Prolonged medial forebrain bundle unit responses to rewarding and aversive intracranial stimuli.

In unanesthetized cerveau isolé rats, brief medial forebrain bundle (MFB) and dorsal midbrain reticular (RET) stimulus trains elicited prolonged MFB unit responses lasting up to ten or more seconds. On the MFB unit responses studied, the effects of MFB and RET stimuli were basically similar, although the stimulations were probably rewarding and aversive respectively. These data agree with the previously reported anatomical localization, in medial regions of thalamus and pallidum, of opposite single cell responses to the behaviorally opposite inputs, and suggest that unit responses to rewarding stimuli should not be characterized as reward-related when aversive stimuli elicit similar responses in the same unit.     

Responses of preoptic thermosensitive neurons to medial forebrain bundle stimulation

HORI, T., T. KIYOHARA, T. NAKASHIMA AND M. SHIBATA. Responses of preoptic thermosensitive neurons tomedial forebrain bundle stimulation. BRAIN RES. BULL. 8(6) 667–675, 1982.—Single-unit responses of neurons in the preoptic and anterior hypothalamus (PO/AH) to local thermal stimulation and electrical stimulation of the medial forebrain bundle (MFB) were studied in urethane-anesthetized male rats. In a total of 286 units (112 warm-units, 37 cold-units and 137 thermally insensitive units), 109 units (49 warm-units, 13 cold-units and 47 thermally insensitive units) responded to single pulse stimulation of MFB. The units initially inhibited by MFB stimulation corresponded to 64.2% (70 of 109), the units with facilitatory responses were 27.5% (30 of 109) and the antidromically activated units were 8.3% (9 of 109). High incidence of inhibition by noradrenaline (NA) applied iontophoretically was observed in the neurons inhibited by the MFB stimulation. Iontophoretic application of dichloroisoproterenol to 2 warm-units blocked both the NA-induced inhibition and the MFB-induced inhibition. These ascending and descending connections of the MFB with PO/AH thermosensitive neurons may be part of the neural circuits responsible for thermoregulation.     

The role of the medial forebrain bundle in the mediation of the hypothalamic-hypophyseal-adrenal responses to acute neurogenic stress

Adult male rats, intact (N) or bearing bilateral lesions in the medial forebrain bundle (MFB), were acutely exposed to visual, audiogenic, or thermal stress, during the following which serum ACTH and corticosterone (CS) levels were determined. The marked elevations in serum concentrations of both ACTH and CS which occurred in intact animals following photic stimulation were absent in MFB rats. The normal ACTH and CS responses to audiogenic stress were slightly delayed and attenuated, respectively, in the operated group, whereas the responses of both hormones to exposure to elevated environmental temperature were partially blocked in lesioned, as compared to intact, animals. These results demonstrate that the MFB is involved in mediating the ACTH, as well as the CS secretory responses to acute stress exposure. More specifically, the role of the MFB, vís-à-vis the hypothalamo-hypophyseal-adrenal axis, appears to be in the transmission of sensory input from rostral brain areas posteriorly.     

Comparisons of refractory periods for medial forebrain bundle fibers subserving stimulation-induced feeding and brain stimulation reward: a psychophysical study

Paired-pulse stimulation techniques were used to infer distributions of refractory periods (RPs) for the directly activated medial forebrain bundle (MFB) substrates of brain stimulation reward (BSR) and stimulation-induced feeding (SIF). Each RP distribution suggested (a) a subpopulation of contributing fibers with refractory periods between 0.4 and 0.6 ms, (b) absence of significant numbers of fibers with refractory periods between 0.6 and 0.7 ms, and (c) a second subpopulation (or set of overlapping subpopulations) with refractory periods between 0.7 and 1.5-2.5 ms. Similar RP estimates were obtained in different animals, despite the fact that stimulation sites ranged from the anterior lateral hypothalamus to the ventral tegmental area; this finding is consistent with the view that the directly activated substrate of both behaviors involves MFB fibers of passage. While the possibility cannot be ruled out that the two behaviors result from activation of distinct sets of fibers with remarkably similar refractory periods, the more likely possibility is that a common--or at least partially common--MFB substrate underlies brain stimulation reward and stimulation-induced feeding.     

