds alpha7-subunit-containing AChRs. The slow component was selectively blocked by 50 nM alpha-conotoxin MII (alpha-CTx-MII), which blocks mammalian AChRs containing an alpha3/beta2 subunit interface. A combination of both alpha-BuTx and alpha-CTx-MII abolished nearly all evoked current. Similar pharmacological results were found for ciliary neurons with monoexponentially decaying EPSCs and for choroid neurons. These results suggest that nerve-evoked transmitter acts on at least two different populations of AChRs on autonomic motor neurons in the ciliary ganglion.     

A behavioral study of temporal processing and visual persistence in young and aged rats.

Young rats were presented with light flash prepulses varying in duration from 1 to 128 msec, with light offset or light onset fixed at 70 msec prior to an acoustic startle stimulus (Experiment 1A), and, with single or paired 1-msec flashes, the 2nd (or only) flash given 100 to 500 msec before the startle, and 1 msec to 400 msec interflash intervals (Experiment 1B). Older rats (10 and 20 mo old) received the same single and double flashes but with the maximum interflash interval extended to 1,500 msec (Experiment 2). Reflex inhibition increased with increased duration from 1 to 8 msec and decreased as light onset progressively exceeded 100 msec. Inhibition for both single and double flashes also declined for onset lead times beyond 100 msec, then increased for a double flash once the interflash interval exceeded 100 msec in young and middle-aged rats and 1,500 msec in the oldest rats. Peak inhibition was much reduced in the oldest rats at short lead times but was greater than that of younger rats at long lead times. These data suggest that aged rats process visual stimuli more slowly than younger rats and show poorer temporal acuity coupled with greater visual persistence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes in self-stimulation at stimulation-bound eating and drinking sites in the lateral hypothalamus during food or water deprivation, glucoprivation, and intracellular or extracellular dehydration.

Examined the effects of hunger induced by food deprivation, 2-deoxy-{d}-glucose (200 mg/kg), or insulin (2 U/kg) and thirst induced by water deprivation, sodium chloride (4 M), or polyethylene glycol (5 ml of 30% w/w) on lateral hypothalamic self-stimulation in 40 male Long-Evans rats. Changes in self-stimulation were evaluated at electrodes that produced stimulation-bound eating and/or drinking or neither behavior. Daily 30-min test sessions consisted of 3 5-min periods of self-stimulation alternated with 3 5-min periods when barpresses resulted in 5-sec time-out from experimenter-delivered stimulation (stimulation escape). Food deprivation significantly increased self-stimulation; insulin, 2-deoxy-{d}-glucose, and sodium chloride significantly suppressed self-stimulation; water deprivation mildly inhibited self-stimulation; and polyethylene glycol had no effect. This pattern of findings was noted at electrodes that did and those that did not elicit eating and/or drinking. Findings do not support the hypothesis that the magnitude of lateral hypothalamic self-stimulation is differentially and predictably controlled by specific drive mechanisms indexed by the consummatory behaviors also elicited by the stimulation. (41 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Food intake and lateral hypothalamic self-stimulation covary after medial hypothalamic lesions or ventral midbrain 6-hydroxydopamine injections that cause obesity.

In rats with perifornical lateral hypothalamic (LH) electrodes that induced feeding, self-stimulation through the same electrodes increased immediately after ventromedial hypothalamic (VMH) lesions and did not return to normal until food intake normalized and the rats had become obese. A unilateral far-LH lesion decreased feeding and contralateral perifornical LH self-stimulation. 6-hydroxydopamine (6-OHDA) injected into the midbrain to destroy the ventral noradrenergic bundle (VNAB) caused hyperphagia and increased LH self-stimulation. In summary, VMH or VNAB damage increased feeding and self-stimulation; contralateral far-LH damage decreased both. Results confirm the earlier suggestion that the VMH region is necessary for normal inhibition of feeding and feeding reward as reflected in self-stimulation rate. Although massive 6-OHDA-induced depletion of the dopamine system that passes through the LH can cause starvation and impair self-stimulation, results suggest that selective catecholamine depletion of ventral midbrain neurons with sparing of the A9 and A10 dopaminergic cells can disinhibit feeding and self-stimulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of electric stimulation of the dentate nucleus of the cerebellum on neuronal activity of the centrum medianum of the optic thalamus

