Activation of neurones in the prefrontal cortex by brain-stimulation reward in the rat

To investigate reward pathways in the brain, recording were made from neurones while electrical stimulation was applied to brain-stimulation reward sites in the rat. Single units in most areas of the neocortex were not activated by the stimulation. In the sulcal prefrontal cortex (which forms the dorsal bank of the rhinal sulcus) and in the medial prefrontal cortex (which forms the medial pregenual wall of the hemisphere) single units were activated by the stimulation. This indication that prefrontal neurones are involved in brain-stimulation reward received support from the observation that the neurones were activated in self-stimulation of many different sites — the lateral hypothalamus, the midbrain tegmentum ventrolateral to the central grey, the nucleus accumbens, and the medial prefrontal cortex. Many of the prefrontal units were directly (probably antidromically) excited, with short latencies (1–10 msec), by stimulus pulses applied to self-stimulation sites other than the nucleus accumbens. Many prefrontal units were trans-synaptically activated with longer latencies (2–30 msec) by stimulus pulses applied to the self-stimulation sites. Further evidence that the prefrontal neurones are involved in brain-stimulation reward is that units in the prefrontal cortex were in general not activated from non-reward sites in the midbrain tegmentum. Also neurones in many other areas of the neocortex did not appear to be activated by the brain-stimulation reward.     

An electrophysiological and behavioural study of self-stimulation in the orbitofrontal cortex of the rhesus monkey

It was found that neurons in the posterior orbitofrontal cortex, area 13, of the rhesus monkey were activated from self-stimulation electrodes (in 142 of 168 possible instances), and that neurons in the anterior orbitofrontal areas were much less likely to be activated from the self-stimulation electrodes (in only 28 of 177 possible instances). This activation of neurons in the posterior orbitofrontal cortex was found mainly from self-stimulation sites in the nucleus accumbens septi, lateral hypothalamus, and the orbitofrontal cortex itself. In a second investigation the orbitofrontal cortex was mapped for self-stimulation, and it was found that self-stimulation occurred in the posterior orbitofrontal area. These results implicate the posterior or caudal orbitofrontal cortex, mainly area 13, but not the more anterior orbitofrontal areas, in self-stimulation.     

Modulation during learning of the responses of neurons in the lateral hypothalamus to the sight of food

Recordings were made from single neurons in the lateral hypothalamus and substantia innominata of the rhesus and squirrel monkey during feeding. A population of these neurons which altered their firing rates while the monkeys looked at food but not at nonfood objects was investigated. Because the responses of these neurons must have been affected by the previous experience of the animals, the activity of the neurons was measured during tasks in which the monkeys learned whether or not objects which they saw were associated with food. During visual discrimination tests these neurons came to respond when the monkey saw one stimulus associated with food (e.g., a black syringe from which the animal was fed glucose), but not when the monkey saw a different stimulus which was not associated with food (e.g., a white syringe from which the animal was offered saline). During extinction tests these units ceased to respond when the monkey saw a visual stimulus such as a peanut if the peanut was repeatedly not given to the monkey to eat. The learning or extinction behavior approximately paralleled the response of the neurons.The findings that the neurons in the lateral hypothalamus and substantia innominata respond when a monkey is shown food only if he is hungry, and as shown here, if as a result of learning the visual stimulus signifies food, provide information on a part of the brain which may be involved in feeding. The findings are consistent with other data which suggest that the responses of these neurons are involved in the autonomic and/or behavioral reactions of the animal to the sight of food.     

Conditioned aversion to brain-stimulation reward: Effects of electrode placement and prior experience

A conditioned aversion to rewarding amygdaloid brain-stimulation was established by injecting rats with toxic doses of 0.15 M LiCl immediately after an initial self-stimulation session. The aversion had extinguished by the third self-stimulation session, 96 h after conditioning. This effect cannot be attributed to general depressant effects of LiCl on self-stimulation as treatment with LiCl 24 h before the second self-stimulation session was ineffective. Furthermore, this conditioned aversion was locus specific as LiCl injections immediately after the first test session had no disruptive effects on self-stimulation in the substantia nigra. The parallels between conditioned aversion to rewarding brain-stimulation in the amygdala and taste aversion were strengthened by the fact that the novelty of brain-stimulation reward was an important factor in the conditioning effect. These data have important implications for understanding the sensory properties of brain-stimulation reward.     

