The spontaneous firing patterns of forebrain neurons. V. Time course of changes in caudate unit activity following dopamine-depleting lesions

The effects of unilateral medial forebrain bundle (‘MFB’) lesions on the spontaneous firing patterns of caudate neurons on both sides of the brain in cats were studied 3 days, 7 days and more than 2 weeks postlesion. Our results indicate that: (1) the spontaneous firing of neurons in the caudate nucleus ipsilateral to the lesion slows significantly by 3 days postlesion and returns to control values by 7 days postlesion, (2) the spontaneous activity of contralateral caudate neurons slows progressively with postlesion time and (3) these changes in neural activity are not correlated with changes in dopamine concentrations in the caudate nucleus.     

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.     

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.     

Rewarding effects of hypothalamic self-stimulation altered by unilateral lesions of superior colliculus in rats

The effects of unilateral lesions of the superior colliculus were determined on self-stimulation of the medial forebrain bundle. It was found that the lesions had different effects depending upon the precise location of the stimulating electrode: self-stimulation on far-laterally located electrodes was abolished while on more medially placed electrodes this behaviour was enhanced. These data are inconsistent with explanations of intracranial self-stimulation which treat it as a unitary phenomenon.     

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.     

Determination of the course of brainstem catecholamine fibers mediating amphetamine anorexia

Previous studies suggest that brainstem catecholamine (CA) fibers which mediate amphetamine (AMPH)-induced anorexia ascend through the midlateral medial forebrain bundle and perifornical region and terminate in the perifornical hypothalamic region (PFH) at the level of the hypothalamic ventromedial nucleus⁴³. Through studies of wire-knife cuts (KCs) placed in the lower brainstem, the present paper further delineates the course of fibers mediating AMPH feeding suppression, as they ascend through the medullary, pontine and midbrain tegmentum. The results indicate that the crucial CA fibers ascend through the ventrolateral medulla just dorsal to the nucleus of the seventh cranial nerve, 1.1–1.9 mm lateral to midline. In their rostral course, these fibers apparently maintain a relatively straight position in the ventral pons and then enter the ventrolateral midbrain just dorsal to the medial lemniscus, between 0.7 and 1.1 mm lateral to midline. These medullary fibers, possibly originating from the norepinephrine/epinephrine-containing ventrolateral cell group (A1/C1), then appear to join additional fibers from the scattered dopamine-containing neurons positioned in the caudal midbrain (A8 CA cell group). Together, these dopamine, epinephrine and norepinephrine systems are believed to ascend into the medial aspect of the medial forebrain bundle on their way to the PFH at the level of the ventromedial nucleus.     

Ascending components of the medial forebrain bundle from the lower brain stem in the rat, with special reference to raphe and catecholamine cell groups. A study by the HRP method

The afferent connections of the medial forebrain bundle (MFB) arising from the lower brain stem have been investigated by means of horseradish peroxidase (HRP) with sensitive substrate. The injection was made iontophoretically into MFB at various levels.After injection of HRP into MFB, a significant number of HRP-labeled neurons were observed in the following structures of the lower brain stem: (1) raphe nuclear group, (2) locus coeruleus, (3) n. laterodorsalis tegmenti, (4) parabrachial area, (5) A₁, A₂, A₄, A₅ and A₇ areas where noradrenaline-containing neurons were disseminated, (6) A₈, A₉ and A₁₀ areas which contain dopamine neurons, (7) surrounding area of the fasciculus longitudinalis medialis at the level of the n. prepositus hypoglossi, (8) n. prepositus hypoglossi and (9) mesencephalic gray matter. As a rule, the ascending projections are ipsilateral and course in the medial part of MFB.Regarding the raphe nuclei, we have demonstrated that the caudal raphe nuclei, such as n. raphe magnus and obscurus (but not n. raphe pallidus), also send their axons to the hypothalamus. Particularly, the axons of n. raphe magnus ascend in MFB to reach the level of the preoptic or anterior septal area. Furthermore, in accordance with previous reports, HRP-labeled cells were also identified in the n. raphe dorsalis, centralis superior and pontis, respectively. It should be further noted that labeled cells appeared in the n. linearis caudalis.In addition, the present study indicates a number of non-aminergic cell groups as sources of ascending MFB fibers.On the whole, the present study further clarified the organization of the components of the MFB ascending from the lower brain stem, and provided some additional anatomical substrates for the physiology of the control of the forebrain by the lower brain stem neurons.     

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.     

