Unit responses in the medial forebrain bundle to rewarding stimulation in the hypothalamus

The effects of different intensities of stimulation were studied on self-stimulation behavior and on the neural responses in the medial forebrain bundle correlated with it. Of the two neural responses observed, an excitatory type was more diffusely distributed throughout this pathway than an inhibitory type, and its properties varied more as a function of the rate of self-stimulation at the various intensities tested than the properties of the inhibitory responses did. The latter were more localized to the caudal portion of the medial forebrain bundle studied, and their threshold was generally lower than the threshold of self-stimulation behavior. Also, the inhibitory responses appeared to be more sensitive indicators of stimulation applied to the medial forebrain bundle, whereas the excitatory responses were more sensitive indicators of variations in the rate of responding for brain reward. The neural responses in the MFB to rewarding stimulation are evaluated in terms of the possibility that they are specific to the positive reinforcement mechanism in the diencephalon.     

Forebrain neurons driven by rewarding stimulation of the medial forebrain bundle in the rat: comparison of psychophysical and electrophysiological estimates of refractory periods

Psychophysically derived estimates of recovery from refractoriness were obtained at self-stimulation sites in the lateral hypothalamus and ventral tegmental area. The refractory periods of single units driven by the same stimulation electrodes and stimulation fields were then measured electrophysiologically. Antidromically driven units with refractory periods longer than those of the neurons responsible for the rewarding effect were concentrated in the septal complex. Units with refractory periods that overlapped the estimates for the reward-related neurons were found in this region as well but were also encountered in neighboring structures lateral, ventral, and/or caudal to the septal nuclei. It is argued that this latter class of units should be considered as possible constituents of the directly stimulated substrate for the rewarding effect because they are driven by rewarding stimulation, have refractory periods similar to those of the reward-related neurons and arise in or near regions in which lesions have been effective in decreasing the rewarding effect of stimulating the medial forebrain bundle.     

Temporary inactivation of the retrorubral fields decreases the rewarding effect of medial forebrain bundle stimulation

Prior studies indicate that lesioning the retrorubral fields (RRF) decreases the rewarding effect of medial forebrain bundle (MFB) stimulation, although these studies did not make the RRF their primary target. This study directly investigates the role of the RRF in MFB self-stimulation using transient lidocaine-induced inactivation of target tissue rather than permanent lesioning. In 18 rats with MFB stimulation electrodes, inactivation of the RRF via 0. 5 and 1.0 microl of 4% lidocaine produced immediate, substantial upward shifts in the frequency required to maintain half-maximal self-stimulation response rates whereas injecting comparable volumes of saline did not. Bilateral inactivation was particularly effective, especially at medium and high stimulation currents, although unilateral inactivation ipsilateral to the stimulation site was also effective. Contralateral inactivation alone did not substantially change the stimulation's reward value, although contralateral inactivation appeared to contribute to the effectiveness of bilateral inactivation. The frequency required to maintain half-maximal responding returned to baseline levels by 15-20 min after lidocaine infusion. In seven rats whose infusion sites were not in the RRF, lidocaine inactivation did not consistently degrade the stimulation's reward value. These results indicate that some neural elements located in the RRF contribute to the rewarding effect of MFB stimulation. Possible roles for these elements in the anatomical substrate for MFB self-stimulation are discussed.     

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

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

Prolonged 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.     

Pathological dynamics of activated microglia following medial forebrain bundle transection

To elucidate the role and pathological dynamics of activated microglia, this study assessed the phagocytic, immunophenotypic, morphological, and migratory properties of activated microglia in the medial forebrain bundle (MFB) axotomized rat brain. Activated microglia were identified using two different monoclonal antibodies: ED1 for phagocytic activity and OX6 for major histocompatibility complex (MHC) class II. Phagocytic microglia, characterized by ED1-immunoreactivity or ED1- and OX6-immunoreactivity, appeared in the MFB and substantia nigra (SN) as early as 1-3 days post-lesion (dpl), when there was no apparent loss of SN dopamine (DA) neurons. Thereafter, a great number of activated microglia selectively adhered to degenerating axons, dendrites and DA neuronal somas of the SN. This was followed by significant loss of these fibers and nigral DA neurons. Activation of microglia into phagocytic stage was most pronounced between 14 approximately 28 dpl and gradually subsided, but phagocytic microglia persisted until 70 dpl, the last time point examined. ED1 expression preceded MHC II expression in phagocytic microglia. All phagocytic microglia sticking to DA neurons showed activated but ramified form with enlarged somas and thickened processes. They were recruited to the SNc from cranial, dorsal and ventral aspects along various structures and finally stuck to DA neurons of the SNc. Characteristic rod-shaped microglia in the white matter were thought to migrate a long distance. The present study strongly suggests that neurons undergoing delayed neurodegeneration may be phagocytosed by numerous phagocytic, ramified microglia at various sites where specific surface signals are exposed or diffusible molecules are released.     

