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

doi:10.1016/S0149-7634(89)80016-8

Neuroscience & Biobehavioral Reviews

Volume 13, Issues 2–3, Summer–Autumn 1989, Pages 91-98

https://doi.org/10.1016/S0149-7634(89)80016-8 Get rights and content

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 μA/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 (37). The excitability properties of this second population are almost identical with those of dopamine (DA) axons (36). Furthermore, the long-refractory period effects of MFB self-stimulation are reduced, but not completely blocked, by peripheral injections of alpha-flupenthixol (14), 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 (34), may help determine where synapses are located in circuits mediating electrically evoked behaviors. A neural model of symmetric, asymmetric and mixed collision is proposed.

References (40)

BielajewC. et al.
The effect of pulse duration on refractory periods of neurons mediating brain-stimulation reward
Behav. Brain Res.
(1987)
BielajewC. et al.
Behaviorally derived measures of conduction velocity in the substrate for rewarding medial forebrain bundle stimulation
Brain Res.
(1982)
FouriezosG. et al.
Refractoriness of neurons mediating intracranial self-stimulation in the anterior basal forebrain
Behav. Brain Res.
(1987)
FouriezosG. et al.
Current-distance relation for rewarding brain stimulation
Behav. Brain Res.
(1984)
GermanD.C. et al.
Electrophysiological examination of the ventral tegmental (A10) area in the rat
Brain Res.
(1980)
GraceA.A. et al.
Intracellular and extracellular electrophysiology of nigral dopaminergic neurons—1. Identification and characterization
Neuroscience
(1983)
MacmillanC. et al.
Self-stimulation of the lateral hypothalamus and ventrolateral tegmentum: Excitability characteristics of the directly stimulated substrates
Physiol. Behav.
(1985)
MilnerP.M. et al.
Behavioural measurement of axonal thresholds
Behav. Brain Res.
(1986)
MilnerP.M. et al.
Strength-duration characteristics of lateral hypothalamic and periaqueductal gray reward-path neurons
Physiol. Behav.
(1982)
SwansonL.W.
The projections of the ventral tegmental area and adjacent regions: A combined fluorescent retrograde tracer and immunofluorescence study in the rat
Brain Res. Bull.
(1982)

SzaboI. et al.

Drive decay theory of self-stimulation: Refractory periods and axon diameters in hypothalamic reward loci

Physiol. Behav.

(1974)

TehovnikE.J. et al.

Contraversive circling elicited from the internal capsule and substantia nigra: Evidence for continuous axons mediating circling

Brain Res.

(1988)

WangR.Y.

Dopaminergic neurons in the rat ventral tegmental area. I. Identification and characterization

Brain Res. Rev.

(1981)

YeomansJ.S.

Absolute refractory periods of self-stimulation neurons

Physiol. Behav.

(1979)

YeomansJ.S. et al.

Excitability properties of medial forebrain bundle axons of A9 and A10 dopamine cells

Brain Res.

(1988)

YeomansJ.S. et al.

Behavioral estimation of current-distance relationships of neurons mediating circling elicited by midbrain stimulation

Brain Res.

(1986)

YeomansJ.S. et al.

Turning responses evoked by stimulation of visuomotor pathways

Brain Res. Rev.

(1988)

BielajewC. et al.

Evidence implicating descending fibers in self-stimulation of the medial forebrain bundle

J. Neurosci.

(1986)

BielajewC. et al.

Self-stimulation sites in the lateral hypothalamic and lateral preoptic areas are functionally connected

Can. Psychol.

(1987)

BoyeS. et al.

Evidence for a direct link between reward-relevant neurons in the ventral tegmental area-posterior hypothalamus and the medial mesencephalon

Soc. Neurosci. Abstr.

