Publications by authors named "Mate D Döbrössy"

27 Publications

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Neuromodulation in Psychiatric disorders: Experimental and Clinical evidence for reward and motivation network Deep Brain Stimulation: Focus on the medial forebrain bundle.

Eur J Neurosci 2021 Jan 30;53(1):89-113. Epub 2020 Sep 30.

Laboratory of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Hospital Freiburg, Freiburg, Germany.

Deep brain stimulation (DBS) in psychiatric illnesses has been clinically tested over the past 20 years. The clinical application of DBS to the superolateral branch of the medial forebrain bundle in treatment-resistant depressed patients-one of several targets under investigation-has shown to be promising in a number of uncontrolled open label trials. However, there are remain numerous questions that need to be investigated to understand and optimize the clinical use of DBS in depression, including, for example, the relationship between the symptoms, the biological substrates/projections and the stimulation itself. In the context of precision and customized medicine, the current paper focuses on clinical and experimental research of medial forebrain bundle DBS in depression or in animal models of depression, demonstrating how clinical and scientific progress can work in tandem to test the therapeutic value and investigate the mechanisms of this experimental treatment. As one of the hypotheses is that depression engenders changes in the reward and motivational networks, the review looks at how stimulation of the medial forebrain bundle impacts the dopaminergic system.
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http://dx.doi.org/10.1111/ejn.14975DOI Listing
January 2021

Medial forebrain bundle DBS differentially modulates dopamine release in the nucleus accumbens in a rodent model of depression.

Exp Neurol 2020 05 5;327:113224. Epub 2020 Feb 5.

BrainLinks-BrainTools Cluster of Excellence, University of Freiburg, Georges-Kohler-Allee 80, 79110 Freiburg, Germany; Laboratory for Stereotaxy and Interventional Neurosciences (SIN), Freiburg University, Department of Stereotactic and Functional Neurosurgery, University Medical Center Freiburg, Breisacher Strasse, 64 79106 Freiburg i.Br, Germany; Center for Basics in Neuromodulation, Freiburg University, Freiburg, Germany. Electronic address:

Background: 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.

Objective: 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.

Method: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1016/j.expneurol.2020.113224DOI Listing
May 2020

Deep Brain Stimulation of the Medial Forebrain Bundle in a Rodent Model of Depression: Exploring Dopaminergic Mechanisms with Raclopride and Micro-PET.

Stereotact Funct Neurosurg 2020 24;98(1):8-20. Epub 2020 Jan 24.

Department of Stereotactic and Functional Neurosurgery, University of Freiburg Medical Center, Freiburg, Germany,

Background: Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) can reverse depressive-like symptoms clinically and in experimental models of depression, but the mechanisms of action are unknown.

Objectives: This study investigated the role of dopaminergic mechanisms in MFB stimulation-mediated behavior changes, in conjunction with raclopride administration and micropositron emission tomography (micro-PET).

Methods: Flinders Sensitive Line (FSL) rats were allocated into 4 groups: FSL (no treatment), FSL+ (DBS), FSL.R (FSL with raclopride), and FSL.R+ (FSL with raclopride and DBS). Animals were implanted with bilateral electrodes targeting the MFB and given 11 days access to raclopride in the drinking water with or without concurrent continuous bilateral DBS over the last 10 days. Behavioral testing was conducted after stimulation. A PET scan using [18F]desmethoxyfallypride was performed to determine D2 receptor availability before and after raclopride treatment. Changes in gene expression in the nucleus accumbens and the hippocampus were assessed using quantitative polymerase chain reaction.

Results: Micro-PET imaging showed that raclopride administration blocked 36% of the D2 receptor in the striatum, but the relative level of blockade was reduced/modulated by stimulation. Raclopride treatment enhanced depressive-like symptoms in several tasks, and the MFB DBS partially reversed the depressive-like phenotype. The raclopride-treated MFB DBS animals had increased levels of mRNA coding for dopamine receptor D1 and D2 suggestive of a stimulation-mediated increase in dopamine receptors.

Conclusion: Data suggest that chronic and continuous MFB DBS could act via the modulation of the midbrain dopaminergic transmission, including impacting on the postsynaptic dopamine receptor profile.
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http://dx.doi.org/10.1159/000504860DOI Listing
January 2020

Enhanced adenosine A receptor and Homer1a expression in hippocampus modulates the resilience to stress-induced depression-like behavior.