Growth of medial forebrain bundle axons into peripheral nerve grafts in the rat

In rats, we intercepted medial forebrain bundle axons just lateral to the hypothalamus with peripheral nerve grafts which terminated extracranially. The neurons which grew into the nerve grafts were labeled with retrogradely transported fluorescent dyes. Catecholamines were labeled with glyoxylic acid histofluorescence. Most nuclei, particularly the raphe complex and locus coeruleus, which project rostrally into the medial forebrain bundle were labeled. Many catecholamine fibers were observed in the graft even after removal of the superior cervical ganglions. Thus, monoaminergic neurons which were located relatively remotely from the implant site exhibited rather selective regrowth into the nerve grafts.     

Dopaminergic neurons: simultaneous measurements of dopamine release and single-unit activity during stimulation of the medial forebrain bundle

Simultaneous electrical and chemical recordings have been made of dopamine neuronal activity in the rat brain during electrical stimulation of the medial forebrain bundle. Tungsten recording electrodes were placed at the level of the substantia nigra and carbon-fiber, Nafion-coated, voltammetric electrodes were placed in the neostriatum. Dopamine units, verified by histology to be in the zona compacta of the substantia nigra, were identified by previously established electrophysiological criteria. Dopamine release was detected by fast-scan cyclic voltammetry, a technique which allows dopamine to be determined in vivo on a sub-second time scale. The majority of dopamine cells examined (7 out of 10) were antidromically activated by 60 Hz stimulation of the medial forebrain bundle. The same stimulus also elicits dopamine overflow in the caudate nucleus. Following stimulation, dopamine concentrations in the extracellular fluid of the neostriatum rapidly declined to prestimulus levels. In addition, impulse flow in dopaminergic neurons was inhibited for 20 s following stimulation. These measurements represent the first direct observation from a neuronal tract of simultaneous unit activity and chemical release of a neurotransmitter in real time.     

Stimulation of the subcallosal fornix excites neurones in the cat preoptic region which project to the medial basal hypothalamus and in the medial forebrain bundle

The projection of neurones in the cat preoptic region driven by stimulation of the subcallosal fornix was systematically explored. We found 19% projected to the medial basal hypothalamus (MBH) and 10% projected in the medial forebrain bundle (MFB). Neurones projecting to 3he MBH were driven more often by stimulation of the lateral aspect of the fornix than the medial aspect (P = 0.006) and these neurones were thought to lie in the medial division of the preoptic nucleus (MPNm) since they were found significantly more often in the medial 0.6 mm of the preoptic region than more laterally (P = 0.028). A reverse projection from the preoptic region in the fornix is also suggested based on the finding of 24 antidromically activated neurones inthe preoptic region following stimulation of the fornix.     

Lidocaine inactivation demonstrates a stronger role for central versus medial extended amygdala in medial forebrain bundle self-stimulation

Given recent attention to the role of the extended amygdala (EA) in brain reward processes, this study examines the relative contributions of the medial versus central aspects of that forebrain macrostructure to the rewarding effects of medial forebrain bundle (MFB) stimulation. Thirty-one rats were self-stimulated at either the rostral or caudal MFB before and after lidocaine-induced inactivation of an EA target. Relative to non-injection baseline tests, the injection of 0.5 or 1.0 microl of 4% lidocaine into the central EA structures of the lateral bed nucleus of the stria terminalis, the central sublenticular EA, and the interstitial nucleus of the posterior limb of the anterior commissure frequently and substantially disrupted the rewarding effect of MFB stimulation, whereas comparable saline infusions did not. The effects were most pronounced when the central EA was inactivated either bilaterally or ipsilateral to the stimulation site. Contralateral inactivation was less effective but did impair the stimulation's reward effects in several cases. Inactivation of medial EA structures did not have as great or as consistent effects on stimulation reward value except when the lidocaine infusion encroached on the MFB itself. These results support prior demonstrations of the EA's role in brain reward and motivational processes and further show that the central rather than medial aspects of the EA are particularly relevant. The results are discussed in the context of possible anatomical substrates supporting MFB self-stimulation.     

