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PubMed1976

Activation and inhibition of the lateral hypothalamic neurones elicited by medial forebrain bundle stimulation.

1. Single neurone discharges were recorded from the lateral hypothalamus (LH) at the level of the ventromedial nucleus. Single stimulation of the medial forebrain bundle (MFB) at the level of the mesodiencephalic junction elicited a strong inhibition lasting for 100-300 msec in these neurones. 2. However, by the use of multiple stimulating electrodes, it was possible to find a circumscribed locus in the MFB which gave rise to an initial activation of firing discharges with a latency of 1-15 msec (in different neurones) preceding the period of inhibition. 3. One class of the LH neurones was antidromically activated, and was thought to give off axons into the descending MFB. The other was activated orthodromically through a highly efficient synaptic connexion, and was viewed as 'relay' neurones of the ascending MFB. 4. Although the former could also be activated orthodromically, the efficacy of driving was distinctly lower than that observed in the latter. Presumably they integrate the messages from the visceral centres of the medulla and pons, thus participating in the viscero-motor outflow from the hypothalamus. 5. Intracellularly recorded spike potentials of these neurones deteriorated rapidly leaving only hyperpolarization which corresponded in its time course to the suppression of extracellular spike discharges following MFB stimulation. It was suggested that the inhibition was elicited via recurrent routes localized within the hypothalamus.

Action Potentials↗
PubMed1993

Differential spatial and temporal gene expression in response to axotomy and deafferentation following transection of the medial forebrain bundle.

Alterations in the levels of neurotransmitter biosynthetic enzymes are a concomitant of many neurodegenerative disorders. In order to elucidate potential mechanisms for longterm alterations in biosynthetic enzyme gene products in response to neuronal injury, an acute axotomy/deafferentation model was employed. A unilateral microknife transection of the medial forebrain bundle (MFB) axotomizes and/or deafferents phenotypically identified neuronal populations important in the function of the basal ganglia. Semi-quantitative in situ hybridization and immunohistochemical analysis demonstrated that the products of the immediate-early gene c-fos were induced postaxotomy in the noradrenergic neurons of the locus ceruleus (LC), but not in the dopaminergic neurons of the substantia nigra pars compacta (SNc). Analysis of the levels of mRNA, protein, and activity for tyrosine hydroxylase demonstrated that the LC neurons survive the injury while the SNc neurons degenerate. After MFB transection, Fos protein also was induced in the corpus striatum within 1 hr, first in large, putatively cholinergic neuronal populations followed at 3 hr by the small, putatively GABAergic neurons. The substantia nigra pars reticulata and the subthalamic nucleus neuronal populations, deafferented by the MFB transection, also exhibited Fos induction beginning at 3 hr. The data suggest that expression of Fos in a neuronal population is correlative with respect to cell survival following either axotomy or deafferentation. Whether Fos induction following injury is either a necessary mechanism of cell survival or merely a marker of increased neuronal activity requires further investigation.

Animals↗
PubMed2003

Effects of sex and hormonal status on astrocytic basic fibroblast growth factor-2 and tyrosine hydroxylase immunoreactivity after medial forebrain bundle 6-hydroxydopamine lesions of the midbrain dopamine neurons.