Neuropharmacology 2020 01 1;162:107834. Epub 2019 Nov 1.

Department for Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 5, 79104, Freiburg, Germany.

Resilience to stress is critical for the development of depression. Enhanced adenosine A receptor (AR) signaling mediates the antidepressant effects of acute sleep deprivation (SD). However, chronic SD causes long-lasting upregulation of brain AR and increases the risk of depression. To investigate the effects of AR on mood, we utilized two transgenic mouse lines with inducible AR overexpression in forebrain neurons. These two lines have identical levels of AR increase in the cortex, but differ in the transgenic AR expression in the hippocampus. Switching on the transgene promotes robust antidepressant and anxiolytic effects in both lines. The mice of the line without transgenic AR overexpression in the hippocampus (A1Hipp-) show very strong resistance towards development of stress-induced chronic depression-like behavior. In contrast, the mice of the line in which AR upregulation extends to the hippocampus (A1Hipp+), exhibit decreased resilience to depression as compared to A1Hipp-. Similarly, automatic analysis of reward behavior of the two lines reveals that depression resistant A1Hipp-transgenic mice exhibit high sucrose preference, while mice of the vulnerable A1Hipp + line developed stress-induced anhedonic phenotype. The A1Hipp + mice have increased Homer1a expression in hippocampus, correlating with impaired long-term potentiation in the CA1 region, mimicking the stressed mice. Furthermore, virus-mediated overexpression of Homer1a in the hippocampus decreases stress resilience. Taken together our data indicate for first time that increased expression of AR and Homer1a in the hippocampus modulates the resilience to stress-induced depression and thus might potentially mediate the detrimental effects of chronic sleep restriction on mood.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107834DOI Listing
January 2020

Enhanced mGlu5 Signaling in Excitatory Neurons Promotes Rapid Antidepressant Effects via AMPA Receptor Activation.

Neuron 2019 10 13;104(2):338-352.e7. Epub 2019 Aug 13.

Department of Stereotactic and Functional Neurosurgery, Medical Center - University Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Str. 64, 79106 Freiburg, Germany; Department for Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 5, 79104 Freiburg, Germany. Electronic address:

Conventional antidepressants have limited efficacy and many side effects, highlighting the need for fast-acting and specific medications. Induction of the synaptic protein Homer1a mediates the effects of different antidepressant treatments, including the rapid action of ketamine and sleep deprivation (SD). We show here that mimicking Homer1a upregulation via intravenous injection of cell-membrane-permeable TAT-Homer1a elicits rapid antidepressant effects in various tests. Similar to ketamine and SD, in vitro and in vivo application of TAT-Homer1a enhances mGlu5 signaling, resulting in increased mTOR pathway phosphorylation, and upregulates synaptic AMPA receptor expression and activity. The antidepressant action of SD and Homer1a induction depends on mGlu5 activation specifically in excitatory CaMK2a neurons and requires enhanced AMPA receptor activity, translation, and trafficking. Moreover, our data demonstrate a pronounced therapeutic potential of different TAT-fused peptides that directly modulate mGlu5 and AMPA receptor activity and thus might provide a novel strategy for rapid and effective antidepressant treatment.
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http://dx.doi.org/10.1016/j.neuron.2019.07.011DOI Listing
October 2019

The effects of bilateral, continuous, and chronic Deep Brain Stimulation of the medial forebrain bundle in a rodent model of depression.

Exp Neurol 2018 05 8;303:153-161. Epub 2018 Feb 8.

Laboratory of Stereotaxy and Interventional Neurosciences, Dept. of Stereotactic and Functional Neurosurgery, University Freiburg Medical Center, Breisacher Str. 64, D-79106 Freiburg, Germany; University of Freiburg, Faculty of Medicine, Freiburg (i.Br.), Germany. Electronic address:

Background: Clinical trials of supra-lateral medial forebrain bundle (MFB) Deep Brain Stimulation (DBS) in treatment resistant major depressive patients have shown rapid and long-term benefits.

Objective/hypothesis: The study used Flinders Sensitive Line (FSL) rats with previously identified depressive-like phenotype to assess the range of behavior modification achieved by MFB DBS.

Methods: Male FSL and wild-type Sprague-Dawley rats as Controls were tested on mood/anxiety/exploration, cognitive and motor behaviors. The animals were implanted with bipolar stimulation electrodes in the MFB, and recovery was followed by 10 days of bilateral, chronic and continuous stimulation.