Organization of projections from the ventromedial nucleus of the hypothalamus: A Phaseolus vulgaris-Leucoagglutinin study in the rat

The organization of projections from the four parts of the ventromedial nucleus (VMH) and a ventrolaterally adjacent region tentatively identified as the tuberal nucleus (TU) have been analyzed with small injections of the anterograde axonal tracer Phaseolus vulgaris-leucoagglutinin (PHA-L). Extrinsic and intranuclear projections of each part of the VMH display clear quantitative differences, whereas the overall patterns of outputs are qualitatively similar. Overall, the VMH establishes massive intrahypothalamic terminal fields in other parts of the medial zone, tending to avoid the periventricular and lateral zones. The ventrolateral VMH is more closely related to other parts of the hypothalamus that also express gonadal steroid hormone receptors, including the medial preoptic, tuberal, and ventral premamillary nuclei, whereas other parts of the VMH are more closely related to the anterior hypothalamic and dorsal premammillary nuclei. All parts of the VMH project to the zona incerta (including the A13 region) and parts of the midline thalamus, including the paraventricular and parataenial nuclei and nucleus reuniens. The densest inputs to the septum are to the bed nuclei of the stria terminalis, where the ventrolateral and central VMH innervate the anteroventral and anterodorsal areas and transverse and interfascicular nuclei, whereas the anterior and dorsomedial VMH innervate the latter two. The central, lateral, and medial amygdalar nuclei receive substantial inputs from various parts of the VMH. Other regions of the telencephalon, including the nucleus accurmbens and the piriform-amygdaloid, infralimbic, prelimbic, anterior cingulate, agranular insular, piriform, perirhinal, entorhinal, and postpiriform transition areas, also receive sparse inputs. All parts of the VMH send a massive, topographically organized projection to the periaqueductal gray. Other brainstem terminal fields include the superior colliculus, peripeduncular area, locus coeruleus, Barrington's nucleus, parabrachial nucleus, nucleus of the solitary tract, and the mesencephalic, pontine, gigantocellular, paragigantocellular, and parvicellular reticular nuclei. The projections of the TU are similar to, and a subset of, those from the VMH and are thus not nearly as widespread as those from adjacent parts of the lateral hypothalamic area. Because of these similarities, the TU may eventually come to be viewed most appropriately as the lateral component of the VMH itself. The functional implications of the present findings are discussed in view of evidence that the VMH plays a role in the expression of ingestive, affective, and copulatory behaviors. © 1994 Wiley-Liss, Inc.     

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.     

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.     

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.     

GABA- and Glutamate-evoked Responses in the Rat Ventral Pallidum are Modulated by Dopamine

Microiontophoresis was used to investigate the influence of dopamine on GABA- and glutamate-induced responses from ventral pallidal neurons recorded extracellularly in chloral hydrate-anaesthetized rats. Modulation was determined by comparing dopamine-induced alterations in amino acid-induced activity ('signal') with dopamine-induced effects on spontaneous firing ('noise'). A dopamine ejection current-response curve was generated to determine the current levels that did not alter spontaneous firing ('subthreshold') and those that produced ∼50% of the maximal dopamine-induced response (ECur₅₀). Co-iontophoresis of dopamine with GABA generally diminished the inhibitory influence of GABA on pallidal neuron firing; 70% of neurons tested with ECur₅₀ dopamine demonstrated a decrease in the signal-to-noise ratio whereas 10% displayed an increase. At subthreshold dopamine ejection currents, 59% of neurons responded with a decrease and 18% responded with an increase in the GABA signal-to-noise ratio. When ECur₅₀ dopamine was co-iontophoresed with glutamate, 84% of the neurons displayed a decrease in the signal-to-noise ratio for glutamate-evoked excitations whereas 11% demonstrated an increase. Subthreshold dopamine ejection currents decreased the signal-to-noise ratio in 62% of the ventral pallidal neurons excited by glutamate and increased the ratio in 23%. These data illustrate that dopamine substantially alters GABA- and glutamate-evoked responses even at ejection currents that are below those necessary to change spontaneous firing. Thus, it appears that neuromodulation is an important means by which dopamine influences ventral pallidal neuronal activity.     

The phylogenetic distribution of electroreception: evidence for convergent evolution of a primitive vertebrate sense modality

Specializations for electroreception in sense organs and brain centers are found in a wide variety of fishes and amphibians, though probably in a small minority of teleost taxa. No other group of vertebrates or invertebrates is presently suspected to have adaptations for electroreception in the definition given here. The distribution among fishes is unlike any other sense modality in that it has apparently been invented, lost completely and reinvented several times independently, using distinct receptors and central nuclei in the medulla. There are so far no clearly borderline or transitional fishes, either physiologically or anatomically. We rather expect a few new electroreceptive taxa to be found. The evoked potential method and the newly validated central anatomical criteria provide two useful tools for searching. Although Myxiniformes probably lack electroreception, it is well developed in Petromyzoniformes and in all other non-teleost fishes except Holostei. Thus Elasmobranchia, Holocephala, Dipneusti, Crossopterygii, Polypteriformes and Chondrostei have the physiological and anatomical specializations in a common form consistent with a single origin in primitive vertebrates. Amphibian ancestors probably inherited the system from a stem similar to one of these and passed it on at least to the ambystomatoid and salamandroid urodeles, apparently after losing the kinocilium of the sense cell. The suggestion of electroreception in ichthyophid apodans from skin histology has not been confirmed physiologically, behaviorally or by brain anatomy. With respect to more advanced fishes the most parsimonious interpretation is that the entire system, peripheral and central was lost in ancestors of holostean and teleostean fishes and new systems reinvented in Siluriformes, in Gymnotiformes, in Xenomystinae and in Mormyriformes. These 4 taxa must represent at least two, and probably 3 or 4 independent inventions, presumably from mechanoreceptive lateral line organs and brain centers.     

