Eleftherios Miliaressis

The curve-shift paradigm in self-stimulation

Eleven rats were trained to press a lever in an operant chamber in order to earn rewarding trains of cathodal rectangular pulses of fixed intensity and variable frequency. The rate-frequency functions were examined under administration of two neuroleptics (pimozide and chlorpromazine) and three manipulations that interfered with bar pressing (muscular relaxation with methocarbamol, increased lever weight, and limitation of maximum response rates by an F1 reinforcement schedule). Chlorpromazine, and pimozide at low dosages produced a near parallel shift of the rate-frequency functions on the logarithmic axis of pulses, suggesting that these drugs decreased the reinforcing efficacy of the stimulation. The three conditions that interfered with bar-pressing decreased the asymptotic rates and produced small or moderate lateral shifts. Changes in the reinforcing efficacy of the stimulation following the above manipulations were inferred from the shift in the number of pulses required at zero and half-maximal performance (theta 0 and M50 indices, respectively). In the cases of the manipulations that interfered with bar-pressing, M50 indicated a larger artifactual change in the efficacy of the stimulation, compared to theta 0. This phenomenon was mainly due to the fact that the asymptote of the altered functions was shifted towards higher pulse numbers.

Pontine and mesencephalic substrates of self-stimulation

Single or twin, moveable monopolar stimulating electrodes were implanted in male adult rats in order to map the medial pons and mesencephalon for self-stimulation behaviour. The electrodes were implanted 6 mm below the surface of the skull and subsequently moved down by steps of 0.13 or 0.16 mm. Each bar press in a Skinner box delivered a train (0.4 s in duration) of cathodal rectangular pulses of fixed intensity (200 microA) and width (0.1 ms). Self-stimulation was recorded from zero to the maximum performance by varying the number of pulses per stimulating train. The rewarding efficacy of the stimulation at each electrode location was inferred from determination of the pulse period corresponding to the threshold and half-maximal performance. Out of 361 mesencephalic and pontine sites sampled, 289 supported self-stimulation. Within the metencephalon, the study revealed a continuous band of positive sites, extending over a dorso-ventral distance of 4 mm, between the floor of the aqueduct and the pontine nuclei. Hence, all electrode locations in the central grey, dorsal raphe and median raphe supported self-stimulation. Within the mesencephalon, the positive band was restricted between the floor of the central grey and the middle part of the interpeduncular nucleus. At the rostral mesencephalon, it shifted laterally towards the substantia nigra. The overlap between the self-stimulation sites and some of the best known ascending and descending pathways is discussed.

Fitting intracranial self-stimulation data with growth models.

Until now, the problem of fitting self-stimulation rate-frequency functions has been dealt with by using linear models applied to the linear portion of the empirical curve. In this article, an alternative procedure is presented, together with three sigmoid growth models that seem to accurately fit rate-frequency data. From any of these models, it is possible to compute the two indices of stimulation efficacy in use in the parametric study of brain stimulation reward (M50 and theta 0), in addition to the inflection point of the curve, which can be used as an alternative to M50. Important relations allowing initial estimation of each parameter are provided, allowing use of computer programs derived from the Gauss-Newton algorithm for nonlinear regression. The considerations relevant to the choice of a nonlinear model are discussed in terms of each efficacy index.

Psychophysical method for mapping behavioral substrates using a moveable electrode

With the use of moveable electrodes, 28 rat mesencephalic sites were examined for self-stimulation behavior (SS). The relative importance of each site in SS was established according to (1) a traditional method which consists of comparing sites based on the rates of responding (2) a psychophysical procedure based on the pulse frequency required at each site in order for the stimulation to elicit a criterion behavioral performance. It was shown that anatomical conclusions reached by the use of behavioral output procedures depend purely on the arbitrary choice of stimulation parameters. It was also demonstrated that the combination of moveable electrodes with psychophysical measurements results in enhanced mapping resolution and enables one to trace the boundaries of behaviorally relevant structures and pathways with significantly better confidence.

Dorsal diencephalic self-stimulation: a movable electrode mapping study.

The function relating electrical self-stimulation (ESS) bar-pressing rate to the frequency of cathodal pulses (0.2 mA and 0.1 ms) was obtained for several positions of a movable electrode in the dorsal diencephalon of the rat. The rate-frequency functions were fitted to a sigmoid model to obtain the asymptotic rate and threshold frequency. ESS was found along the epithalamic route (stria medullaris, habenula, and fasciculus retroflexus) and in the following thalamic nuclei: mediodorsal, paratenial, interanteromedial, centromedial, reuniens, and rhomboid. The lowest threshold (approximately 5 pulses/train), which was found in the stria medullaris and the junction of the paratenial and centromedial nuclei, was comparable to that usually obtained for the brain areas where the ESS is most effectively rewarding (medial forebrain bundle, dorsal raphe, and amygdala). However, most of threshold estimates were 4 to 8 times higher. In most brain sites, ESS was accompanied by epileptiform, motor, or aversive reactions (or a combination of these). These reactions may explain the fact that the maximum rates were generally very low. Nevertheless, no correlation was found between maximum rates and threshold frequencies.

