Peter Shizgal

Neural Basis of Utility Estimation

The allocation of behavior among competing activities and goal objects depends on the payoffs they provide. Payoff is evaluated among multiple dimensions, including intensity, rate, delay, and kind. Recent findings suggest that by triggering a stream of action potentials in myelinated, medial forebrain bundle axons, rewarding electrical brain stimulation delivers a meaningful intensity signal to the process that computes payoff.

Behaviorally derived measures of conduction velocity in the substrate for rewarding medial forebrain bundle stimulation

The results of collision and refractory period tests were used to compute conduction velocity estimates for reward-relevant neurons activated by electrodes aimed approximately 3 mm apart along the trajectory of the medial forebrain bundle (MFB). Collision tests consisted of delivering pairs of pulses in alternating fashion to the lateral hypothalamus and ventral tegmental area. As the interval between pulses was increased the behavioral effectiveness of double-pulse stimulation abruptly increased and then levelled off at longer pulse-pair intervals. In 6 subjects the C-T interval at which the abrupt rise was observed ranged from 1.0 to 3.0 ms. Refractory periods were estimated using an analogous paradigm but with both pulses applied through the same electrode. Recovery was first evident at pulse-pair intervals greater than 0.4-0.6 ms. Conduction velocity was determined for each subject by dividing the interelectrode distance by the difference between the collision interval and the refractory period; a range of 1.0-4.5 m/s was obtained, values that are inconsistent with the reported conduction velocities for catecholaminergic fibers. It is proposed that the substrate for brain-stimulation reward in the MFB consists of small, myelinated, non-catecholaminergic fibers.

Prolonged rewarding stimulation of the rat medial forebrain bundle: Neurochemical and behavioral consequences.

Extracellular dopamine levels were measured in the rat nucleus accumbens by means of in vivo microdialysis. Delivery of rewarding medial forebrain bundle stimulation at a low rate (5 trains/min) produced a sustained elevation of dopamine levels, regardless of whether train onset was predictable. When the rate of train delivery was increased to 40 trains/min, dopamine levels rose rapidly during the first 40 min but then declined toward the baseline range. The rewarding impact of the stimulation was reduced following prior delivery of stimulation at the high, but not the low, rate. These results support the idea that dopamine tone plays an enabling role in brain stimulation reward and is elevated similarly by predictable and unpredictable stimulation.

The substrates for lateral hypothalamic and medial pre-frontal cortex self-stimulation have different refractory periods and show poor spatial summation ☆

Refractory periods of the substrates for lateral hypothalamic (LH) and medial pre-frontal cortex (MPFC) self-stimulation were behaviorally estimated. The beginning of recovery from refractoriness was estimated as the time at which recovery was 20% complete. In all 7 rats, this estimate differed substantially across sites, averaging 0.66 msec and 1.59 msec for the LH and MPFC substrates, respectively. The recovery of excitability approached asymptote later in the MPFC substrate (3.5 msec) than in the LH substrate (1.5 msec). These findings are consistent with the view that different fibers subserve the reinforcing consequences of LH and MPFC stimulation. This notion is strengthened by the observation that the rewarding effects of stimulation summated poorly when stimulating pulses were concurrently delivered to these two sites.

Competition and summation between rewarding effects of sucrose and lateral hypothalamic stimulation in the rat.

Rats were offered a forced choice between a train of brain stimulation that varied in strength from trial to trial and a fixed standard reward. This standard reward consisted of an intraoral sucrose infusion presented either alone or paired with an equipreferred train of brain stimulation. Postingestional effects were minimized by opening a gastric cannula. The presence of a sucrose standard led the subjects to forgo trains of brain stimulation for which they had responded when the sucrose was absent. The strength of the brain stimulation required to balance the compound reward exceeded the stimulation strength required to balance a reward consisting of sucrose alone. These results imply that the rewarding effects of brain stimulation and intraoral sucrose can be evaluated in a common system of measurement and combined.

