by rewarding brain stimulation, comprehensive mapping of brain areas for self-stimulation and other stimulation-induced behaviors, and examination of the ...
Self-Stimulation: A Rewarding Decade Catherine H. Bielajew, Tamara Harris School of Psychology, University of Ottawa Accepted: August 16, 1991
In the past decade, there has been considerable emphasis on developing and refining the measurement instruments used to assess the rewarding effect of brain stimulation. These efforts have given rise to quantitative methods aimed at revealing the underlying neurophysiology and neuroanatomy by tracing the trajectories of the relevant neurons. In this paper, we summarize some of the quantitative findings that have resulted from research at the University of Ottawa in the neurobiology of motivated behavior. These include studies using markers to reveal which structures are metabolically activated by rewarding brain stimulation, comprehensive mapping of brain areas for self-stimulation and other stimulation-induced behaviors, and examination of the effects of benzodiazepines on feeding and reward.
Keywords: brain-stimulation reward, self-stimulation, stimulation-induced feeding, benzodiazepines, diazepam, psychophysics Durant la derniere decennie, on a mis beaucoup d'emphase sur le developpement et le raffinement d'instruments de mesure pour evaluer la valeur de renforcement de la stimulation intra-cerebrale. Ces efforts ont mene au developpement des methodes quantitatives permettant de mettre en lumiere la neurophysiologie et la neuroanatomie sous-jacentes en determinant les trajectoires des neurones impliques. Dans cet article, nous resumons certaines observations de nature quantitative resultant des recherches sur la neurobiologie du comportement motive, menees a l'Universite d'Ottawa. Ceci inclut des etudes utilisant des marqueurs pour identifier les structures activees metaboliquement par la stimulation intra-cerebrale, une cartographie complete des regions du cerveau propices a l'autostimulation et d'autres comportements induits par stimulation, et enfin un examen des effets des benzodiazepines sur la recompense et l'alimentation. Mots clks: renforcement intra-cerebral, auto-stimulation, benzodiazepines, diazepam, psychophysique
The discovery of self-stimulation by Olds and Milner in 1954 provided an animal model for examining the processes underlying natural appetitive states. While a Address reprint requests to: Catherine H. Bielajew, Ph.D., School of Psychology, University of Ottawa, 275 Nicholas, Ottawa, Ontario, KIN 6N5, Canada. For a thorough discussion of the psychophysics of reward and the major contributions in this area, the reader should consult the following - Gallistel et al 1981; Liebman 1983; Miliaressis et al 1986; Milner 1991; Stellar and Stellar 1985; Yeomans 1990.
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variety of methodologies have been employed to study selfstimulation, the development of quantitative and psychophysical techniques in the last decade has significantly advanced our understanding of the circuitry underlying brain-stimulation reward and the properties of the cells that form its substrate'. With the use of these psychophysical methods, the neuronal characteristics that have been described include refractory period, conduction velocity, strength duration, current spread, and the nature of the anatomical linkage between structures that support selfstimulation. Both hypothalamic and extrahypothalamic re-
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ward sites have been documented in this manner. These behavioral techniques have also been adapted to other stimulation-elicited behaviors, such as circling, exploration, aversion, and feeding. In addition, the logic underlying this approach has been applied to pharmacological studies, in order to distinguish between compounds that impair or boost performance from those that influence reward. These refinements in the measurement of reward and other stimulation-elicited behaviors have yielded much information concerning the neurophysiological and neuroanatomical profile of the underlying substrate that can be used to guide electrophysiological identification of the relevant cells (Shizgal 1989, Shizgal et al 1989). In the following we review selected studies in this area that have been generated in our laboratory and others at the University of Ottawa. One approach has been to employ histochemical markers to reveal which structures are metabolically activated by rewarding brain stimulation followed by behavioral techniques to infer the neurophysiological properties and the nature of the anatomical linkage of loci identified in the metabolic studies. In addition, studies which address the anatomical and pharmacological specificity of reward and other stimulation-induced behaviors are described. Histochemical Studies In order to identify which structures are activated by rewarding medial forebrain bundle stimulation, we have been using cytochrome oxidase (CO), an endogenous mitochondrial enzyme that is linked to metabolic processes (Wong-Riley 1989), as one marker for labelling functionally relevant projections. The distribution of CO is quantified by comparing the degree of enzymatic reactivity, in relative optical densities between stimulated and unstimulated hemispheres, following chronic exposure to rewarding brain stimulation (Bielajew 1991, Bielajew and Fouriezos 1986, Gow et al 1990). This procedure is analogous to 2-deoxyglucose autoradiography (Gallistel et al 1985, Kennedy et al 1975, Porrino et al 1984, 1990, Yadin et al 1983); although CO appears to be less sensitive to stimulationinduced