The latency of activation of neurones in the lateral hypothalamus and substantia innominata during feeding in the monkey

To investigate whether the responses of neurones in the lateral hypothalamus and substantia innominata associated with the sight of food could control the responses of the hungry monkey to the food, the latency of activation of these neurones by food was measured. It was found that when an electromagnetically operated wide-aperture shutter opened to reveal food or non-food objects, these hypothalamic neurones responded with a latency of 150–200 msec to the food objects, and did not respond to the non-food objects. To measure the latency of the monkey's responses to the food, a visual discrimination task was set in which the monkey could lick a tube to obtain fruit juice if a food-related visual stimulus was shown, but obtained hypertonic saline, which was aversive, if a different visual stimulus was shown. In this situation the typical latencies of the neuronal responses to the food were 150–200 msec, of the lick responses 350–400 msec. and of the EMG activity associated with these lick responses 250–400 msec. Thus the responses of these hypothalamic neurones precede the monkey's responses to the food, and could mediate the feeding and other responses of the animal to the food.It was also shown that a different population of hypothalamic neurones with responses associated with the sight of aversive visual stimuli had response latencies of 150–200 msec.     

Activity of neurones in the inferotemporal cortex of the alert monkey.

The activity of neurones in the inferotemporal cortex of the alert rhesus monkey was recorded while the monkey was shown visual stimuli, which included both food and non-food objects for comparison with the activity of neurones in the lateral hypothalamus and substantia innominata. In the anteroventral part of the inferotemporal cortex, neurones were found with visual responses which were sustained while the animal looked at the appropriate visual stimuli. The latency of the responses was 100 msec or more. The majority (96/142 or 68%) of these neurones responded more strongly to some stimuli than to others. These units usually had different responses when objects were shown from different views, and physical factors such as shape, size, orientation, colour and texture appeared to account for the responses of some of these units. Association of visual stimuli with a food reward (glucose solution) or an aversive taste (5% saline solution) did not affect the magnitude of the responses of the neurones to the stimuli either during the learning or after the period of learning. Nor did feeding the monkey to satiety affect the responses of the neurones to their effective stimuli.     

Connection between the prefrontal cortex and pontine brain-stimulation reward sites in the rat

Electrical stimulation of sites in the pontine tegmentum near the locus ceruleus excited some neurons in the prefrontal cortex antidromically, and activated other nearby neurons transsynaptically. The prefrontal neurons were activated by the pontine stimulation at current intensities lower than those which had previously provided brain-stimulation reward. A comparable strong activation of neurons was not found in other neocortical areas. It is concluded that because neurons in the sulcal and medial prefrontal cortex are activated by rewarding stimulation of the far-distant pontine tegmentum, as well as of other reward sites, activation of the demonstrated pathway between the prefrontal cortex and the pontine tegmentum may be involved in brain-stimulation reward. In addition it is concluded that self-stimulation of the region of the locus ceruleus does not necessarily depend on the activation of the noradrenaline-containing neurons of the locus ceruleus.     

Role of the limbic system in hypothalamically elicited attack behavior

The present review summarizes our research findings concerning the role of the limbic system in hypothalamically-elicited aggression in the cat. Utilizing a dual-stimulation procedure, our results indicate that much of the limbic system suppresses quiet biting attack behavior. The most potent inhibitory effects were obtained from the basomedial amygdala and the prefrontal cortex. Other structures displaying suppression of attack following electrical stimulation include the dorsal hippocampus, pyriform cortex, lateral septal nucleus, lateral aspect of substantia innominata, and anterior cingulate gyrus. Sites producing facilitation of attack include the ventral hippocampus, far lateral aspect of the lateral septal nucleus, medial aspect of the substantia innominata, and lateral amygdaloid nucleus. Anatomical studies suggest that the medial forebrain bundle and stria terminalis are utilized by limbic structures to provide direct modulation of the hypothalamus while the substantia innominata, mediodorsal thalamic nucleus and bed nucleus of the stria terminalis contain important interneurons in the control of quiet biting attack. Further studies indicate that the amygdala, ventral hippocampus, and substantia innominata may control aggressive behavior by modulating the trigeminal sensory components of the attack response.     