Electrical stimulation of the medial forebrain bundle in pre-clinical studies of psychiatric disorders

Modulating neuronal activity by electrical stimulation has expanded from the realm of motor indications into the field of psychiatric disorders in the past 10 years. The medial forebrain bundle (MFB), with a seminal role in motor, reward orientated and affect regulation behaviors, and its afferent and efferent loci, have been targeted in several DBS trials in patients with psychiatric disorders. However, little is known about the consequences of modulating the MFB in affective disorders. The paper reviews the relevant pre-clinical literature investigating electrical stimulation of regions associated with the MFB in the context of several models of psychiatric disorders, in particular depression. The clinical data is promising but limited, and pre-clinical studies are essential for improved understanding of the anatomy, the connectivity, and the consequences of stimulation of the MFB and regions associated with the neurocircuitry of psychiatric disorders. Current data suggests that the MFB is at a “privileged” position on this circuitry and its stimulation can simultaneously modulate activity at other key sites, such as the nucleus accumbens, the ventromedial prefrontal cortex or the ventral tegmental area. Future experimental work will need to shed light on the anti-depressive mechanisms of MFB stimulation in order to optimize clinical interventions.     

Effect of 6-hydroxydopamine lesions of the medial forebrain bundle on the distribution of cholecystokinin in rat forebrain

The quantitative contribution of ascending dopaminergic fibers of the medial forebrain bundle to the cholecystokinin-like immunoreactivity (CCK-LI) in rat forebrain areas has been studied using unilateral 6-hydroxydopamine lesions of this pathway. The lesions produced depletions of CCK-LI in only two of the 18 areas studied. The results suggest that the terminal areas of the mesolimbic dopamine neurons also contain substantial CCK-LI innervations from other non-dopaminergic neurons.     

Neuropharmacological and electrophysiological evidence implicating the mesolimbic dopamine system in feeding responses elicited by electrical stimulation of the medial forebrain bundle

The contribution of the mesolimbic dopamine pathway to feeding behavior was investigated in rats in which feeding responses were elicited by electrical stimulation of the medial forebrain bundle at the level of the lateral hypothalamus. Injections of spiroperidol, a dopamine antagonist, into the nucleus accumbens ipsilateral to the stimulating electrode significantly attenuated the elicited feeding responses whereas injecting spiroperidol into the contralateral nucleus accumbens had no effect. The spontaneous discharge rates of neurons of the ventral tegmental area, identified by their electrophysiological characteristics as dopaminergic, were both increased and decreased in response to single pulse stimulation of sites in the medial forebrain bundle from which feeding responses had been elicited. These observations suggest that mesolimbic dopaminergic neurons may have a role in feeding behavior and indicate the need for chronic electrophysiological recording experiments to see whether or not the activity of these neurons is correlated with the initiation of elicited and spontaneous feeding responses.     

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.     

Two substrates for medial forebrain bundle self-stimulation: myelinated axons and dopamine axons

The directly activated substrates for medial forebrain bundle (MFB) self-stimulation are primarily low threshold, myelinated axons with absolute refractory periods of 0.4 to 1.2 msec, conduction velocities of 1 to 8 m/sec and current-distance constants of 1000 to 3000 microA/mm2. When small electrode tips or high currents are used, however, a second population of long refractory period (1.2 to 5 msec) axons is added. The excitability properties of this second population are almost identical with those of dopamine (DA) axons. Furthermore, the long-refractory period effects of MFB self-stimulation are reduced, but not completely blocked, by peripheral injections of alpha-flupenthixol, suggesting that dopamine axons make small contributions to MFB self-stimulation when small tips are used. Collision data, strength-duration data and refractory period data in various self-stimulation experiments are compared. Asymmetric collision effects, recently observed in cortical and striatal sites mediating electrically evoked turning, may help determine where synapses are located in circuits mediating electrically evoked behaviors. A neural model of symmetric, asymmetric and mixed collision is proposed.     