Results: Weight dynamics was assessed continuously and indicated similar growth rates although the FSL rats weighed approximately 20-25% less. MFB DBS had no impact on ultrasound calls emitted and the FSL rats continued to vocalize significantly less in the positive affect frequency compared to controls. Similarly, stimulation did not influence the FSL's exploration level (Elevated Plus Maze), nor locomotion (Open Field), although it reduced their freezing behavior (Open Field). Importantly, MFB DBS improved cognitive performance (Double-H) compared to Controls by reducing the time required and the number of errors committed to complete a spatial task.

Conclusion: MFB DBS in the FSL animals selectively affected certain types of behaviors. Exploration and vocalization remained unaltered, but cognitive performance such as speed and precision of memory recall improved compared to unstimulated and stimulated controls. Future studies should focus on the mechanisms of action of MFB DBS, and in particular on the role of dopamine in the stimulation-dependent phenotype changes.
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http://dx.doi.org/10.1016/j.expneurol.2018.02.002DOI Listing
May 2018

Anodal Transcranial Direct Current Stimulation Enhances Survival and Integration of Dopaminergic Cell Transplants in a Rat Parkinson Model.

eNeuro 2017 Sep-Oct;4(5). Epub 2017 Sep 19.

Department of Neurology, University Hospital Freiburg, Freiburg, 79106, Germany.

Restorative therapy concepts, such as cell based therapies aim to restitute impaired neurotransmission in neurodegenerative diseases. New strategies to enhance grafted cell survival and integration are still needed to improve functional recovery. Anodal direct current stimulation (DCS) promotes neuronal activity and secretion of the trophic factor BDNF in the motor cortex. Transcranial DCS applied to the motor cortex transiently improves motor symptoms in Parkinson's disease (PD) patients. In this proof-of-concept study, we combine cell based therapy and noninvasive neuromodulation to assess whether neurotrophic support via transcranial DCS would enhance the restitution of striatal neurotransmission by fetal dopaminergic transplants in a rat Parkinson model. Transcranial DCS was applied daily for 20 min on 14 consecutive days following striatal transplantation of fetal ventral mesencephalic (fVM) cells derived from transgenic rat embryos ubiquitously expressing GFP. Anodal but not cathodal transcranial DCS significantly enhanced graft survival and dopaminergic reinnervation of the surrounding striatal tissue relative to sham stimulation. Behavioral recovery was more pronounced following anodal transcranial DCS, and behavioral effects correlated with the degree of striatal innervation. Our results suggest anodal transcranial DCS may help advance cell-based restorative therapies in neurodegenerative diseases. In particular, such an assistive approach may be beneficial for the already established cell transplantation therapy in PD.
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http://dx.doi.org/10.1523/ENEURO.0063-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617080PMC
May 2018

Rehabilitation training in neural restitution.

Prog Brain Res 2017 7;230:305-329. Epub 2017 Mar 7.

Brain Repair Group, School of Biosciences, Cardiff University, Cardiff, United Kingdom.

Over the last decade, neural transplantation has emerged as one of the more promising, albeit highly experimental, potential therapeutics in neurodegenerative disease. Preclinical studies in rat lesion models of Huntington's disease (HD) and Parkinson's disease (PD) have shown that transplanted precursor neuronal tissue from a fetus into the lesioned striatum can survive, integrate, and reconnect circuitry. Importantly, specific training on behavioral tasks that target striatal function is required to encourage functional integration of the graft to the host tissue. Indeed, "learning to use the graft" is a concept recently adopted in preclinical studies to account for unpredicted profiles of recovery posttransplantation and is an emerging strategy for improving graft functionality. Clinical transplant studies in HD and PD have resulted in mixed outcomes. Small sample sizes and nonstandardized experimental procedures from trial to trial may explain some of this variability. However, it is becoming increasingly apparent that simply replacing the lost neurons may not be sufficient to ensure the optimal graft effects. The knowledge gained from preclinical grafting and training studies suggests that lifestyle factors, including physical activity and specific cognitive and/or motor training, may be required to drive the functional integration of grafted cells and to facilitate the development of compensatory neural networks. The clear implications of preclinical studies are that physical activity and cognitive training strategies are likely to be crucial components of clinical cell replacement therapies in the future. In this chapter, we evaluate the role of general activity in mediating the physical ability of cells to survive, sprout, and extend processes following transplantation in the adult mammalian brain, and we consider the impact of general and specific activity at the behavioral level on functional integration at the cellular and physiological level. We then highlight specific research questions related to timing, intensity, and specificity of training in preclinical models and synthesize the current state of knowledge in clinical populations to inform the development of a strategy for neural transplantation rehabilitation training.
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http://dx.doi.org/10.1016/bs.pbr.2016.12.006DOI Listing
May 2018

Chronic deep brain stimulation of the medial forebrain bundle reverses depressive-like behavior in a hemiparkinsonian rodent model.

