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Feasibility and safety of continuous and chronic bilateral deep brain stimulation of the medial forebrain bundle in the naïve Sprague-Dawley rat.

Furlanetti LL, Döbrössy MD, Aranda IA, Coenen VA - Behav Neurol (2015)

Bottom Line: MFB-DBS led to increased and long-lasting c-fos expression in target regions of the mesolimbic/mesocortical system.Bilateral continuous chronic MFB-DBS is feasible, safe, and without impact on the rodent's health.MFB-DBS results in temporary increase in exploration, which could explain the initial weight loss, and does not produce any apparent behavioral abnormalities.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Medical Center Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany.

ABSTRACT

Objective: Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (MFB) has provided rapid and dramatic reduction of depressive symptoms in a clinical trial. Early intracranial self-stimulation experiments of the MFB suggested detrimental side effects on the animals' health; therefore, the current study looked at the viability of chronic and continuous MFB-DBS in rodents, with particular attention given to welfare issues and identification of stimulated pathways.

Methods: Sprague-Dawley female rats were submitted to stereotactic microelectrode implantation into the MFB. Chronic continuous DBS was applied for 3-6 weeks. Welfare monitoring and behavior changes were assessed. Postmortem histological analysis of c-fos protein expression was carried out.

Results: MFB-DBS resulted in mild and temporary weight loss in the animals, which was regained even with continuing stimulation. MFB-DBS led to increased and long-lasting c-fos expression in target regions of the mesolimbic/mesocortical system.

Conclusions: Bilateral continuous chronic MFB-DBS is feasible, safe, and without impact on the rodent's health. MFB-DBS results in temporary increase in exploration, which could explain the initial weight loss, and does not produce any apparent behavioral abnormalities. This platform represents a powerful tool for further preclinical investigation of the MFB stimulation in the treatment of depression.

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Related in: MedlinePlus

Immunohistochemical visualization of c-fos expression. Following MFB-HFS, strong c-fos expression was observed in prelimbic cortex (a), layers 3 and 5/6 of the somatosensory cortex (b), paraventricular thalamus, lateral habenula (e, f), and shell of the nucleus accumbens (d), suggesting that the stimulation activated mesolimbic and mesocortical pathways and its projection targets. However, little or no c-fos expression was observed in the dorsal striatum where the stimulated pathways do not project to. See Table 1 and text for more details. PrL: prelimbic cortex; NAC: nucleus accumbens; PV: paraventricular thalamic nucleus; LHb: lateral habenular nucleus; PC: paracentral thalamic nucleus; aca: anterior commissure; SS: somatosensory cortex; ec: external capsule; CPu: striatum. Scale bar = 50 µm in (a), (b), (d), and (e); 250 µm in (c) and (f).
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fig8: Immunohistochemical visualization of c-fos expression. Following MFB-HFS, strong c-fos expression was observed in prelimbic cortex (a), layers 3 and 5/6 of the somatosensory cortex (b), paraventricular thalamus, lateral habenula (e, f), and shell of the nucleus accumbens (d), suggesting that the stimulation activated mesolimbic and mesocortical pathways and its projection targets. However, little or no c-fos expression was observed in the dorsal striatum where the stimulated pathways do not project to. See Table 1 and text for more details. PrL: prelimbic cortex; NAC: nucleus accumbens; PV: paraventricular thalamic nucleus; LHb: lateral habenular nucleus; PC: paracentral thalamic nucleus; aca: anterior commissure; SS: somatosensory cortex; ec: external capsule; CPu: striatum. Scale bar = 50 µm in (a), (b), (d), and (e); 250 µm in (c) and (f).

Mentions: Selective stimulation of the ascending ventral mesencephalic DA fibers, that is, originating from the VTA (A10), led to upregulation and increase of c-fos expression in the shell of NAC, prelimbic cortex, mediodorsal thalamic nucleus, and lateral habenula. The semiquantitative assessment of c-fos expression in these terminal structures of the dopaminergic MFB projections revealed a long-lasting upregulation following chronic continuous bilateral MFB-HFS (Table 1). The stimulation induced long-term plastic changes in neural activity as the upregulation was present even in the group DBS A for whom the stimulation seized for up to two months prior to perfusion. Conversely, the dorsolateral striatum that receives dopaminergic neurons mainly from the substantia nigra (A9) [29] did not present positive staining for this marker suggesting that predominantly the mesolimbic/cortical pathway was stimulated. A subset of animals also received an acute, 2-hour continuous stimulation just prior to perfusion, which resulted in strong upregulation of c-fos, particularly in the prelimbic frontal cortex and shell of the NAC (Figures 8(a)–8(f)).