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.     

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.     

Unilaterally activated systems in rats self-stimulating at sites in the medial forebrain bundle, medial prefrontal cortex, or locus coeruleus

Rats with electrodes in either the posterior medial forebrain bundle (MFB), the anterior MFB, the medial prefrontal cortex, or the locus coeruleus self-stimulated during a 45 min period following the injection of [14C]2-deoxyglucose. They were then sacrificed and their brains prepared for autoradiography. The autoradiographs were analyzed for unilaterally activated neural systems, using a computerized image analyzing system to compare the darkness of neural structures on the stimulated side with the darkness of the same structures on the unstimulated side. There was extensive overlap in the neural structures unilaterally activated by stimulation in the anterior and posterior MFB; but there was no overlap between the structures activated by MFB stimulation and the structures activated by stimulation at either of the extradiencephalic sites; nor did the forebrain, diencephalic, and midbrain sites have any readily apparent bilateral effects in common. If there is a substrate common to MFB self-stimulation and extradiencephalic self-stimulation, its activation is not revealed by 2-deoxyglucose autoradiography.     

Interactions of septal evoked responses to stimulation of the fornix and medial forebrain bundle

Gross and single unit septal evoked response to stimulation of the fornix and medial forebrain bundle (MFB) were studied in anesthetized, acutely prepared rats. Stimulation of the fornix and MFB produced short-latency antidromic and synaptic activation of localized groups of septal target cells. In addition, stimulation of either pathway produced inhibition of spontaneous single cell activity. The interactions of these responses were studied by delivering paired stimuli to the fornix and/or MFB. A prior stimulus to the fornix potentiated the responses of cell groups synaptically activated by subsequent fornical stimulation, but briefly depressed the sunaptic activation of septal cells by subsequent MFB stimulation. A prior stimulus to the MFB slightly potentiated the synaptic activation of septal cells by a subsequent MFB stimulus, but depressed the responses of cell groups synaptically activated by a subsequent stimulus to the fornix. These results were discussed in terms of their implications for septal organization and function.     

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.     

Voltammetry of extracellular dopamine in rat striatum during ICSS-like electrical stimulation of the medial forebrain bundle

Fast-scan voltammetry cyclic in the striatum of anesthetized rats has been used to monitor extracellular dopamine during forced electrical stimulation of the media forebrain bundle using parameters that mimic intracranial self-stimulation. The temporal resolution provided by microelectrodes positioned very near sites of dopamine release allows resolution of the response to individual 500-ms stimulation trains separated by 500-ms intervals. Uptake inhibition by Nomifensine alters the resolution obtained at short times after initiation of stimulation.     

Brain stem self-stimulation attenuated by lesions of medial forebrain bundle but not by lesions of locus coeruleus or the caudal ventral norepinephrine bundle.

Midbrain tegmental intracranial self-stimulation (ICSS) was not attenuated by ipsilateral or bilateral locus coeruleus lesions. Certain of these lesions were followed by histochemical confirmation that the majority of locus coeruleus neurons was destroyed, and biochemical evidence that over 80% of the cortical norepinephrine was depleted. To test the possibility that the surviving ICSS was due to stimulation of another norepinephrine system, histochemically verified ipsilateral or bilateral lesions of the ventral norepinephrine bundle were administered to a second group of midbrain tegmental ICSS animals. These lesions resulted in marked loss of body weight, but had no effect on ICSS. In a third experiment, lesions were made in the medial forebrain bundle (MFB) ipsilateral to midbrain tegmental ICSS electrodes. These lesions resulted in attenuation of ICSS which was directly proportional to the extent of MFB damage. On the basis of these data alone, however, it was not possible to identify the ciritical fibers supporting ICSS. It was oncluded that the locus coeruleus does not play a necessary role in midbrain tegmental ICSS.     

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.     

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.