We examined astrocytic basic fibroblast growth factor immunoreactivity (FGF-2-IR) and tyrosine hydroxylase immunoreactivity (TH-IR) in the cell-body region of midbrain dopaminergic neurons after unilateral infusions of the neurotoxin 6-hydroxydopamine into the medial forebrain bundle in male and female rats. In addition, to determine whether neonatal exposure to gonadal hormones has consequences on the expression of astrocytic FGF-2 and cell loss in response to injury in adulthood, we studied the effects of these lesions in adult male and female rats that had been exposed or not to testosterone in the neonatal period. In both males and females there was a progressive loss of TH-expressing cells that peaked 5 weeks after the lesions. Females showed less loss of TH-expressing cells than males, but this effect was not estrogen dependent. Lesions led to an increase in expression of astrocytic FGF-2 that was greater in males than in females. Finally, it was found that, regardless of genetic sex, rats exposed to testosterone neonatally showed greater astrocytic FGF-2 expression after lesions than those not exposed, and that among those not exposed to testosterone, estrogen treatment had a modest protective effect. Analysis of behavior and striatal dopamine content showed that the percent of striatal dopamine depletion 14 days after the lesion correlated with the amount of behavioral asymmetry displayed by animals on all tests conducted after lesioning. In groups killed 2 and 5 weeks after the lesion, the amount of behavioral asymmetry correlated with the percent loss of TH-IR cells and with the percent increase in FGF-2-IR cells in the midbrain. These relationships were not evident in groups killed 3 and 7 days after the lesion, possibly because the changes in the number of FGF-2- and TH-IR cells were not fully manifested. The present findings show that hormonal events early in life can alter the response of midbrain dopamine neurons to insult and injury in adult life and suggest that the slow degeneration of these neurons may release signals triggering a sustained activation of adjacent astrocytes which, in turn, may lead to induction of astrocytic FGF-2.

Animals↗
PubMed1995

Time dependent changes in DA uptake sites, D1 and D2 receptor binding and mRNA after 6-OHDA lesions of the medial forebrain bundle in the rat brain.

Quantitative receptor autoradiography and in situ hybridization techniques were used to examine the temporal pattern of changes in dopamine uptake sites, D1 and D2 receptors and their transcripts in the striata of animals lesioned with 6-hydroxydopamine. Animals were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4, 6, 8, and 16 weeks postlesion. Degeneration of the nigrostriatal pathway induced a significant loss of dopamine uptake sites in the ipsilateral caudate putamen of all lesioned animals. D1 receptor binding was significantly increased in the caudate putamen on the lesioned side from 1 week to 16 weeks postlesion, whereas the expression of D1 receptor mRNA did not show any change during this period. There was a significant upregulation of D2 receptor binding as well as D2 mRNA from 2 weeks to 8 weeks postlesion. However, at 16 weeks postlesion, D2 receptor binding continued to increase, whereas the mRNA appeared to compensate. These studies show that a different regulatory mechanism may exist between these two DA receptor subtypes. D1 receptor changes occur at the post-transcriptional or translational level, whereas D2 alterations occur by both transcriptional and translational processes. These studies also indicate that the postsynaptic supersensitivity observed in D1 receptors may not be accompanied by a corresponding increase in D1 receptor mRNA.

Animals↗
PubMed1978

Failure of medial forebrain bundle or raphe ablation to alter the daily temperature rhythm of the rat.

The data presented in the present study suggest that neither the ascending noradrenergic fibres confined to the MFB nor the serotonergic fibres originating in or passing through the mesencephalic raphe are essential for periodicity in body temperature. Both control and experimental groups, i.e., rats subjected to medial forebrain bundle or raphe ablation presented circadian periodicity in body temperature and neither the phase, amplitude or overall mean of experimentals differed significantly from controls.

Animals↗
PubMed1997

Time course changes in the dopaminergic nigrostriatal system following transection of the medial forebrain bundle: detection of oxidatively modified proteins in substantia nigra.

We studied the time course of oxidatively modified proteins in the nigrostriatal dopaminergic system following transection of the medial forebrain bundle by quantifying the number of carbonyl groups coupled to striatal and nigral protein homogenates, an index of metal-catalyzed oxidations. We found a striking effect of axotomy on the number of oxidatively modified proteins in the substantia nigra but not in the striatum within the first 5 days postlesion. This effect was correlated with the neurochemical activity of the dopaminergic and serotoninergic systems in the substantia nigra, which suggests a role of dopamine- and serotonin-derived radical oxygen species in the oxidative stress detected in this brain area. We then searched for the type of cell death in the substantia nigra following axotomy. The fragmentation pattern obtained by agarose gel electrophoresis of DNA isolated from nigral tissue was indicative of cell death being entirely necrotic. In fact, no evidence of apoptosis was detected at any postlesion time as revealed by TdT-mediated dUTP-biotin nick end-labeling (TUNEL) staining. The course of necrotic cell death in the substantia nigra coincided with the maximal levels of oxidatively modified proteins in the substantia nigra, suggesting a link between oxidative stress and nerve cell death and also coinciding with the neurochemical activity of both dopaminergic and serotoninergic systems.