(1987)

Cited by (57)

Brain stimulation rewarding experience attenuates neonatal clomipramine-induced adulthood anxiety by reversal of pathological changes in the amygdala
2020, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
Moreover, informational lesion and jamming theory are derived from acute DBS data from a subset of movement disorder patients, which does not explain the adaptive changes occurring in depression and other psychiatric diseases (Ashkan et al., 2017; Lozano et al., 2019). Interestingly, earlier experiments on ICSS of MFB have consistently demonstrated the activation of dopaminergic axons with HFS stimulation at a pulse duration of 0.1 ms (Gallistel et al., 1981; Wise, 1996; Yeomans, 1989). Consistent with earlier views of ICSS experiments (Wise, 1996; Yeomans, 1989), we speculate that HFS self-stimulation might drive the activity of MFB.
Major depressive disorder (MDD) is associated with enhanced anxiety and reduced reward processing leading to impaired cognitive flexibility. These pathological changes during depression are accompanied by dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its impaired regulation by the amygdala. Notably, the electrical stimulation of brain reward areas produces an antidepressant effect in both MDD patients and animal models of depression. However, the effects of chronic electrical self-stimulation of lateral hypothalamus - medial forebrain bundle (LH-MFB) on depression-associated anxiety and accompanying changes in plasma corticosterone levels, structural, and neurochemical alterations in the amygdala are unknown. Here, we used the neonatal clomipramine (CLI) model of depression. During adulthood, neonatal CLI and vehicle administered rats were subjected to bilateral electrode implantation at LH-MFB and trained to receive intracranial self-stimulation (ICSS) for 14 days. Rats were then tested for anhedonic and anxiety-like behaviors, followed by estimation of plasma corticosterone levels, assessment of amygdalar volumes and neuronal/glial numbers, levels of monoamines and their metabolites in the amygdala. We found that chronic ICSS of LH-MFB reverses CLI-induced anhedonia and anxiety. Interestingly, amelioration of CLI-induced enhanced anhedonia and anxiety in ICSS rats was associated with partial reversal of enhanced plasma corticosterone levels, hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. We suggest that beneficial effects of ICSS on CLI-induced anxiety at least in part mediated by the restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that brain stimulation rewarding experience might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.
Medial forebrain bundle DBS differentially modulates dopamine release in the nucleus accumbens in a rodent model of depression
2020, Experimental Neurology
Citation Excerpt :
The dopaminergic projection neurons originating in the VTA are themselves diverse, not only in their projection areas, but also whether they are fast-firing (medial VTA) or slow-firing (lateral VTA) (Roeper, 2013). Conforming with indirect mechanism, the correlation between the pulse duration and the evoked response implies that the variations in pulse width facilitate spanning different excitation thresholds in compliance with the anatomical structure of MFB, e.g. fiber type and fiber diameter (Bielajew et al., 1987; Shizgal et al., 1991; Yeomans, 1989) in the volume of activated tissue (Fig. 6d). In addition to the anatomical parameters, the stimulation efficacy is also impacted by implantation precision (Supplementary-Figure1), and the distance of the target fiber from the electrode (Grill and Mortimer, 1995; Min et al., 2016) has a quadratic relationship with the excitation threshold (denoted as L in Fig. 6f).
Medial forebrain bundle (MFB) deep brain stimulation (DBS) has anti-depressant effects clinically and in depression models. Currently, therapeutic mechanisms of MFB DBS or how stimulation parameters acutely impact neurotransmitter release, particularly dopamine, are unknown. Experimentally, MFB DBS has been shown to evoke dopamine response in healthy controls, but not yet in a rodent model of depression.
The study investigated the impact of clinically used stimulation parameters on the dopamine induced response in a validated rodent depression model and in healthy controls.
The stimulation-induced dopamine response in Flinders Sensitive Line (FSL, n = 6) rat model of depression was compared with Sprague Dawley (SD, n = 6) rats following MFB DSB, using Fast Scan Cyclic Voltammetry to assess the induced response in the nucleus accumbens. Stimulation parameters were 130 Hz (“clinically” relevant) with pulse widths between 100 and 350 μs.