Exp Brain Res 2015 Nov 21;233(11):3073-85. Epub 2015 Jul 21.

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

Preclinical and clinical evidence suggests that depression might be associated with a dysfunction in the reward/motivation circuitry. Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (MFB) has been shown in a recent clinical trial to provide a prompt and consistent improvement of depressive symptoms in treatment-resistant patients. In order to better understand the underlying mechanisms of neuromodulation in the context of depression, the effects of chronic bilateral MFB-DBS were assessed in a combined rodent model of depression and Parkinson's disease. Female Sprague-Dawley rats received unilateral 6-OHDA injection in the right MFB and were divided into three groups: CMS-STIM, CMS-noSTIM and control group. The CMS groups were submitted to chronic unpredictable mild stress (CMS) protocol for 6 weeks. MFB-DBS was applied only to the CMS-STIM group for 1 week. All groups were repeatedly probed on a series of behavioral tasks following each intervention, and to a postmortem histological analysis. CMS led to an increase in immobility in the forced swim test, to a decrease in sucrose solution consumption in the sucrose preference test, as well as to an increased production of ultrasonic vocalizations in the 22 kHz range, indicating increased negative affect. MFB-DBS reversed the anhedonic-like and despair-like behaviors. The results suggest that unilateral dopamine depletion did not preclude MFB-DBS in reversing depressive-like and anhedonic-like behavior in the rodent. Further understanding of the importance of hemispheric dominance in neuropsychiatric disorders is essential in order to optimize stimulation as a therapeutic strategy in these diseases.
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http://dx.doi.org/10.1007/s00221-015-4375-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4623086PMC
November 2015

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

Behav Neurol 2015 15;2015:256196. Epub 2015 Apr 15.

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

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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http://dx.doi.org/10.1155/2015/256196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414266PMC
September 2015

Continuous High-Frequency Stimulation of the Subthalamic Nucleus Improves Cell Survival and Functional Recovery Following Dopaminergic Cell Transplantation in Rodents.

Neurorehabil Neural Repair 2015 Nov-Dec;29(10):1001-12. Epub 2015 Apr 9.

University Freiburg Medical Center, Freiburg im Breisgau, Germany.

Subthalamic nucleus (STN) high-frequency stimulation (HFS) is a routine treatment in Parkinson's disease (PD), with confirmed long-term benefits. An alternative, but still experimental, treatment is cell replacement and restorative therapy based on transplanted dopaminergic neurons. The current experiment evaluated the potential synergy between neuromodulation and grafting by studying the effect of continuous STN-HFS on the survival, integration, and functional efficacy of ventral mesencephalic dopaminergic precursors transplanted into a unilateral 6-hydroxydopamine medial forebrain bundle lesioned rodent PD model. One group received continuous HFS of the ipsilateral STN starting a week prior to intrastriatal dopaminergic neuron transplantation, whereas the sham-stimulated group did not receive STN-HFS but only dopaminergic grafts. A control group was neither lesioned nor transplanted. Over the following 7 weeks, the animals were probed on a series of behavioral tasks to evaluate possible graft and/or stimulation-induced functional effects. Behavioral and histological data suggest that STN-HFS significantly increased graft cell survival, graft-host integration, and functional recovery. These findings might open an unexplored road toward combining neuromodulative and neuroregenerative strategies to treat severe neurologic conditions.
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http://dx.doi.org/10.1177/1545968315581419DOI Listing
July 2016

Electrical stimulation of the medial forebrain bundle in pre-clinical studies of psychiatric disorders.

Neurosci Biobehav Rev 2015 Feb 9;49:32-42. Epub 2014 Dec 9.

Laboratory of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Freiburg-Medical Center, Germany.

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.
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http://dx.doi.org/10.1016/j.neubiorev.2014.11.018DOI Listing
February 2015

Organization of the human fetal subpallium.