Sensory-specific satiety: Food-specific reduction in responsiveness of ventral forebrain neurons after feeding in the monkey

It has been shown previously that some neurons in the lateral hypothalamus and substantia innominata respond to the sight of food, others to the taste of food, and others to the sight or taste of food, in the hungry monkey. It is shown here that feeding to satiety decreases the responses of hypothalamic neurons to the sight and/or taste of a food on which the monkey has been satiated, but leaves the responses of the same neurons to other foods on which the monkey has not been satiated relatively unchanged. This suggests that the responses of these neurons in the ventral forebrain are related to sensory-specific satiety, an important phenomenon which regulates food intake. In sensory-specific satiety, the pleasantness of the sight or taste of a food becomes less after it is eaten to satiety, whereas the pleasantness of the sight or taste of other foods which have not been eaten is much less changed; correspondingly, food intake is greater if foods which have not already been eaten to satiety are offered.     

The substrate for brain-stimulation reward in the lateral preoptic area. I. Anatomical mapping of its boundaries

Given the putative role of the lateral preoptic area as a primary contributor of the cell bodies of origin of the descending pathway linking a subset of lateral hypothalamic and ventral tegmental area reward neurons, the distribution of self-stimulation sites in this structure was mapped in 22 animals using moveable electrodes and threshold procedures. Ninety-seven electrode sites were evaluated with placements ranging from just rostral to the midline convergence of the anterior commissure back to the transition zone between the lateral preoptic and lateral hypothalamic areas; of these, roughly 2/3 supported self-stimulation which was widely observed throughout the lateral preoptic area and medial forebrain bundle. In general, self-stimulation thresholds obtained from lateral sites were most stable, and progressively so approaching more caudal regions. Examination of the slopes of the period/current trade-off functions revealed a tendency for higher values in lateral and caudal sites; in contrast, dorsoventral excursions did not influence these estimates. Taken together, these data provide support for the notion that the substrate for brain-stimulation reward in the lateral preoptic area has a relatively homogeneous distribution that is more diffusely organized than that found in reward sites activated further caudally in the medial forebrain bundle.     

Visual responses of neurons in the dorsolateral amygdala of the alert monkey

There is evidence that the inferotemporal visual cortex in the monkey projects to the amygdala, and evidence that damage to this region impairs the learning of associations between visual stimuli and reward or punishment. In recordings made in the amygdala to determine whether or not visual responses were found, and if so how they were affected by the significance of the visual stimuli, neurons were found in the dorsolateral part of the amygdala with visual responses which in most cases were sustained while the animal looked at effective visual stimuli. The latency of the responses was 100 to 140 ms or more. The majority (85%) of these neurons responded more strongly to some stimuli than to others, but physical factors which accounted for the responses of the neurons, such as shape, size, orientation, color, or texture, could not usually be identified. Although 22 (19.5%) of these neurons responded primarily to food objects, the responses were not uniquely food-related. Furthermore, although some neurons responded in a visual discrimination test to a visual stimulus which indicated reward, and not to a visual stimulus which indicated saline, only minor modifications of the magnitude of the neuronal responses to the stimuli were obtained when the reward-related significance of the stimuli was reversed. The visual responses of these amygdaloid neurons were thus intermediate in some respects between those of neurons in the inferotemporal cortex, which are not affected by the significance of visual stimuli, and those of neurons in a region to which the amygdala projects, the lateral hypothalamus and substantia innominata, where neurons respond to visual stimuli associated with food reward.     