Electrical stimulation of the cerebellar dentate nucleus elicits in neurons of the center median responses with either constant or altering latencies. The constant latencies ranged from 2-3 to 8-12 msec. Responses with altering latencies were more numerous and had the latencies up to 20 msec. In both responses with early and late components were recorded as well. Dentate stimulations induced "periods of inhibition" in CM neurons with leading duration of 50-100 msec. Synchronization of the SM unit activity during low-frequency stimulation was also revealed, in many cases it was preceded by the "periods of inhibition". Activity of 49% of reactive neurons during 1, 7-12, and 70-100/sec stimulations was facilitated, 31% depressed, and 20% had a mixed type of responses: facilitation on one frequency and depression on another. Immediate cessation of the effects after termination of stimulations was observed in 34% of neurons, while tonic influences were manifest in 66%.     

The paired-pulse index: a measure of hippocampal dentate granule cell modulation

This study was undertaken to assess whether the paired-pulse index (PPI) is an effective measure of the modulation of dentate granule cell excitability during normal development. Paired-pulse stimulations of the perforant path were, therefore, used to construct a PPI for 15-, 30-, and 90-day old, freely moving male rats. Significant age-dependent differences in the PPI were obtained. Fifteen-day old rats showed significantly less inhibition at short interpulse intervals [interpulse interval (IPI): 20 to 30 msec), a lack of facilitation at intermediate IPIs (50 to 150 msec), and significantly less inhibition at longer IPIs (300 to 1,000 msec) than adults.     

Refractory periods of neurons mediating stimulation-elicited eating and brain stimulation reward: Interval scale measurement and tests of a model of neural integration.

Paired-pulse stimulation methods have been used in many studies to measure the excitability properties of the directly stimulated neurons mediating stimulation-elicited behaviors. The present study quantitatively evaluated the methods with 7 male Sprague-Dawley rats in 2 experiments. The most frequently used method, in which rate of behavior is measured as a function of conditioning–test (C–T) interval, was inadequate since the results obtained depended on the frequency of stimulation. To account for this dependence, a physical model of brain stimulation that implies that the effects of frequency and C–T interval should be multiplicative is proposed. In separate experiments, conjoint and functional measurement methods were used to test this model and to measure the refractory periods of neurons mediating stimulation-elicited eating and brain stimulation reward. Results support the multiplicative model for C–T intervals in the refractory period range (.4–2.0 msec) and indicate that the frequency threshold method (J. S. Yeomans, see PA, Vol 55:11721; and the present Exp II) provides interval scale measurement of refractory period effects. The refractory period curves obtained for neurons mediating stimulation-elicited eating and brain stimulation reward were similar, rising steeply at C–T intervals from .4 to 1.2 msec and more gradually at intervals from 1.2 msec to 2.0 msec. (52 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of amphetamine and food deprivation on self-stimulation of the lateral hypothalamus and medial frontal cortex.

Intracranial self-stimulation of the lateral hypothalamus in 5 male Sprague-Dawley rats was markedly increased by subcutaneous dextroamphetamine administration and by food deprivation. In contrast, similar self-stimulation response rates obtained in the same Ss from the medial frontal cortex were unaffected by food deprivation and only slightly increased by dextroamphetamine administration. Furthermore, a large difference between dextro- vs levoamphetamine on response rate was obtained for lateral hypothalamic but not for medial frontal cortex self-stimulation. Results are consistent with a noradrenergic self-stimulation system for the lateral hypothalamus. Medial frontal cortex self-stimulation, however, appears to be mediated by a neuroanatomical and neurochemical system different from that of the lateral hypothalamus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sinus node recovery time and abnormal postpacing phase in the aged patients with sick sinus syndrome