Disruption of maternal behaviour in virgin and postparturient rats following sagittal plane knife cuts in the preoptic area-hypothalamus

Parasagittal knife cuts along the medial preoptic area-medial anterior hypothalamus were placed at either the medial (near lateral or NL cuts) or lateral (far lateral or FL cuts) border of the medial forebrain bundle in separate groups of virgin (Experiment 1) and postparturient (Experiment 2) rats. FL cuts were placed so as to spare preoptic-hypothalamic efferent connections with the medial forebrain bundle. NL and FL knife cuts were equally effective in preventing the induction of maternal behaviour produced by repeated exposure of virgin rats to foster pups. Both types of cuts also reduced nest building in virgins. In postparturient rats, NL and FL cuts both abolished pup retrieval and reduced nursing behaviour. However, only NL cuts disrupted lactation and nest building. NL cuts also produced chronic hyperthermia. The deficits in maternal behaviour and nest building may be independent of this hyperthermia, as shaving the fur in animals with NL cuts reduced body temperatures to control levels but did not restore these behaviours. These findings indicate that while preoptic/hypothalamic connections through the medial forebrain bundle are important for nest building and possibly lactation, other lateral connections must also be important for pup retrieval and nursing behaviour. The identity of these connections remains to be determined.     

In vivo voltammetric characterization of low affinity striatal dopamine uptake: Drug inhibition profile and relation to dopaminergic innervation density

Electrical stimulation of the median forebrain bundle evoked dopamine release in the ipsilateral striatum which was monitored with high-speed cyclic voltammetry. After stimulation, the extracellular concentration of dopamine fell due to uptake in a biphasic manner, showing zero-order and first-order components. The zero-order phase corresponded to a Vmax of 42.8 +/- 1.8 nmol/min/g tissue. The uptake system could be blocked by D-amphetamine, methylphenidate and nomifensine, but not by benztropine, amfonelic acid or mazindol. The density of uptake sites showed a correlation with the density of striatal dopamine innervation.     

Inhibitory Effect of MK-801 on Amantadine-Induced Dopamine Release in the Rat Striatum

In the present study, we examined the effect of amantadine on extracellular dopamine levels in the rat striatum using an in vivo microdialysis. Perfusion of amantadine (0.1–1 mM) through the microdialysis probe caused an increase both in extracellular dopamine and glutamate levels in rat striatum. Amantadine was found to increase extracellular dopamine concentration in Ca²⁺-dependent manner, but the effect was not abolished by ω-conotoxin. Although intraperitoneal administration of MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine] alone could not significantly alter the concentration of dopamine, it attenuated amantadine-induced increase in dopamine level. These findings suggest that an interaction between dopaminergic and glutamatergic neurotransmission is an important component in the regulation of striatal dopamine levels. Copyright © 1996 Elsevier Science Inc.     

Lentivector-mediated delivery of GDNF protects complex motor functions relevant to human Parkinsonism in a rat lesion model

Although viral vector-mediated delivery of glial cell-line derived neurotrophic factor (GDNF) to the brain has considerable potential as a neuroprotective strategy in Parkinson's disease (PD), its ability to protect complex motor functions relevant to the human condition has yet to be established. In this study, we used an operant task that assesses the selection, initiation and execution of lateralized nose-pokes in Lister Hooded rats to assess the efficacy with which complex behaviours are protected against neurotoxic lesions by prior injection of a lentiviral vector expressing GDNF. Unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) caused rats to attempt fewer trials and to make more procedural errors. Lesioned rats also developed a pronounced ipsilateral bias, with a corresponding drop in contralateral accuracy. They were also slower to react to contralateral stimuli and to execute movements bilaterally. Rats that were pre-treated 4 weeks prior to lesion surgery with an equine infectious anaemia virus (EIAV) vector carrying GDNF [EIAV-GDNF, injected into the striatum and above the substantia nigra (SN)] performed significantly better on all of these parameters than control rats. In addition to the operant task, EIAV-GDNF successfully rescued contralateral impairments in the corridor, staircase, stepping and cylinder tasks, and prevented drug-induced rotational asymmetry. This study confirms that GDNF can protect against 6-OHDA-induced impairments in complex as well as simple behaviours, and reinforces the use of EIAV-based vectors for the treatment of PD.