Linear mixed model analysis showed significant impact in both models following MFB DBS both at 130 and 60 Hz with 100 μs pulse width in inducing dopamine response. Furthermore, at 130 Hz the evoked dopamine responses were different across the groups at the different pulse widths.
The differential impact of MFB DBS on the induced dopamine response, including different response patterns at given pulse widths, is suggestive of physiological and anatomical divergence in the MFB in the pathological and healthy state. Studying how varying stimulation parameters affect the physiological outcome will promote a better understanding of the biological substrate of the disease and the possible anti-depressant mechanisms at play in clinical MFB DBS.
Catecholaminergic axons in the neocortex of adult mice regrow following brain injury
2020, Experimental Neurology
Citation Excerpt :
If so, the axons of the other monamine neuromodulators such as the catecholamines, norepinephrine and dopamine, are good candidates. They also originate within nuclei of the midbrain/brainstem region, are unmyelinated (Beaudet and Descarries, 1978; Yeomans, 1989) and run in a roughly similar course to innervate the forebrain: through the medial forebrain bundle prior to ascending and then passing through the neocortex in the anterior-to-posterior direction (Fig. 1A; Papadopoulos and Parnavelas, 1991; Nakamura et al., 2000; Berridge and Waterhouse, 2003; Shnitko and Robinson, 2014; Sara, 2009; Juarez and Han, 2016). Immunohistochemical experiments with antibodies directed against the catecholamine marker tyrosine hydroxylase (TH) show that catecholaminergic axons in the adult mammalian brain can regrow following a chemical lesion.
Serotonin axons in the adult rodent brain can regrow and recover their function following several forms of injury including controlled cortical impact (CCI), a neocortical stab wound, or systemic amphetamine toxicity. To assess whether this capacity for regrowth is unique to serotonergic fibers, we used CCI and stab injury models to assess whether fibers from other neuromodulatory systems can also regrow following injury. Using tyrosine-hydoxylase (TH) immunohistochemistry we measured the density of catecholaminergic axons before and at various time points after injury. One week after CCI injury we observed a pronounced loss, across cortical layers, of TH+ axons posterior to the site of injury. One month after CCI injury the same was true of TH+ axons both anterior and posterior to the site of injury. This loss was followed by significant recovery of TH+ fiber density across cortical layers, both anterior and posterior to the site of injury, measured three months after injury. TH+ axon loss and recovery over weeks to months was also observed throughout cortical layers using the stab injury model. Double label immunohistochemistry revealed that nearly all TH+ axons in neocortical layer 1/2 are also dopamine-beta-hyroxylase+ (DBH+; presumed norepinephrine), while TH+ axons in layer 5 are a mixture of DBH+ and dopamine transporter+ types. This suggests that noradrenergic axons can regrow following CCI or stab injury in the adult mouse neocortex and leaves open the question of whether dopaminergic axons can do the same.
Diversity in the lateral hypothalamic input to the ventral tegmental area
2019, Neuropharmacology
Citation Excerpt :
The VTA dopaminergic projection to the nucleus accumbens (NAc) plays a key role in motivated behaviour (Garris et al., 1999; Nicola et al., 2005; Westerink et al., 1994). This rostral projection forms a tract of small unmyelinated axons that are a major component in the medial forebrain bundle (Nieuwenhuys et al., 1982; Yeomans, 1989). Dopamine is both tonically and phasically released at terminals in the NAc.
The obesity epidemic is one of the biggest health challenges globally and rates have tripled since 1975. Overeating is the largest determinant of obesity, yet little is understood of the neural mechanisms underlying why individuals consume food regardless of satiety. The lateral hypothalamic (LH) input to the ventral tegmental area (VTA) has been critically implicated in regulating appetitive and reward-related behaviours. However, these projections are genetically heterogeneous and have different responses to leptin. Therefore each of these projections may play a different role in modulating the VTA. This review characterizes each of these known LH to VTA projections in their roles in regulating appetitive behaviour.