The sinus node function was evaluated by rapid atrial pacing in 35 aged patients (mean age 78.2 years) including 10 aged controls, 12 cases with various degrees of AV block, 6 with bradycardia-tachycardia syndrome (BTS), and 7 with sinus bradyarrhythmia (SB). AV block was further divided into A-H block (7 cases) and H-V block (5 cases) by His bundle electrogram which was simultaneously recorded with 3 leads of surface electrocardiogram. Sinus node recovery time (SRT) was measured and its maximum value (SRTmax) was selected from SRTs obtained after pacing with various rates and durations in each patient. SRTmax was also expressed as percentage of the control P-P interval (%SRTmax). For patients in whom the study was repeated 3 to 8 months later, %SRTmax was reproducible in 9 of 14 instances. Prolongation of SRT was not always observed as the rate and/or duration of pacing was increased. SRTmax and %SRTmax were 1,363 +/- 188 msec and 147 +/- 19% (mean +/- SD), respectively, for aged controls, 1,597 +/- 442 msec and 156 +/- 31% for patients with AV block, 2,087 +/- 1,315 msec and 203 +/- 132% for those with BTS, and 3,069 +/- 1,287 msec and 247 +/- 115% for those with SB. SRTmax exceeding the range for aged controls was noted in 4 of 7 cases (57%) with A-H block, 2 of 6 (33%) with BTS, and 5 of 7 (71%) with SB; normal SRT was not infrequently observed in patients with sick sinus syndrome, especially in those with BTS. Analysis of 10 consecutive atrial cycles following cessation of pacing revealed that in 8 cases the first P-P interval (SRT) was followed by longer ones in some occasions (secondary suppression). It was observed almost exclusively in patients with sick sinus syndrome. The possibility of this phenomenon to reflect another feature of sinus node abnormality was discussed.     

Behaviorally measured refractory periods are lengthened by reducing electrode tip exposure or raising current.

Measured the effects of current and tip surface area on stimulation parameters required to produce a constant rate of self-stimulation of lateral hypothalamic sites or of circling when stimulating medial brain stem sites. Data from 20 male Wistar rats show that thresholds for circling decreased when tip surface area was decreased to 0.01 mm–2. Refractory period curves for both circling and self-stimulation were shifted to slightly longer intrapair intervals when tip surface area was decreased or current was increased. This suggests that long refractory period axons make larger contributions when current density is increased. Chronaxies were not lengthened by small tip exposures but were reduced when electrodes were placed far lateral to the circling substrate. Threshold differences between axons stimulated by different tip exposures and currents are discussed. (31 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Firing properties of rat lateral mammillary single units: head direction, head pitch, and angular head velocity

Many neurons in the rat anterodorsal thalamus (ADN) and postsubiculum (PoS) fire selectively when the rat points its head in a specific direction in the horizontal plane, independent of the animal's location and ongoing behavior. The lateral mammillary nuclei (LMN) are interconnected with both the ADN and PoS and, therefore, are in a pivotal position to influence ADN/PoS neurophysiology. To further understand how the head direction (HD) cell signal is generated, we recorded single neurons from the LMN of freely moving rats. The majority of cells discharged as a function of one of three types of spatial correlates: (1) directional heading, (2) head pitch, or (3) angular head velocity (AHV). LMN HD cells exhibited higher peak firing rates and greater range of directional firing than that of ADN and PoS HD cells. LMN HD cells were modulated by angular head velocity, turning direction, and anticipated the rat's future HD by a greater amount of time (approximately 95 msec) than that previously reported for ADN HD cells (approximately 25 msec). Most head pitch cells discharged when the rostrocaudal axis of the rat's head was orthogonal to the horizontal plane. Head pitch cell firing was independent of the rat's location, directional heading, and its body orientation (i.e., the cell discharged whenever the rat pointed its head up, whether standing on all four limbs or rearing). AHV cells were categorized as fast or slow AHV cells depending on whether their firing rate increased or decreased in proportion to angular head velocity. These data demonstrate that LMN neurons code direction and angular motion of the head in both horizontal and vertical planes and support the hypothesis that the LMN play an important role in processing both egocentric and allocentric spatial information.     