activity, the technique has the advantage of better spatial resolution. Using CO histochemistry, we have found metabolic asymmetries resulting from lateral hypothalamic stimulation in several structures (Bielajew and Fouriezos 1986, Gow et al 1990), most notably in the nucleus accumbens and the lateral septal nucleus (Bielajew 1991). Increasing the pulse width from 0.1 to 2.0 msec in selfstimulation trials reveals a different pattern of CO, giving rise to greater activity on the stimulated side in many dopaminergic projections, including the frontal cortex, lateral habenula, and olfactory nucleus (Bielajew 1991), suggesting that these areas may play a role in medial forebrain bundle reward. There is good support for the view that the properties of the first-stage reward neurons, those directly excited by the electrode, reflect the recruitment of small, myelinated axons that descend into the midbrain (Bielajew et al 1981,
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1982,BielajewandShizgal 1980,1982,1986,Chiodo 1988, Durivage and Miliaressis 1987, Fouriezos and Wise 1984, Gallistel 1978, Gallistel et al 1981, Gratton and Wise 1988, Matthews 1977, Miliaressis and Rompre 1980, Nieuwenhuys et al 1982, Rompre and Miliaressis 1980, Schenk and Shizgal 1982, Shizgal et al 1980, Skelton and Shizgal 1980, Szabo et al 1974, Waxman and Bennett 1972, Yeomans 1975, 1979, Yeomans et al 1988); this is incompatible with the old hypothesis that the activation of the unmyelinated and caudorostrally oriented dopaminergic fibers are essential for self-stimulation. However, there is mounting evidence that a system with electrophysiological properties that match those of dopaminergic axons can be directly activated with self-stimulation electrodes, when appropriate stimulation parameters and electrode tip diameters are used (Bielajew et al 1982, 1985, Yeomans et al 1985). Psychophysical Studies
This work is based on measurement techniques that provide a quantitative assessment of the rewarding effect of brain stimulation. This is accomplished by systematically varying one stimulus (eg. current) and measuring its effect on different values of another (eg. frequency or its inverse, period) at a constant behavioral level - typically half of the maximum response rate in self-stimulation experiments (Figure 1). Such trade-off relationships characterize important properties of the anatomical substrate and provide a means of identifying the first-stage reward neurons. In practice, the curve shift paradigm is commonly used in parametric investigations of self-stimulation to measure changes in response rate over a wide range of stimulus values, and thus samples the full capacity of behavior, from minimum to maximum responding. A threshold value can then be extracted from some point along the linear portion of the curve (see Figure 1). This procedure permits a comparison of curves generated in different experimental treatments. Furthermore, the curve-shift analysis (Edmonds and Gallistel 1974) is used to distinguish manipulations that influence performance capability from those that alter the rewarding value of stimulation. The reliability of the curveshift paradigm to different performance challenges has been carefully evaluated and shown to be stable within reasonable performance demands (Fouriezos et al 1990, Miliaressis et al 1986). Using double electrode techniques developed in Shizgal's laboratory (Shizgal et al 1980), we have been examining the connectivity of lateral preoptic and ventral tegmental area structures underlying self-stimulation (Harris and Bielajew 1989) using a behavioral adaptation of the collision test which is based on the conduction failure that occurs between antidromic and orthodromic impulses that propagate along the same axon bundle. Collision is inferred from a sudden increase in effectiveness of double-pulse stimulation at pulse-pair intervals that exceed the sum of the inter-electrode conduction time and the refractory period (Bielajew and Shizgal 1980, 1982, Durivage and Miliaressis
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1987, Gallistel et al 1981, Gratton and Wise 1988, Shizgal et al 1980) and is interpreted to reflect activation of a subset of the same reward-relevant neurons. Because we had earlier shown such effects between the lateral preoptic area and lateral hypothalamus (Bielajew et al 1987) and between the lateral hypothalamus and ventral tegmental area (Bielajew and Shizgal 1982, 1986, Shizgal et al 1980) with significant overlap in the conduction velocity estimates obtained at each pair of sites, we reasoned that the same reward fibers might course from the lateral preoptic area to the ventral tegmental area. With a moveable electrode positioned in compartments c and e of the lateral preoptic area (Nieuwenhuys et al 1982) and a fixed electrode in the ventral tegmental area, 45 pairs of sites were tested, with no evidence that the two structures were linked by
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PERIOD (msec) Fig. 1. Illustration of the determination of self-stimulation period thresholds in order to generate a period/ current tradeoff function. The curves show the response rates over a range of periods for three currents. The threshold is defined as the period which corresponds to the half-maximal rate for each curve. Thus, for a current of 200 IAA, the halfmaximal rate is 96 responses/minute (horizontal dashed line) and the period threshold is 16.3 msec (vertical solid line). Note that as the current is increased (increased reward), the period threshold increases (decreased reward) in order to maintain a constant behavioral output.