Front Neuroanat 2013 16;7:54. Epub 2014 Jan 16.

Department of Neurology, University Freiburg - Medical Center Freiburg, Germany.

The subpallium comprises large parts of the basal ganglia including striatum and globus pallidus. Genes and factors involved in the development of the subpallium have been extensively studied in most vertebrates, including amphibians, birds, and rodents. However, our knowledge on patterning of the human subpallium remains insufficient. Using double fluorescent immunohistochemistry, we investigated the protein distribution of transcription factors involved in patterning of the subventricular zone (SVZ) in the human forebrain at late embryonic development. Furthermore, we compared the development of cortical and striatal precursors between human fetal brain and E14 and E16 fetal rat brains. Our results reveal that DLX2 marks SVZ precursors in the entire subpallium. Individual subpallial subdomains can be identified based on co-expression of DLX2 with either PAX6 or NKX2-1. SVZ precursors in the dorsal LGE and preopto-hypothalamic boundary are characterized by DLX2/PAX6 co-expression, while precursors in the MGE and preoptic region co-express DLX2/NKX2-1. SVZ precursors in the ventral LGE are DLX2(+)/PAX6(-)/NKX2-1(-). In terms of staging comparisons, the development of the corpus striatum in the human fetal brain during late embryonic stages corresponds well with the development of the striatum observed in E14 fetal rat brains. Our study demonstrates that the pattern underlying the development of the subpallium is highly conserved between rodents and humans and suggests a similar function for these factors in human brain development. Moreover, our data directly influence the application of ganglionic eminence derived human tissue for cell therapeutic approaches in neurodegenerative disorders such as Huntington's disease.
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http://dx.doi.org/10.3389/fnana.2013.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893616PMC
January 2014

Donor age dependent graft development and recovery in a rat model of Huntington's disease: histological and behavioral analysis.

Behav Brain Res 2013 Nov 3;256:56-63. Epub 2013 Aug 3.

Lab of Stereotaxy and Interventional Neurosciences, Department of Stereotactic and Functional Neurosurgery, University Freiburg - Medical Centre, Freiburg, Germany.

Neural cell replacement therapy using fetal striatal cells has provided evidence of disease modification in clinical trials in Huntington's disease (HD) patients, although the results have been inconsistent. One of the contributing factors to the variable outcome could be the different capacity of transplanted cells derived from the primordial striatum to proliferate and maturate into striatal projection neurons. Based on the rodent lesion model of HD, the current study investigated how intrastriatal-striatal grafts from variable aged donors develop in vivo and how they influence functional recovery. Young adult female Sprague-Dawley rats were lesioned unilaterally in the dorso-striatum with quinolinic acid (0.12 M) and transplanted 14 days later with single cell suspension grafts equivalent of one whole ganglionic eminence (WGE) from donors of embryonic developmental age E13, E14, or E15; animals with or without striatal lesion served as controls. All animals were tested on the Cylinder and the Corridor tests, as well as on apomorphine-induced rotation at baseline, post-lesion/pre-grafting, and at 6 and 10 weeks post-grafting. A week prior to perfusion, a sub-group in each grafted group received fluorogold injections into the ipsilateral globus pallidus to study graft efferent projections. In summary, the data demonstrates that the age of the embryonic donor tissue has an impact on both the graft mediated functional recovery, and on the in vivo cellular composition of the striatal transplant. E13 tissue grafts gave the best overall outcome indicating that WGE from different donor ages have different potential to promote functional recovery. Understanding the stages and process in rodent striatal development could improve tissue selection in clinical trials of cell therapy in HD.
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http://dx.doi.org/10.1016/j.bbr.2013.07.053DOI Listing
November 2013

Pencilbeam irradiation technique for whole brain radiotherapy: technical and biological challenges in a small animal model.

PLoS One 2013 28;8(1):e54960. Epub 2013 Jan 28.

Division of Stereotactic and Functional Neurosurgery, Freiburg University Medical Center, Freiburg, Germany.