Feasibility and safety of continuous and chronic bilateral deep brain stimulation of the medial forebrain bundle in the naïve Sprague-Dawley rat.

Furlanetti LL, Döbrössy MD, Aranda IA, Coenen VA - Behav Neurol (2015)

Immunohistochemical visualization of c-fos expression. Following MFB-HFS, strong c-fos expression was observed in prelimbic cortex (a), layers 3 and 5/6 of the somatosensory cortex (b), paraventricular thalamus, lateral habenula (e, f), and shell of the nucleus accumbens (d), suggesting that the stimulation activated mesolimbic and mesocortical pathways and its projection targets. However, little or no c-fos expression was observed in the dorsal striatum where the stimulated pathways do not project to. See Table 1 and text for more details. PrL: prelimbic cortex; NAC: nucleus accumbens; PV: paraventricular thalamic nucleus; LHb: lateral habenular nucleus; PC: paracentral thalamic nucleus; aca: anterior commissure; SS: somatosensory cortex; ec: external capsule; CPu: striatum. Scale bar = 50 µm in (a), (b), (d), and (e); 250 µm in (c) and (f).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4414266&req=5

fig8: Immunohistochemical visualization of c-fos expression. Following MFB-HFS, strong c-fos expression was observed in prelimbic cortex (a), layers 3 and 5/6 of the somatosensory cortex (b), paraventricular thalamus, lateral habenula (e, f), and shell of the nucleus accumbens (d), suggesting that the stimulation activated mesolimbic and mesocortical pathways and its projection targets. However, little or no c-fos expression was observed in the dorsal striatum where the stimulated pathways do not project to. See Table 1 and text for more details. PrL: prelimbic cortex; NAC: nucleus accumbens; PV: paraventricular thalamic nucleus; LHb: lateral habenular nucleus; PC: paracentral thalamic nucleus; aca: anterior commissure; SS: somatosensory cortex; ec: external capsule; CPu: striatum. Scale bar = 50 µm in (a), (b), (d), and (e); 250 µm in (c) and (f).
Mentions: Selective stimulation of the ascending ventral mesencephalic DA fibers, that is, originating from the VTA (A10), led to upregulation and increase of c-fos expression in the shell of NAC, prelimbic cortex, mediodorsal thalamic nucleus, and lateral habenula. The semiquantitative assessment of c-fos expression in these terminal structures of the dopaminergic MFB projections revealed a long-lasting upregulation following chronic continuous bilateral MFB-HFS (Table 1). The stimulation induced long-term plastic changes in neural activity as the upregulation was present even in the group DBS A for whom the stimulation seized for up to two months prior to perfusion. Conversely, the dorsolateral striatum that receives dopaminergic neurons mainly from the substantia nigra (A9) [29] did not present positive staining for this marker suggesting that predominantly the mesolimbic/cortical pathway was stimulated. A subset of animals also received an acute, 2-hour continuous stimulation just prior to perfusion, which resulted in strong upregulation of c-fos, particularly in the prelimbic frontal cortex and shell of the NAC (Figures 8(a)–8(f)).

Bottom Line: MFB-DBS led to increased and long-lasting c-fos expression in target regions of the mesolimbic/mesocortical system.Bilateral continuous chronic MFB-DBS is feasible, safe, and without impact on the rodent's health.MFB-DBS results in temporary increase in exploration, which could explain the initial weight loss, and does not produce any apparent behavioral abnormalities.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Medical Center Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany.

ABSTRACT

Objective: Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (MFB) has provided rapid and dramatic reduction of depressive symptoms in a clinical trial. Early intracranial self-stimulation experiments of the MFB suggested detrimental side effects on the animals' health; therefore, the current study looked at the viability of chronic and continuous MFB-DBS in rodents, with particular attention given to welfare issues and identification of stimulated pathways.

Methods: Sprague-Dawley female rats were submitted to stereotactic microelectrode implantation into the MFB. Chronic continuous DBS was applied for 3-6 weeks. Welfare monitoring and behavior changes were assessed. Postmortem histological analysis of c-fos protein expression was carried out.

Results: MFB-DBS resulted in mild and temporary weight loss in the animals, which was regained even with continuing stimulation. MFB-DBS led to increased and long-lasting c-fos expression in target regions of the mesolimbic/mesocortical system.

Conclusions: Bilateral continuous chronic MFB-DBS is feasible, safe, and without impact on the rodent's health. MFB-DBS results in temporary increase in exploration, which could explain the initial weight loss, and does not produce any apparent behavioral abnormalities. This platform represents a powerful tool for further preclinical investigation of the MFB stimulation in the treatment of depression.

Show MeSH
Related in: MedlinePlus