Animals↗
PubMed1975

A comparison of drug-induced rotation in rats lesioned in the medial forebrain bundle with 5,6-dihydroxytryptamine or 6-hydroxydopamine.

Drug-induced rotational behaviour was studied in two groups of rats with differing chemical lesion of the right medial forebrain bundle (MFB). 6-hydroxydopamine (6-OH-DA), 3.5 mug, injected in one group, induced a marked lowering of dopamine (DA) and noradrenaline (NA) in the right hemiforebrain. 5,6-Dihydroxytryptamine (5,6-HT), 10 mug, injected in a second group, produced a profound and long-lasting depletion of 5-hydroxytryptamine (5-HT) and DA, but not of NA. Rotational behaviour induced in both groups by DA receptor agonists (apomorphine, piribedil, L-DOPA, ergometrine, ergocornine, 2-bromo-alpha-ergocryptine, ergocristine, methylergometrine) and agents releasing DA (d-methamphetamine, methylphenidate) were qualitatively identical and quantitatively very similar, suggesting a minor role of 5-HT striatal terminals in these experimental conditions. LSD induced contralateral rotation by direct stimulation of the DA receptor, while L-5-hydroxy-tryptophan (L-5HTP) was inactive.

5,6-Dihydroxytryptamine↗
PubMed1991

Fetal neocortical transplants into the medial forebrain bundle attract ingrowth of catecholaminergic fibers in adult rat brain.

The hypothesis that fetal tissue grafts may exert a trophic influence on damaged catecholaminergic fibers was examined. Ascending dopamine and norepinephrine axons normally innervate frontal cortex targets in the intact rat brain. These and other ascending catecholaminergic fibers were disrupted with stereotaxic injections of 6-hydroxydopamine into the medial forebrain bundle (mfb), followed after 1 or 14 days by grafts of fetal neocortical tissue placed into the injection site, or by sham grafts. Glyoxylic acid histofluorescence techniques were then used to examine catecholaminergic fiber distribution. When such lesions were made without subsequent grafting, virtually no growth of catecholaminergic fibers occurred beyond the injection site and frontal cortex norepinephrine levels were depleted to 15% of control levels. However, when grafts of fetal neocortical tissue were made into the lesion site and animals examined 3 months later, catecholaminergic fibers grew through the lesion site to ramify within the graft tissue. Catecholaminergic fibers were seen in all portions of most grafts, though they were most dense on the caudal and ventral edges of the graft, close to the path of the mfb. Similar densities of graft innervation were seen 3 months after animals received grafts placed into the same site without prior lesioning of catecholaminergic fibers. Fetal neocortical grafts thus induce collateral sprouting from intact host catecholaminergic axons and may also promote regenerative sprouting when such fibers are otherwise irreparably damaged.

Animals↗
PubMed1993

Reduction in cortical 5-HT3 binding sites following a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle in rats.

Serotonergic mechanisms have been implicated in pathophysiology of Parkinson's disease, an illness where the dopamine deficiency represents the prime biochemical deficit. Present interest centres on the possible involvement of serotonergic receptors in modulating dopamine transmission. In this paper the binding of the selective 5-HT3 antagonist [3H]GR 65630 was studied in rats with a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. The maximal density of specific [3H]GR 65630 binding was reduced in homogenates of entorhinal (17.1%, P < 0.05) and prefrontal cortex (27.5%, P < 0.05) on the lesioned side of the rat brain compared to the control tissues. An increase in affinity for [3H]GR 65630 binding was also found in homogenates of prefrontal cortex (33.8%, P < 0.05). No changes in the characteristics of [3H]GR 65630 binding to homogenates from the amygdala and hippocampus were observed. These data suggest that altered dopamine function may affect serotonergic mechanisms in the cortex in Parkinson's disease.

Animals↗
PubMed1987

Self-training for brain stimulation in the medial forebrain bundle of rats: a comparison of saline with amphetamine.