We have conducted the first in-vivo experiments in pencilbeam irradiation, a new synchrotron radiation technique based on the principle of microbeam irradiation, a concept of spatially fractionated high-dose irradiation. In an animal model of adult C57 BL/6J mice we have determined technical and physiological limitations with the present technical setup of the technique. Fifty-eight animals were distributed in eleven experimental groups, ten groups receiving whole brain radiotherapy with arrays of 50 µm wide beams. We have tested peak doses ranging between 172 Gy and 2,298 Gy at 3 mm depth. Animals in five groups received whole brain radiotherapy with a center-to-center (ctc) distance of 200 µm and a peak-to-valley ratio (PVDR) of ∼ 100, in the other five groups the ctc was 400 µm (PVDR ∼ 400). Motor and memory abilities were assessed during a six months observation period following irradiation. The lower dose limit, determined by the technical equipment, was at 172 Gy. The LD50 was about 1,164 Gy for a ctc of 200 µm and higher than 2,298 Gy for a ctc of 400 µm. Age-dependent loss in motor and memory performance was seen in all groups. Better overall performance (close to that of healthy controls) was seen in the groups irradiated with a ctc of 400 µm.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054960PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557252PMC
July 2013

Role of experience, training, and plasticity in the functional efficacy of striatal transplants.

Prog Brain Res 2012 ;200:303-28

Laboratory of Molecular Neurosurgery, Division of Stereotactic Neurosurgery, Department of General Neurosurgery, University of Freiburg Medical Center, Freiburg, Germany.

Cell-based treatments of neurodegenerative diseases have been tested clinically with partial success. In the context of Huntington's disease (HD), experimental studies show that the grafted embryonic striatal cells survive, integrate within the host brain, and reverse some functional deficits. Importantly, once transplanted, the grafted striatal neurons retain a significant level of cellular, morphological, and functional plasticity which allows the experimental modification of their character through the manipulation of environmental cues or learning protocols. Using embryonic striatal grafts in the rodent model of HD as the principal example, this chapter summarizes seminal experiments that demonstrate that environmental factors, training, and activity can tap into mechanisms that influence the development of the grafted cells and can change the profile of graft-mediated behavioral recovery. Although currently there is limited understanding of the biological rationale behind the recovery, we put forward experimental data indicating that striatal grafts can express experience-dependent physiological plasticity at the synaptic as well as at the systemic functional level.
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http://dx.doi.org/10.1016/B978-0-444-59575-1.00014-4DOI Listing
November 2013

Early deficits in declarative and procedural memory dependent behavioral function in a transgenic rat model of Huntington's disease.

Behav Brain Res 2013 Feb 5;239:15-26. Epub 2012 Nov 5.

Laboratory for Molecular Neurosurgery, Stereotactic and Functional Neurosurgery, University Hospital Freiburg, Engesserstrasse 4,Freiburg, Germany.

In Huntington's disease (HD) cognitive deficits co-exist with motor impairments, both contributing to the overall disease symptomology. Despite short-term and working memory impairments, learning and other non-motoric behavioral deficits arising from the damage to frontostriatal loop being common in HD patients, most of the experimental work with transgenic animals focuses on motor symptoms. The transgenic rat model (tgHD) recapitulates many hallmark HD-like symptoms, such as huntingtin aggregates, cellular loss and dysfunction, and motor, and some cognitive deficits. In the current study we tested tgHD rats in two different cognitive, water maze competition paradigms to learn more about the impact of the transgene on learning and memory processing using hippocampal- and striatal-based memory systems. The tgHD rats had early and robust cognitive deficits in learning and memory function in both paradigms. Specifically, the transgenic animals were impaired in task acquisition and committed more procedural errors with the strongest phenotype amongst the homozygote tgHD. Although the transgenic animals were capable of using both procedural and declarative memory, their response patterns were distinct from wild-type animals. Wide spread huntingtin aggregates were observed at 13 months, but neither PET nor autoradiography indicated neuronal loss or dysfunction in striatal dopamine receptor population. In summary, the homozygote tgHD showed a robust learning and memory impairment prior to any clear motor deficits, or striatal dysfunction. However, the data were not conclusive regarding how the memory systems were compromised and the precise nature and underlying mechanism of the cognitive deficit in the tgHD model requires further investigation.
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http://dx.doi.org/10.1016/j.bbr.2012.10.048DOI Listing
February 2013

[18F]desmethoxyfallypride as a novel PET radiotracer for quantitative in vivo dopamine D2/D3 receptor imaging in rat models of neurodegenerative diseases.

Nucl Med Biol 2012 Oct 15;39(7):1077-80. Epub 2012 May 15.