Dissociable contributions of the orbitofrontal and lateral prefrontal cortex of the marmoset to performance on a detour reaching task

To gain insight into the nature and neural specificity of the relationship between simple problem solving, inhibitory control and prefrontal cortex, comparison of the effects of excitotoxic lesions of the orbitofrontal and lateral prefrontal cortex were examined on the performance of common marmosets on a detour reaching task. Monkeys were required to inhibit reaching directly for food reward in a transparent box and instead make a detour reach around to the side of the box either having had (i) no prior experience on the task (experiment 1) or (ii) previous experience in reaching around the sides of an opaque box (experiment 2). Whilst monkeys with orbitofrontal lesions had difficulty in inhibiting direct reaches to visible food reward (experiment 1), they could resist this prepotent response tendency following extensive prior experience of detour reaching with an opaque box (experiment 2). In marked contrast, monkeys with lateral prefrontal lesions exhibited no difficulty in inhibiting reaching to visible food reward or acquiring detour reaching per se (experiment 1). However, having been given the opportunity to acquire an efficient detour reaching strategy to hidden food reward these lateral prefrontal lesioned monkeys were impaired at transferring this strategy to the new context in which the food reward was made visible (experiment 2). This double dissociation between the effects of orbitofrontal and lateral prefrontal lesions on detour reaching provides evidence for a clear distinction in the level of control over responding exerted by the orbitofrontal and lateral prefrontal cortex, consistent with hierarchical ordering of response control processes within prefrontal cortex.     

Afferent connections of the substantia innominata/basal nucleus of Meynert in carnivores and primates

Afferent connections to the substantia innominata/nucleus basalis complex of monkeys and cats were traced by using the method of retrograde transport of horseradish peroxidase (HRP). Altogether ten injections of HRP were performed in four monkeys (Saimiri sciureus, Callithrix jacchus, Galago senegalensis) and in four cats, with either vertical or oblique needle approaches. The entire brains excluding the olfactory bulbs and the cerebellum were then screened for labeled neurons. In both monkey and cat brains, many retrogradely labeled neurons could be detected in the amygdala, hypothalamus, midline thalamus, zona incerta, and the fields of Forel. Further but weaker labeling occurred in the medial septal nucleus, diagonal band of Broca, olfactory tubercle, paraventricular, anterior, mediodorsal, and central lateral thalamic nuclei, lateral habenula, ventral tegmental area of Tsai, interpeduncular nucleus, parabrachial, raphe, dorsal tegmental nucleus and the locus caeruleus. Cortically, prefrontal, insular, entorhinal, prepiriform, and periamygdaloid areas of both species showed considerable labeling as well as the whole temporal lobe of the monkeys used. The perirhinal and basal temporal cortex of all cats showed moderate labeling. In both monkeys and cats, extremely scarce labeling occurred within the cingulate, retrosplenial, and subicular cortex. From an anatomical point of view, the manifold connections of the substantia innominata/basal nucleus of Meynert found in this study underscore the participation of these nuclear groups in motivational, emotional, and cognitive (e.g. mnemonic) functions. Considering the widespread cortical efferents of this complex, it is suggested that the substantia innominata/nucleus basalis of Meynert serves the transmission of information arising within the limbic system to the whole neocortex.     

Effects of hunger on the responses of neurons in the lateral hypothalamus to the sight and taste of food

Recordings were made from single neurons in the monkey lateral hypothalamus and substantia innominata which had previously been shown to respond with an increase or decrease of their firing rates when the hungry monkey tasted food, and/or when he looked at food. It was found that the responsiveness of these neurons to food decreased over the course of a meal of glucose as satiety increased. When satiety, measured by whether the monkey rejected the glucose, was complete, there was no response of the neurons to the taste and/or to the sight of glucose. The spontaneous firing rates of these cells were not affected by the transitions from hunger to satiety. This modulation of responsiveness to food of hypothalamic cells was specific to them in that it was not seen in cells in the globus pallidus which responded in relation to swallowing and mouth movements, or in cells in the visual inferotemporal cortex which responded when the monkey looked at the glucose-containing syringe. On the basis of this and other evidence it is suggested that the hypothalamic cells described here could be involved in the autonomic, the endocrine, and/or the feeding responses which occur when an animal sees or tastes food.     