Effects of excitotoxic lesions of the basal forebrain on MFB self-stimulation

Electrolytic lesions of the anterior medial forebrain bundle (MFB) have been shown to attenuate the rewarding impact of stimulating more caudal MFB sites. In the present study, excitotoxic lesions were employed to determine the relative contribution of somata or fibers of passage contributing to that effect. Changes in reward efficacy were inferred, at three currents, from lateral displacements of the curve relating the rate of responding to the number of stimulation pulses per train. After baseline data were collected from stimulation sites in the lateral hypothalamus (LH) and the ventral tegmental area (VTA), 70 nmol of N-methyl-D-aspartic acid was injected via cannulae aimed at basal forebrain sites. Three subjects were injected with vehicle and served as controls. In 5 out of 15 cases, lesions encompassing the lateral preoptic area, anterior LH, and substantia innominata resulted in long-lasting, large increases (0.2-0.47 log10 units) in the number of pulses required to maintain half-maximal rates of self-stimulation for low currents delivered via the LH electrode; smaller increases (0.08-0.33 log10 units) were noted at moderate and high currents. Seven rats with similar or more dorsally located damage showed moderate or transient increases in the number of pulses required to maintain half-maximal rates of LH or VTA self-stimulation. Vehicle injections did not affect behaviour. Varying degrees of demyelination were seen, mostly removed from the electrode tip, and in locations that varied substantially across subjects manifesting similar changes in self-stimulation. These results support the notion that somata in the basal forebrain give rise to some of the directly activated fibers subserving self-stimulation of the MFB.

Brain reward circuitry and the regulation of energy balance

Reward signals contribute to the regulation of energy balance by influencing switching between feeding and competing behaviors. Properties of natural rewards are mimicked by electrical stimulation of certain brain regions. The rewarding effect produced by stimulating the perifornical region of the hypothalamus is modulated by body weight and is attenuated both by leptin and insulin. Research is reviewed concerning the dependence of the rewarding effect of perifornical stimulation on long-term energy stores and the effects of two neuropeptides implicated in the regulation of energy balance, neuropeptide Y and corticotropin-releasing hormone. It is proposed that the potentiating effect of weight loss on perifornical self-stimulation is not tied to an increased propensity to eat or to an enhancement of food reward per se, but resembles the influence of long-term energy stores on non-ingestive behaviors that defend body weight, such as hoarding.

Refractory periods and anatomical linkage of the substrates for lateral hypothalamic and periaqueductal gray self-stimulation

Abstract The pulse-pair technique was employed (a) to investigate the refractory periods of the reward-related neurons activated by lateral hypothalamic (LH) and periaqueductal gray (PAG) stimulation, and (b) to examine whether these two sites are linked by the same reward-related neurons. These properties of the reward substrate were inferred from self-stimulation data. In eight out of ten subjects, recovery from refractoriness began at about the same time at both sites (0.4–0.6 msec). However, the time course of recovery was consistently slower at the PAG placements. A behavioral adaptation of the collision test failed to reveal reward-related fibers that directly link the LH and PAG. Nonetheless, the rewarding effects of stimulation at the two sites summated with roughly 60% efficiency. These data are consistent with the notion that the rewarding effects of LH and PAG stimulation are mediated by different pathways that ultimately converge.

Electrophysiological characteristics of neurons in forebrain regions implicated in self-stimulation of the medial forebrain bundle in the rat

In an attempt to identify neurons likely to play a role in self-stimulation of the medial forebrain bundle (MFB), action potentials of single neurons in the septum and basal forebrain of anesthetized rats were recorded by means of extracellular electrodes. Refractory period estimates were obtained from cells antidromically activated by stimulation of the lateral hypothalamus or ventral tegmental area, and estimates of interelectrode conduction time were obtained from cells that were driven by stimulation of both sites. The results show that some descending MFB axons arising in the medial septum, diagonal band of Broca and neighboring forebrain structures have characteristics comparable to properties of MFB reward neurons inferred from behavioral experiments.

Electrical stimulation of the rat diencephalon: Differential effects of interrupted stimulation on on- and off-responding

Rats were trained to turn on and to turn off electrical stimulation of the hypothalamus. Breaking trains of stimulation into bursts of pulses separated by intervals of no-stimulation attenuated off-responding more than on-responding. Current intensity was raised in an attempt to maintain a constant level of performance when either burst duration was decreased or interburst interval was increased. Current increases necessary to maintain on-responding were consistently smaller than the increments required to maintain off-responding. At shorter burst durations, off-responding usually ceased while on-responding continued. Four interpretations of the results are discussed: (1) temporal integration characteristics of the underlying neural systems, (2) reward adaptation, (3) electrode location, and (4) procedural artifacts. Only the first explanation which holds that the buildup of activity in the rewarding system is more rapid than in the aversive system is consistent with all the results. If correct, this conclusion indicates that multiple effects of electrical stimulation at a single brain site can be differentiated by manipulating the temporal pattern of the stimulation.