This article is part of the Special Issue entitled ‘Hypothalamic Control of Homeostasis’.
Deep brain stimulation of the medial forebrain bundle elevates striatal dopamine concentration without affecting spontaneous or reward-induced phasic release
2017, Neuroscience
Citation Excerpt :
The next question is how DBS of the MFB induces increased DA release in striatal regions. With the stimulus parameters commonly used for DBS (high frequency, low pulse width, and a relatively large electrode surface), direct activation of DA axons is unlikely (Yeomans et al., 1988; Yeomans, 1989). Although DA axons are capable of following high-frequency stimulation for a limited time period (1–3 s), sustained stimulation at high frequencies is not accompanied by steady DA release, probably due to adjustment of DA neurons (Stamford et al., 1987).
Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) induces rapid improvement of depressive symptoms in patients suffering from treatment-refractory major depressive disorder (MDD). It has been hypothesized that activation of the dopamine (DA) system contributes to this effect. To investigate whether DBS in the MFB affects DA release in the striatum, we combined DBS with fast-scan cyclic voltammetry (FSCV) in freely moving rats. Animals were implanted with a stimulating electrode at the border of the MFB and the ventral tegmental area, and a FSCV microelectrode in the ventromedial striatum to monitor extracellular DA during the acute onset of DBS and subsequent continued stimulation. DBS onset induced a significant increase in extracellular DA concentration in the ventromedial striatum that was sustained for at least 40 s. However, continued DBS did not affect amplitude or frequency of so-called spontaneous phasic DA transients, nor phasic DA release in response to the delivery of unexpected food pellets. These findings suggest that effects of DBS in the MFB are mediated by an acute change in extracellular DA concentration, but more research is needed to further explore the potentially sustained duration of this effect. Together, our results provide both support and refinement of the hypothesis that MFB DBS activates the DA system: DBS induces an increase in overall ambient concentration of DA, but spontaneous or reward-associated more rapid, phasic DA dynamics are not enhanced. This knowledge improves our understanding of how DBS affects brain function and may help improve future therapies for depressive symptoms.
Utility of Intracranial Self-Stimulation in the Assessment of the Abuse Liability of New Pharmaceuticals
2015, Nonclinical Assessment of Abuse Potential for New Pharmaceuticals
All drugs entering the central nervous system (CNS) may initially be viewed as having a potential risk for abuse. As there is no single test or assessment procedure likely to offer a complete characterization of abuse liability, preclinical assessment uses several experimental approaches. This chapter discusses intracranial self-stimulation (ICSS) as a tool that could complement existing assessment strategies. Many drugs of abuse facilitate ICSS in laboratory animals prepared with electrodes implanted into brain “reward” areas. In addition to fairly robust predictive validity, ICSS may have a number of important advantages relative to other procedures in studying: (1) drug–drug interactions; (2) quantitative comparisons among drugs; (3) complex drug formulations, especially those intended to be abuse resistant; and (4) repeated drug exposures. This chapter argues for the standardization of ICSS experimental protocols to enable a definitive assessment of the usefulness of ICSS in predicting the abuse potential of drugs.

View all citing articles on Scopus

View full text

ArticleTwo substrates for medial forebrain bundle self-stimulation: Myelinated axons and dopamine axons

Behav. Brain Res.

Brain Res.

Behav. Brain Res.

Behav. Brain Res.

Brain Res.

Neuroscience

Physiol. Behav.

Behav. Brain Res.

Physiol. Behav.

Brain Res. Bull.

Physiol. Behav.

Brain Res.

Brain Res. Rev.

Physiol. Behav.

Brain Res.

Brain Res.

Brain Res. Rev.

Evidence implicating descending fibers in self-stimulation of the medial forebrain bundle

J. Neurosci.

Self-stimulation sites in the lateral hypothalamic and lateral preoptic areas are functionally connected

Can. Psychol.

Evidence for a direct link between reward-relevant neurons in the ventral tegmental area-posterior hypothalamus and the medial mesencephalon

Soc. Neurosci. Abstr.

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