Self-stimulation of the nucleus accumbens and ventral tegmental area of tsai attenuated by microinjections of spiroperidol into the nucleus accumbens

The contribution of dopaminergic neurons to self-stimulation of the ventral tegmental area, nucleus accumbens and prefrontal cortex was investigated. The ventral tegmental area is the site of non-striatal dopaminergic neurons and their axons project to the nucleus accumbens and prefrontal cortex. Injections of spiroperidol, a dopamine antagonist, into the nucleus accumbens significantly reduced self-stimulation of the ipsilateral ventral tegmental area but did not influence self-stimulation of the contralateral ventral tegmental area. Injections of spiroperidol into the prefrontal cortex did not reduce self-stimulation of the ipsilateral or contralateral ventral tegmental area. Electrical stimulation of sites in the nucleus accumbens positive for self-stimulation antidromically activated neurons of the ventral tegmental area, and a reduction of discharge of these neurons following administration of apomorphine suggested that they were dopaminergic neurons. These observations provide additional evidence implicating dopaminergic neurons in brain-stimulation reward and suggest that dopaminergic neurons contribute to self-stimulation of the nucleus accumbens but not the prefrontal cortex.     

Glutamate-induced vocalization in the squirrel monkey

In the squirrel monkey, 164 brain sites yielding vocalization when electrically stimulated were tested for their capability to produce vocalization when injected with mono-sodium-L-glutamate. The sites were located in the anterior limbic cortex, n. accumbens, substantia innominata, amygdala, n. striae terminalis, hypothalamus, midline thalamus, field H of Forel, substantia nigra, periventricular and periaqueductal gray, inferior colliculus, reticular formation of midbrain, pons and medulla, inferior olive, lateral reticular nucleus and nucleus of solitary tract. Of the 164 sites tested, 31 were positive. These were located in the substantia innominata, caudal periventricular and periaqueductal gray, lateral pontine and medullary reticular formation. While all the calls obtained from the forebrain and midbrain had a normal acoustic structure, most pontine and all medullary vocalizations had an artificial character. It is concluded that: the substantia innominata, caudal periventricular and periaqueductal gray, lateral pontine and medullary reticular formation represent relay stations of vocalization-controlling pathways; the periaqueductal gray represents the lowest relay station above the level of motor coordination; neurons responsible for motor coordination of vocalization lie in the reticular formation around the caudal brachium conjunctivum, the superior olive, n. facialis, n. ambiguus and below the n. solitarius; not all areas from which vocalization can be obtained by electrical stimulation of nerve cell bodies, dendrites and nerve endings (in contrast to fibers en passage) also yield vocalization when stimulated with glutamate.     

Role of oxytocin in the control of stress and food intake

Oxytocin neurones in the hypothalamus are activated by stressful stimuli and food intake. The oxytocin receptor is located in various brain regions, including the sensory information‐processing cerebral cortex; the cognitive information‐processing prefrontal cortex; reward‐related regions such as the ventral tegmental areas, nucleus accumbens and raphe nucleus; stress‐related areas such as the amygdala, hippocampus, ventrolateral part of the ventromedial hypothalamus and ventrolateral periaqueductal gray; homeostasis‐controlling hypothalamus; and the dorsal motor complex controlling intestinal functions. Oxytocin affects behavioural and neuroendocrine stress responses and terminates food intake by acting on the metabolic or nutritional homeostasis system, modulating emotional processing, reducing reward values of food intake, and facilitating sensory and cognitive processing via multiple brain regions. Oxytocin also plays a role in interactive actions between stress and food intake and contributes to adaptive active coping behaviours.     

Midbrain,diencephalic and cortical relationships of the basal nucleus of meynert and associated structures in primates

The structure and connectivity of the basal nucleus of Meynert, the substantia innominata in which it lies, and certain related areas have been examined in New World and Old World Monkeys, using retrograde and anterograde axonal transport methods. Experiments using the retrograde, horseradish peroxidase method confirm the observations of Kievet and Kuypers ('75) that the basal nucleus and substantia innominata project directly, heavily and with a somewhat crude topography upon the neocortex. Experiments involving the anterograde, autoradiographic method show that the basal nucleus and substantia innominata form part of a complex pathway that links them together with the lateral hypothalamus, certain parts of the amygdala and the peripeduncular nucleus of the midbrain. The peripeduncular nucleus is often regarded as a part of the central auditory pathway; it gives rise to a fiber bundle of considerable size that ascends on the dorsal surface of the ipsilateral optic tract and terminates ultimately in the lateral hypothalamic area of both sides. As well as distributing fibers to the basal nucleus, substantia innominata and lateral hypothalamus, this pathway provides a heavy projection to a cytoarchitectonically distinct posterior part of the lateral nucleus of the amygdala, the medial and intercalated nuclei of the amygdala and a less dense projection to the bed nucleus of the stria terminalis. Certain parts of the hypothalamus and possibly the preoptic areas give rise to a complementary descending pathway that distributes fibers to the ipsilateral basal nucleus, substantia innominata and amygdala, and ends in the peripeduncular nuclei of both sides. Decussating fibers in both the ascending and descending pathways cross in the ventral supraoptic commissure. It is concluded that the basal nucleus should include most of the aggregated and unaggregated large cells that lie in the substantia innominata and which in places intrude upon the preoptic regions and the nucleus of the diagonal band of Broca. Together, these may form a complex that receives inputs from a variety of brainstem sources, and projects widely and diffusely upon all cortical structures of the telencephalon.     