Anatomical dissociation of the substrates of medial forebrain bundle self-stimulation and exploration.

The purpose of this research was to determine whether brain stimulation reward and exploration are induced by activation of the same set of neurons along the medial forebrain bundle. The behavioral version of the collision test was utilized with electrodes in the lateral hypothalamus (LH) and the ventral tegmental area (VTA). A collision effect obtained between LH and VTA in one behavior at the exclusion of the other was treated as evidence of the involvement of two different sets of fibers. In 4 rats, a collision effect was observed only in self-stimulation, whereas in 1 rat, a collision was obtained in exploration at the exclusion of self-stimulation. Three animals showed no collision in either behavior. These data suggest that coexistence of self-stimulation and exploration following medial forebrain bundle stimulation can be explained by current spread on two different sets of fibers.

Effects of concomitant motor reactions on the measurement of rewarding efficacy of brain stimulation.

In self-stimulation behavior, the rate-frequency (R-F) function relates bar-pressing performance to the number of cathodal pulses of constant intensity, delivered in a train of fixed duration. The lateral position of the R-F function depends on the rewarding efficacy of the stimulation; a shift of the function toward larger pulse numbers after some experimental manipulation indicates a decrease in the efficacy of the stimulation. Because self-stimulation is often accompanied by stimulation-contingent motoric reactions, it is required to show that such reactions do not alter the estimates of rewarding efficacy of the stimulation. We describe an experiment in which the presence and severity of motoric reactions were controlled experimentally by simultaneous stimulation through a second electrode, located in a motoric brain region. Rats were implanted with one hypothalamic (LH) electrode (which elicited self-stimulation) and one reticular (RF) electrode (which elicited head and body movements). The rate-frequency function for each LH electrode was obtained under a single-pulse condition (LH electrode alone) and under a paired-pulse condition repeated three times, in which each LH pulse was accompanied by three different intensities of an RF pulse. Despite its severe effect on the slope and the asymptotic rate of R-F function, the interfering reaction failed to shift the R-F function to any significant degree. We concluded that these interfering reactions do not alter the estimates of neuronal density obtained through application of the curve-shift paradigm.

Serotonergic basis of reward in median raphé of the rat

Rats were trained to self-stimulate simultaneously in the ventromedian tegmentum (VMT) and the median raphe (MR) by pressing two independent bars. Bar-pressing rates for VMT self-stimulation (SS) were increased following methamphetamine and decreased following alpha-methyl-para-tyrosine while no appreciable effects were observed on SS in the MR. On the other hand, MR SS was specifically decreased following para-chlorophenylalanine. The above results taken together support the hypothesis that SS in the MR is due to the stimulation of serotonergic neuronal elements.

Summation and saturation properties in the rewarding effect of brain stimulation.

We used a two-lever self-stimulation chamber and rats with central grey and hypothalamic electrodes to obtain a choice-frequency (C/F) function, which plots the relative choice of an electrical stimulus of fixed pulse frequency (the standard stimulus) as a function of the frequency of a second competing stimulus (the alternative stimulus). A family of C/F functions was obtained using increasing frequencies for the standard. A choice index, varying from -1.0 (exclusive choice of the fixed stimulus) to 1.0 (exclusive choice of the alternative stimulus) was computed by using the barpressing rates on the two levers. Reward saturation was assumed to occur when the C/F function obtained with the largest standard reached an asymptote below the value of 1.0. For the hypothalamic subjects, the pulse frequency at the point of reward saturation was twice as high as the frequency required for the maximum rate of self-stimulation in the usual single-lever chamber. Decreasing the pulse intensity always increased the saturation frequency, indicating that the saturation was not due to a frequency blocking effect in the directly activated neurons. Reward saturation occurred with a considerably higher frequency in the central grey than in the hypothalamus. Thus, the asymptotic rate of self-stimulation in the usual single-lever chamber is not conditioned by the processes that summate the central grey and hypothalamic rewarding effects. From the central grey data we obtained the relation between the slope and the position of the C/F function on the frequency axis. We used the slope/frequency profile to delimit the most probable profile of summation rate in the rewarding process. We found that the slope/frequency function has an early plateau followed by a rapidly decelerating phase. We proposed that these two distinct phases reflect an early accelerating rate of summation, followed by a decelerating rate of summation. In other words, reward summation would be predicted by a sigmoid growth model.

A miniature, moveable electrode for brain stimulation in small animals

Abstract A moveable, nonrotating electrode of tiny dimensions for brain stimulation in small animals is described. Its usefulness is demonstrated in a mapping study of circling behavior in mesencephalic areas of the rat.