Rats were implanted with stimulating electrodes in the medial forebrain bundle-lateral hypothalamus (MFB-LH). Following recovery from surgery, they were placed in 3 groups prior to brain self-stimulation training. This consisted of one 15-min session on each of 5 consecutive days. Animals in the first group (controls) were placed in a conventional, single lever operant chamber without any additional manipulation. There were no priming stimuli, there was no experimenter intervention of any kind, and no exteroceptive cues in the chamber to indicate the availability or otherwise of the reinforcement. Animals in the second group (saline-injected) were treated similarly to the first group except that they were weighed and injected subcutaneously with saline (1 ml/kg) immediately before being placed in the chamber. Animals in a third group (D-amphetamine-injected) were weighed and administered D-amphetamine (0.5 mg/kg in saline) immediately before being placed in the chamber. The number of lever-presses made per 15-min session was recorded. In addition, the time taken to achieve a lever-pressing rate of 10 presses per min was recorded. There were no significant differences between groups in the number of presses per 15-min session. Animals administered D-amphetamine reached the rate of 10 presses per min significantly more rapidly than animals administered saline, but the latter did so significantly more rapidly than controls. These results demonstrated that the simple manipulation, and perhaps the mild stress, associated with a saline injection strongly affected the acquisition of a brain self-stimulation task.

Animals↗
PubMed1997

The effect of unilateral neurotoxic lesions to serotonin fibres in the medial forebrain bundle on the metabolism of [3H]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-dihydroxy-tryptamine (5,7-DHT, 1.6 micrograms) into the right medial forebrain bundle (MFB), rats received [3H]DOPA (200 microCi,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.

5,7-Dihydroxytryptamine↗
PubMed2003

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.

Amygdala↗
PubMed2002

Long-term high-frequency electro-acupuncture stimulation prevents neuronal degeneration and up-regulates BDNF mRNA in the substantia nigra and ventral tegmental area following medial forebrain bundle axotomy.

Electroacupuncture (EA) has been used in China for many years to treat Parkinson's disease (PD) with reportedly effective results. However, the physiological and biological mechanism behind its effectiveness is still unknown. In the present study, different frequencies of chronic EA stimulation (0, 2, 100 Hz) were tested in a partially lesioned rat model of PD which was induced by transection of the medial forebrain bundle (MFB). After 24 sessions of EA stimulation (28 days after MFB transection), dopaminergic neurons in the ventral midbrain were examined by immunohistochemical staining, and brain-derived neurotrophic factor (BDNF) mRNA levels in ventral midbrain were measured by in situ hybridization. The results show a marked decrease of dopaminergic neurons on the lesioned side of the substantia nigra (SN) comparing with the unlesioned side. Zero Hz and 2 Hz EA stimulation had no effect on the disappearance of dopaminergic neurons. However, after 100 Hz EA, about 60% of the tyrosine hydroxylase (TH)-positive neurons remained on the lesioned side of the SN. In addition, levels of BDNF mRNA in the SN and ventral tegmental area (VTA) of the lesioned side were significantly increased in the 100 Hz EA group, but unchanged in the 0 and 2 Hz groups. Our results suggest that long-term high-frequency EA is effective in halting the degeneration of dopaminergic neurons in the SN and up-regulating the levels of BDNF mRNA in the subfields of the ventral midbrain. Activation of endogenous neurotrophins by EA may be involved in the regeneration of the injured dopaminergic neurons, which may underlie the effectiveness of EA in the treatment of PD.

Animals↗
PubMed2005

Theory for the impact of basal turnover on dopamine clearance kinetics in the rat striatum after medial forebrain bundle stimulation and pressure ejection.