The effect of unilateral neurotoxic lesions to serotonin fibres in the medial forebrain bundle on the metabolism of [H]DOPA in the telencephalon of the living rat

We used quantitative autoradiography to measure the contribution of the 5-hydroxytryptamine (5-HT, serotonin) innervation of rat telencephalon to the synthesis of dopamine (DA) from exogenous l-DOPA. One week after stereotaxic infusions of 5,7-dihydroxytryptamine (5,7-DHT, 1.6 μg) into the right medial forebrain bundle (MFB), rats received [³H]DOPA (200 μCi, i.v.), which circulated for 90 min. The specific bindings in vitro of the 5-HT uptake site ligand [³H]citalopram and the DA uptake site ligand [¹²⁵I]RTI-55 were measured in cryostat sections from the prosencephalon. In most structures ipsilateral to the lesion, [³H]citalopram specific binding was substantially reduced (50–90%). In the lateral habenula specific binding declined by only 30–40%, reflecting the presence of a 5-HT pathway deviating from the MFB at the mesencephalic flexure. [¹²⁵I]RTI-55 binding in the basal ganglia was reduced by 50% on the side of the 5,7-DHT lesion, but was unperturbed in rats pretreated with desmethylimipramine (DMI). 5,7-DHT infusions decreased the synthesis of [³H]DA from [³H]DOPA in vivo in the basal ganglia by (40–90%). Pretreatment with DMI protected [³H]DA synthesis in the basal ganglia, but not in the olfactory tubercle and amygdala ipsilateral to the lesion. Whereas the 5-HT innervation does not contribute greatly to [³H]DA synthesis in the basal ganglia, a substantial proportion of [³H]DA synthesis in olfactory tubercle and amygdala requires an intact 5-HT innervation.     

Angiotensin II receptor binding sites in the ventral portion of the bed nucleus of the stria terminalis are reduced by interruption of the medial forebrain bundle

Many techniques have been utilized to discern the localization of angiotensin II (Ang II) receptors to specific cellular components (glia, neuronal cell bodies and nerve terminals) in the brain. In the present study, we used lesioning techniques to localize Ang II receptors to cellular components in the rat forebrain. In the first experiment, axons ascending to the hypothalamus and forebrain from neurons in the brainstem were destroyed by unilaterally cutting the medial forebrain bundle (MFB). In the second experiment, a single injection of the neurotoxin, ibotenic acid, was injected unilaterally into the ventral portion of the bed nucleus of the stria terminalis (BSTV) to destroy neuronal cell bodies, thus determining if Ang II receptors are present on neuronal cell bodies. In both experiments, the animals were sacrificed after two weeks recovery and the brains processed for in vitro receptor autoradiography using -sar¹,ile⁸ Ang II (-SI Ang II). Unilateral knife-cut lesions of the MFB caused a significant reduction in -SI Ang II binding in the BSTV (30±6%) and the piriform cortex (PC; 26±4%) ipsilateral to the knife cut. Unilateral injection of the neurotoxin into the BSTV failed to alter -SI Ang II binding in this nucleus. These experiments suggest that at least a subpopulation of Ang II receptors in the BSTV and PC are located on terminals of neurons that have their cell bodies in the brainstem and their axons in the MFB.     

Role of medial forebrain bundle catecholaminergic fibers in the modulation of glucocorticoid negative feedback effects

The possible role of medial forebrain bundle (MFB) catecholaminergic fibers in the previously observed MFB-mediated modulation of hypothalamic sensitivity to glucocorticoid negative feedback effects has been investigated. MFB catecholaminergic fibers were destroyed by bilateral MFB injections of 6-hydroxydopamine (6-OHDA) to adult male rats. The inhibitory effect of dexamethasone (10 μg, i.p., 4h) upon the adrenocortical secretory response to ether stress, as estimated by serum corticosterone levels, was enhanced in the 6-OHDA-treated animals, as compared to vehicle-injected controls. This study suggests that MFB noradrenergic neurons are at least partially responsible for the MFB-mediated modulation of hypothalamic sensitivity to glucocorticoid hormones.     