Effects of kainic acid lesions of the striatum on self-stimulation in the substantia nigra and ventral tegmental area

Unilateral kainic acid lesions of the dorsal striatum provided evidence for a dissociation of neural substrates of brain-stimulation reward at sites in the ventral tegmental area and substantia nigra. The lesions caused a significant increase in current intensity thresholds at substantia nigra placements, whereas similar lesions had no effect on self-stimulation thresholds at sites in the ventral tegmentum. In addition, the rate-increasing effects of d-amphetamine (0.1–1.0 mg/kg) on self-stimulation were determined before and after lesions to the dorsal striatum. No significant changes in dose-response curves were observed at either loci. Amphetamine-induced rotation was used to confirm damage to the dorsal striatum and lesioned animals were observed to rotate towards the side of the lesion. In contrast, sham-lesioned animals showed turning away from the side stimulated electrically in previous tests. The results of the self-stimulation and rotation experiments are discussed in the context of neural substrates of reward and motor activity.     

Efferent systems of primary visual cortex: A review of structure and function

In an attempt to further characterize the nature of the functional organization of the amygdala, patterns of uptake of [¹⁴C]2-deoxyglucose (2-DG) were assessed following electrical stimulation of various sites within the amygdala and associated structures in the rat. The experimental paradigm consisted of electrical brain stimulation delivered continuously for periods of 30 s on and 30 s off for 45 min following injection of 2-DG. Brains were removed and processed for autoradiography. It was noted that a specificity existed regarding nuclei, which when stimulated, resulted in demonstrable metabolic activation of the hypothalamus. Amygdaloid structures producing such activation included the medial, cortical, and basomedial nuclei, and the amygdalo-hippocampal area. Stimulation of these nuclear regions differentially activated areas within the hypothalamus. Stimulation of the medial and cortical nuclei effectively labeled fibers supplying the ventromedial nucleus. Stimulation of the amygdalo hippocampal area activated fibers which innervated the medial preoptic region. In contrast, activated fibers supplying the ventrolateral hypothalamus were present following stimulation of the basomedial nucleus. Activated fibers were observed in the lateral region of the medial forebrain bundle following stimulation of the central nucleus. Since these fibers could be followed directly into the substantia nigra, it was not possible to determine the extent to which they may have terminated within the lateral hypothalamus. Stimulation of other regions of the amygdala produced no demonstrable activation of any region of hypothalamus.The overall patterns of subcortical activation following stimulation of amygdaloid nuclei revealed the presence of considerable quantities of labeled fibers within the bed nucleus of the stria terminalis and substantia innominata. In addition, stimulation of the bed nucleus activated fibers which predominantly supply the ventromedial hypothalamus while stimulation of the substantia innominata activated fibers which supply the lateral hypothalamus. These data, taken collectively with previous anatomical data, suggest the likelihood that these two regions may serve as important relays through which much of the amygdala can communicate with the hypothalamus.An analysis was also made of the distribution of labeled fibers following the generation of seizure activity induced by focal injections of penicillin placed into various regions of amygdala. The data suggest that the pathways involved in the manifestation of a given induced seizure follow the known routes of axons, either arising from or passing through the structure associated with the seizure focus. While the activation pattern associated with focal seizures induced by the placement of penicillin into the basal nuclear complex appeared to be limited to first-order neurons, the patterns associated with seizures induced from the posterior cortical nucleus reflected the additional activation of second and third-order neurons of the hippocampal-septal system.