Neural basis of stimulus-bound locomotor activity in the rat.

Stimulated lateral hypothalamic sites in male hooded rats. Locomotor activity was elicited in 9 Ss which supported self-stimulation and stimulus-bound motivational behavior. Results of 4 experiments show that this kind of locomotor activity (a) was elicited through directly excited neurons with absolute refractory periods in the range .75-1.1 msec.; (b) accumulated during stimulation and decays gradually after the end of stimulation; (c) had a magnitude dependent on the number of brief trains of stimulation applied; and (d) was not elicited by nucleus accumbens stimulation. Neuronal activity in a brainstem arousal system excited by the lateral hypothalamic situation showed the same 4 characteristics. Because of the comparability of these electrophysiological and behavioral characteristics, it is concluded that activity in the brainstem arousal system at least partly mediates the stimulus-bound locomotor activity. (16 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Perceptual timing in cerebellar degeneration

This study examined time perception in 12 patients with cerebellar degeneration (CD) and in 13 normal controls (NC). We used a time bisection procedure with four interval conditions (100-900 msec; 8-32 sec; 100-600 msec; 100-325 msec). Each subject's bisection point, discrimination ability (the Weber ratio) and precision (the inverse of the proportion of unexplained variance) was calculated for each condition. CD patients' performance on the 100-900 msec time bisection condition suggested a possible time discrimination deficit, which was confirmed with intervals in the range of 100-600 msec. Time discrimination was normal on the 100-325 msec condition and impaired on the 8-32 sec bisection task. However, when discriminating long intervals, CD patients also showed a precision deficit, which points to impaired sustained attention and/or decision processes. Our findings corroborate the view that cerebellar timing processes are not limited to the motor system but are also used in perceptual computations.     

Three types of reticular neurons involved in the spino-bulbo-spinal reflex of cats

Reticular neuron activity was recorded in 28 chloralosed cats in order to analyze the reflex arc of the spino-bulbo-spinal (SBS) reflex. Three types of reticular neurons, types I (input), II(output) and III (relay), were identified by unit discharges in response to stimulation of the sural nerve. (1) Type I (input) neurons received spinal ascending volleys monosynaptically and responded to stimulation of the sural nerve with spikes of low amplitude and short latency. Unit spikes, however, were not produced by stimulation of the superficial radial nerve and the sensorimotor cortex. These input neurons were located in the dorsocaudal part of the medial bulbar reticular formation. (2) Type II (output) neurons were part of the reticulospinal tract, which sends axons to the spinal cord, since these neurons exhibited antidromic spikes following stimulation of the ventrolateral funiculus of the spinal cord. Unit spikes were evoked by stimulation either to the sural or superficial radial nerves. These neurons were located in the ventrocaudal part of the medial bulbar reticular formation. (3) Type III neurons included relay neurons. Unit spikes were evoked by stimulation of the sural nerve, superficial radial nerve and sensorimotor cortex. However, unit discharges were not obtained by antidromic stimulation to the reticulospinal tract. These neurons were distributed widely in the brain stem, both in the bulb and pons. (4) Latency difference of unit discharges between input and output neurons was 3.5--5 msec, indicating the presence of interneurons (relays) between input and output neurons. Spikes of output neurons with 3.8--4.2 msec latency were observed following stimulation of the region where input neuron activity was found. We may conclude that three kinds of reticular neurons, input, relay and output, were involved in pathways of the SBS reflex.     