Lesions of pontomesencephalic cholinergic nuclei do not substantially disrupt the reward value of medial forebrain bundle stimulation

This study examines the effects of lesioning the pedunculopontine tegmentum (PPTg) and laterodorsal tegmentum (LDTg) on the reward effectiveness of medial forebrain bundle (MFB) stimulation. Although the focus is on the effects of unilateral lesions made ipsilateral to stimulation sites in the hypothalamic and ventral tegmental MFB, the effects of contralateral lesions of both targets are also investigated. Reward effectiveness was assessed using the rate–frequency curve shift paradigm. In nine rats with unilateral PPTg lesions and five rats with unilateral LDTg lesions, the frequency required to maintain half-maximal response rats was generally not changed by more than 0.1 log units relative to prelesion baseline mean. In three rats with contralateral PPTg lesions and four rats with contralateral LDTg lesions, required frequency was also not substantially changed. The results are interpreted in terms of a previously proposed hypothesis regarding the role in MFB self-stimulation of ascending cholinergic input from the pontomesencephalon to ventral tegmental dopaminergic neurons.     

Brain stimulation reward in the lateral hypothalamic medial forebrain bundle: Mapping of boundaries and homogeneity

The boundaries and relative fiber concentration of the brain stimulation reward (BSR) sustaining system coursing through the lateral hypothalamic medial forebrain bundle (MFB) were mapped using a dorso-ventral moveable electrode. High response rates for BSR were found in a region extending dorso-ventrally from the zona incerta (ZI) to the base of the brain and medio-laterally from the fornix to the medial tip of the internal capsule (IC). Self-stimulation associated with perifornical area and self-stimulation associated with the tip of the internal capsule were mixed with aversion and forced movements, respectively. Current intensity threshold variations suggest: (i) that the reward system has a well-defined dorsal boundary ventral to the ZI, and (ii) that the core of the MFB contains a relatively higher concentration of reward relevant fibers than do its lateral, medial, dorsal and ventral components. No evidence was seen of independent mid-lateral and far-lateral MFB systems, though independent BSR sites in the dorsomedial and ventromedial hypothalamus were seen.     

Effects of neonatal destruction of the medial forebrain bundle in the cat: long-term disturbances in learning ability, response to amphetamine challenge, and reactivity to auditory stimuli

These experiments ascertain some of the long-term behavioral effects of neonatal medial forebrain bundle (MFB) lesions in the cat. Bilateral electrolytic lesions (N = 27) were made when the animals were 11 to 22 days of age. The long-term behavioral development of cats with these lesions were compared with that of a group of intact littermates (N = 37) and a group of littermates that received lesions that did not encroach upon the MFB. When the animals were 18 to 40 days of age they were tested in a spatial discrimination. Animals with bilateral MFB lesions were capable of learning the discrimination but made more repeated errors than animals in the other groups. This effect was compensated for with additional training. When tested on a visual discrimination at 3 to 4 months of age, kittens with MFB lesions learned the discrimination in a normal manner. When the discrimination cues were reversed, however, they responded more frequently to the previously reinforced cue. The effects of d-amphetamine were assessed when animals were 7 to 12 months of age. Animals with bilateral MFB lesions displayed less frequent and intense head movement stereotypies and more locomotor responses to amphetamine than animals in other groups. The reactivity to a series of auditory stimuli was assessed when the animals were 1 to 2 years of age. Neonatal MFB lesions produced an impaired pattern of habituation of reactivity to auditory stimuli. Cats with these lesions responded normally to the initial presentations of the vocalizations. However, 24 h later they responded to the stimuli more vigorously than animals in the other groups. Taken together the results of this experiment and the previous report indicate that some effects of neonatal MFB damage were qualitatively different from those of lesions inflicted in mature animals and that a complex interaction among a number of factors was probably responsible for these differences.