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the same axon bundle; instead, our data suggest either a synaptic linkage or weak to moderate summation of lateral preoptic and ventral tegmental area outputs. Although the latter finding could be due to a misalignment of the stimulation fields, one would then predict better summation of the effects of combined lateral preoptic and ventral tegmental area self-stimulation. Alternatively, if rostral fibers contribute to a continuous axon bundle between the two structures, they may be located in other compartments of the lateral preoptic area. The single-electrode double-pulse stimulation technique to infer the excitability cycle of the directly stimulated reward neurons was pioneered by Deutsch (1964) and further refined by Yeomans (1975, 1979) who showed that the refractory period underlying medial forebrain bundle selfstimulation ranged from from 0.4 to 1.5 msec. This strategy has been extensively employed to compare the excitability properties of sites that give rise to other stimulation-induced behaviors. For example, exploration and self-stimulation, which can be elicited from the same lateral hypothalamic electrode, exhibit a similar time course of recovery from refractoriness, suggesting that either the same fibers subserve both behaviors or different fibers with similar excitability properties (Rompre and Miliaressis, 1980). The same conclusion is drawn when self-stimulation is compared to stimulation-induced escape (Skelton and Shizgal 1980) and stimulation-induced feeding (Gratton and Wise 1988) using this paradigm. In contrast, the excitability cycles of selfstimulation and circling, which are elicited from different structures, do not entirely overlap (Miliaressis and Rompre 1980). When self-stimulation and exploration were further investigated using the collision technique, Durivage and Miliaressis (1987) found evidence of direct anatomical linkage in only one of the behaviors, suggesting that their electrodes activated separate fiber systems. In the medial forebrain bundle, self-stimulation has been anatomically distinguished from stimulation-escape on these grounds (Bielajew and Shizgal 1980). A novel method for determining the current-distance relationship for rewarding brain-stimulation using doublepulse stimulation through two electrodes was devised by Fouriezos and Wise (1984). With a pair of electrodes positioned to lie in a horizontal plane in the medial forebrain bundle, they inferred the overlap in the effective stimulation fields at high currents while stimulating concurrently through both electrodes, and found values that are compatible with the range of behaviorally derived refractory period and conduction velocity estimates reported elsewhere. The refractory properties of several forebrain structures that support self-stimulation have been assessed, including the mediodorsal thalamus (Bielajew and Fouriezos 1985), the medial prefrontal cortex, and the caudate nucleus, with the latter two appearing to have closely matched estimates of recovery (Schenk and Shizgal 1982, Trzcinska and Bielajew 1990). Our observation that caudate self-stimulation is transferable to the medial prefrontal cortex, which
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is a site that is characterized by gradual acquisition (Corbett et al 1982), and the extensive corticostriatal projections (Nieuwenhuys et al 1982), suggest that these sites may form a common reward substrate; we are currently testing this idea. A noteworthy technical achievement that has significantly improved mapping studies in brain-stimulation reward has been the development of electrodes that can be moved dorsoventrally (Miliaressis and Gratton 1981). In the medial pons and mesencephalon, for example, Rompre and Miliaressis (1985) sampled 361 sites in 11 animals, resulting in a comprehensive map of positive and negative self-stimulation sites in this area. The distribution of self-stimulation foci in amygdaloid structures has been recently examined by Kane et al (1991 a, 1991 b). With the finer resolution permitted by the use of moveable electrodes, they showed that all amygdaloid compartments, except for the lateral one, support self-stimulation with similar reward thresholds; these findings argue against the traditional view of a secondary role for the amygdala in brain-stimulation reward. Finally, an important advantage of moveable electrodes is highlighted in collision studies, allowing many stimulation sites to be tested within a subject, thereby increasing the probability of aligning both electrodes in the same fiber bundle. The combination of moveable electrodes with sophisticated measurement techniques has extended behavioral analysis of brain-stimulation reward from coarse maps to fine delineation of the boundaries and density of reward substrates.