A presynaptic role for the ADP ribosylation factor (ARF)-specific GDP/GTP exchange factor msec7-1

ADP ribosylation factors (ARFs) represent a family of small monomeric G proteins that switch from an inactive, GDP-bound state to an active, GTP-bound state. One member of this family, ARF6, translocates on activation from intracellular compartments to the plasma membrane and has been implicated in regulated exocytosis in neuroendocrine cells. Because GDP release in vivo is rather slow, ARF activation is facilitated by specific guanine nucleotide exchange factors like cytohesin-1 or ARNO. Here we show that msec7-1, a rat homologue of cytohesin-1, translocates ARF6 to the plasma membrane in living cells. Overexpression of msec7-1 leads to an increase in basal synaptic transmission at the Xenopus neuromuscular junction. msec7-1-containing synapses have a 5-fold higher frequency of spontaneous synaptic currents than control synapses. On stimulation, the amplitudes of the resulting evoked postsynaptic currents of msec7-1-overexpressing neurons are increased as well. However, further stimulation leads to a decline in amplitudes approaching the values of control synapses. This transient effect on amplitude is strongly reduced on overexpression of msec7-1E157K, a mutant incapable of translocating ARFs. Our results provide evidence that small G proteins of the ARF family and activating factors like msec7-1 play an important role in synaptic transmission, most likely by making more vesicles available for fusion at the plasma membrane.     

Comparison of the effects of morphine, pentazocine, cyclazocine and amphetamine on intracranial self-stimulation in the rat

Rats were trained to press a lever in order to stimulate their hypothalamus through a chronically implanted electrode. Dose-response curves were determined for the effects of morphine (0.3-10 mg/kg), pentazocine (1.0-30 mg/kg), cyclazocine (0.03-30 mg/kg) and d-amphetamine (0.1-3.0 mg/kg) on responding for intracranial stimulation, and then were redetermined in the presence of one or two doses of naloxone. The three analgesics produced only dose-related decreases in responding with the following relative potencies: cyclazocine greater than morphine greater than pentazocine. The well-documented rate-increasing effects of d-amphetamine on intracranial self-stimulation were observed at 0.3 and 1.0 mg/kg of the drug; decreases in responding at 3.0 mg/kg were associated with stereotyped behavior. Naloxone, which had no effect of its own on self-stimulation, increased the dose of the analgesics required to depress response rate in a manner consistent with a competitive antagonism. In contrast, response rates at all doses of d-amphetamine tested in the presence of naloxone. Thus, the interaction between naloxone and d-amphetamine is qualitatively different from the one between naloxone and the analgesics. This finding extends to intracranial self-stimulation the generality of a previous report of interactions between d-amphetamine and naloxone on behavior in the rat.     

Self-stimulation in the rat: Quantitative characteristics of the reward pathway.

Quantitative characteristics of the neural pathway that carries the reinforcing signal in electrical self-stimulation of the male Sprague-Dawley rat's brain were established by finding which combinations of stimulation parameters give the same performance in a runway. The reward for each run was a train of evenly spaced monophasic cathodal pulses from a monopolar electrode. With train duration and pulse frequency held constant, the required current was a hyperbolic function of pulse duration, with chronaxie c?=?1.5 msec. With pulse duration held constant, the required strength of the train (the charge delivered per second) was a hyperbolic function of train duration, with chronaxie C?=?500 msec. To a first approximation, the values of c and C were independent of the choice either of train duration and pulse frequency or of pulse duration, respectively. Hence, the current intensity required by any choice of train duration, pulse frequency, and pulse duration depended on only 2 basic parameters, c and C, and 1 quantity, Qi, the required impulse charge. These may reflect, respectively, current integration by directly excited neurons; temporal integration of neural activity by synaptic processes in a neural network; and the peak of the impulse response of the network, assuming that the network has linear dynamics and that the reward depends on the peak of the output of the network. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)