Although microdialysis measurements suggest that extracellular dopamine concentrations in the rat striatum are in the low nanomolar range, some recent voltammetry studies suggest that the concentration may be considerably higher, perhaps in the micromolar range. The presence of such high dopamine levels in the extracellular space has to be rationalized with the rapid, linear clearance of extracellular dopamine observed after electrical stimulation of the medial forebrain bundle. Kinetic analysis of dopamine clearance after evoked release suggests that the basal extracellular dopamine concentration is below the K(M) of dopamine uptake, which is near 0.2 microm. However, dopamine clearance after pressure ejection of dopamine into the rat striatum is slow and non-linear, which may alternatively be a sign that basal dopamine release is only slightly slower than the maximal velocity of dopamine uptake, Vmax. A high basal extracellular dopamine concentration would exist if basal dopamine release were only slightly slower than the Vmax of uptake. This report introduces a new kinetic analysis of dopamine uptake that sheds light on the possible source of the different clearance rates observed following evoked dopamine release and dopamine pressure ejection. Furthermore, the analysis rationalizes the rapid dopamine clearance after evoked release with the possibility that basal extracellular dopamine levels are above the K(M) of the transporter.

Animals↗
PubMed1982

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.

Animals↗
PubMed1981

Anatomical demonstration of the involvement of the substantia nigra in contraversive circling elicited by electrical stimulation of the medial forebrain bundle in the cat: a retrograde transport study using horseradish peroxidase subsequent to an electrolytic lesion.

A method is described for the anatomical identification of groups of neurones likely involved in the elaboration of component acts of a centrally elicited behaviour, when involvement of fibres of passage is suspected. The contraversive circling which accompanied the predatory attack of a cat upon a rat elicited electrical stimulation within the hypothalamic and ventral midbrain trajectory of the medial forebrain bundle (MFB) was used as a model because of the established role played by the nigrostriatal dopamine system in the production of the circling. Following horseradish peroxidase (HRP) injections, made after electrolytic lesion at such MFB sites, substantial numbers of labelled cells were found in the substantia nigra, pars compacta (SNC). In contrast, many fewer SNC neurones were labelled following:(1) HRP injections made after electrolytic lesion at MFB sites at which the elicited predatory behaviour was not accompanied by contraversive circling; and (2) HRP injections made without a prior lesion at MFB sites at which the elicited predatory behaviour was accompanied by contraversive circling.

Animals↗
PubMed1981

The behavioral effects of hallucinogens in rats following 5,7-dihydroxytryptamine administration into the medial forebrain bundle.

The hypothesis that 5-hydroxytryptamine (5-HT) neurons and/or receptors are involved in the mechanism of action of hallucinogens is supported by the fact that intraventricular administration of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) selectively destroys central 5-HT neurons in the brain and potentiates the behavioral effects of lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM) and mescaline. The locus in the brain where this potentiation might occur is not known. In the present experiment, the medial forebrain bundle (MFB) was studied because it is the primary tract containing fibers from the cell bodies in the raphe nuclei to forebrain structures receiving 5-HT input. Male rats received 5,7-DHT (6 micrograms/2 microliter) or vehicle injections bilaterally into the MFB; this procedure caused a significant reduction of 5-HT in the cortex, hippocampus and hypothalamus of lesioned rats, but not in the striatum. Regional dopamine and norepinephrine concentrations were not affected by this treatment. The behavioral effects of the hallucinogens were tested in a situation in which the animals pressed a bar under a fixed ratio-40 (FR-40) schedule of food reinforcement. The disruptive effects of LSD on responding were enhanced in the 5,7-DHT-treated animals, while the effects of DOM were diminished; there was no change in the response to mescaline. These data suggest that, while 5-HT neurons are involved in the behavioral effects of hallucinogens, the precise sites and/or mechanisms of action of LSD, DOM and mescaline may differ.

5,7-Dihydroxytryptamine↗
PubMed1982

Blood supply of the rat hypothalamus. VII. The lateral hypothalamus (medial forebrain bundle).

Using the double ink-filling technique the arteries and veins of the lateral hypothalamus are described in detail. This region occupied mainly by the fibres and interposed cells of the medial forebrain bundle is supplied by some own arteries and branches of the large basal vessels. Most of the arteries running to the rostral part of the lateral hypothalamus originate from the internal carotid, others belong to the anterior and middle cerebral arteries. Blood supply of the middle part comes from the middle hypothalamic and three tuberal arteries. All arteries of the caudal part originate from the posterior communicans. The abundant drainage of the lateral hypothalamus is collected by the basal and anterior interpeduncular veins from the rostral two-thirds and the caudal one-third, respectively.

Animals↗