Pharmacological Studies Recently, we have been studying the effects of two benzodiazepines, diazepam and brotizolam, on self-stimulation thresholds. Because of the frequent and severe seizures that accompany many forebrain self-stimulation sites, we were initially interested in exploiting the anticonvulsant properties of these compounds. The literature dealing with the effects of these agents on self-stimulation is unclear (Caudarella et al 1982, 1984, Olds 1976), mainly because it has been based on response rate which is a performanceconfounded measure of reward (Edmonds and Gallistel 1974, Liebman 1983, Miliaressis et al 1986). Employing threshold procedures, we have found a more consistent pattern of results (Harris and Bielajew 1991). Essentially, reward thresholds are unchanged by diazepam in animals that are not seizure prone. In subjects experiencing seizures, frequency thresholds are significantly reduced as are the occurence of the seizures, suggesting that these agents do not interact directly with the reward substrate. With the related longer-acting compound, brotizolam (Seyrig et al 1986), thresholds are only slightly altered, which like diazepam may be related to seizure propensity. More importantly, behaviorally derived refractory measures are unchanged and far less variable with drug challenge than without. Baseline thresholds appear to be very stable over several months of administration (Harris and Bielajew 1990).
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Stimulation-Induced Feeding In comparative studies of the effects of diazepam on feeding and reward, we found that diazepam unmasked stimulation-induced feeding in self-stimulation sites in which feeding was either not observed or required high currents in placebo tests (Bushnik-Harris and Bielajew 1988, Soper and Wise 1971). These data suggest that it is the anxiolytic action of benzodiazepines that promotes feeding while its anticonvulsant property is responsible for reducing thresholds for self-stimulation in seizure-prone sites. The main purpose of these investigations was to determine whether the same population of neurons supports feeding and reward, an issue that despite much attention has yet to be resolved (Berridge and Valenstein 1991, Gratton and Wise 1988, Valenstein et al 1970, Wise 1968, 1971). Using moveable electrodes, we mapped sites in the medial forebrain bundle for self-stimulation and stimulationinduced feeding. Where there was evidence of both behaviors, their current-frequency trade-off functions were compared to provide information about the boundaries and densities of the relevant substrates (Yeomans et al 1984). The difference in the slopes of the trade-off functions observed by us and others (Waraczynski and Kaplan 1990), with feeding always shallower and displaying non-linearities at higher currents, suggests that the integration of neural activity for feeding is different from that for self-stimulation, even if the first-stage elements underlying the two behaviors form part of a common substrate (Gratton and Wise 1988). The work described here illustrates some of the directions that have been pursued by psychologists at the University of Ottawa exploring the neurobiology of motivation. The goal of these psychophysical experiments is to characterize the neurons responsible for brain-stimulation reward and other elicited behaviors in order to generate a list of properties that distinguish the relevant substrate and reveal its neurochemical identification. This approach, in combination with electrophysiological and neuroanatomical techniques, provides a powerful means of assessing the neural circuitry underlying motivated behavior. While some medial forebrain bundle structures have been well-documented in this context, there is increasing interest in exploring other brain regions and determining the nature of the anatomical linkage between different nuclei, beyond the directly stimulated stage of activation. REFERENCES
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