Stereotactic Neurosurgery, Department of General Neurosurgery, University Freiburg Medical Center, Breisacher Str 64, 79106, Freiburg, Germany.

Introduction: [(18)F]desmethoxyfallypride ([(18)F]DMFP) is a promising tracer for longitudinal assessment of striatal dopamine D2/D3-receptor (D2R) availability by positron emission tomography (PET) in small animal models. We explored the feasibility of [(18)F]DMFP-PET to image D2R availability in rat models of Huntington's (HD) and Parkinson's disease (PD).

Methods: Animals received either unilateral intrastriatal quinolinic acid lesions or medial forebrain bundle injections of 6-OHDA to produce the loss of striatal projection neurones or deplete the striatal dopamine, corresponding to established animal models for HD and PD, respectively. Three weeks after lesioning, PET scans were acquired on a microPET Focus 120 system following the tail vein injection of [(18)F]DMFP.

Results: [(18)F]DMFP-PET clearly visualized lesion induced decreases and increases of D2R availability. In vivo estimates of D2R binding and changes thereof gained by pharmacokinetic analyses correlated significantly with D2R density and its change provided by in vitro [(3)H]raclopride-autoradiography.

Conclusions: In conclusion, [(18)F]DMFP-PET is a suitable method for in vivo D2R-assessment in preclinical research, e.g for monitoring cell-based therapies.
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http://dx.doi.org/10.1016/j.nucmedbio.2012.04.003DOI Listing
October 2012

Behavioral and histological analysis of a partial double-lesion model of parkinson-variant multiple system atrophy.

J Neurosci Res 2012 Jun 20;90(6):1284-95. Epub 2012 Feb 20.

Neurological Research Laboratory, University Hospital, Innsbruck, Austria.

Multiple system atrophy (MSA) is a neurodegenerative disease with progressive autonomic failure, cerebellar ataxia (MSA-C), and parkinsonism (MSA-P) resulting from neuronal loss in multiple brain areas associated with oligodendroglial cytoplasmic α-synuclein inclusion bodies. No effective treatments exists, and MSA-P patients often fail to respond to L-DOPA because of the loss of striatal dopaminergic receptors. Rendering MSA-P patients sensitive to L-DOPA administration following striatal tissue transplantation has been proposed as a possible novel therapeutic strategy to improve the clinical condition. Here we describes simple, skilled, and sensorimotor behavior deficits in a unilateral partial double-lesion (DL) rat model of MSA-P. The sequential striatal double-lesion model mimicks early MSA-P pathology by combining partial 6-hydroxydopamine (6-OHDA) followed by striatal quinolinic acid (QA) lesion. Animals were tested on spontaneous, learned, or drug-induced behavioral tasks on multiple occasions pre- and postsurgery. The data show robust, lateralized deficits, and the partial 6-OHDA and the double-lesioned animals were most impaired. Importantly, this study identified a behavioral deficit profile unique to the double-lesion animals and distinctive from the single 6-OHDA- or the QA-lesioned animals. Histology confirmed an approximately 40% dopamine loss in the striatum in the 6-OHDA and double-lesion animals as well as a similar loss of striatal projection neurons in the QA and double-lesion animals. In summary, we have established the behavioral deficit profile of a partial double-lesion rat model mimicking the early stage of MSA-P.
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http://dx.doi.org/10.1002/jnr.23021DOI Listing
June 2012

Environmental housing and duration of exposure affect striatal graft morphology in a rodent model of Huntington's disease.

Cell Transplant 2008 ;17(10-11):1125-34

Brain Repair Group, School of Biosciences, Cardiff University, Cardiff CF10 3US, UK.

Clinical trials of cell replacement therapy in Huntington's disease have shown its safety, feasibility, and potentially long-lasting effects. However, more needs to be known regarding the conditions that stimulate plasticity and compensation achieved by neural grafts to maximize posttransplantation recovery of such neurorehabilitative therapies. The effects of enriched environment (EE), behavioral experience, and transplantation can each separately influence neuronal plasticity and recovery of function after brain damage, and the mechanisms by which these factors interact to modify the survival, integration, or function of grafted tissues are at present unknown. To investigate the effects of variable housing conditions and duration on morphological and cellular changes within embryonic striatal transplants, rats received unilateral excitotoxic lesions of the striatum, followed by E15 whole-ganglionic eminence suspension grafts. The rats were divided into three groups according to housing: full-time EE, 1 h/day exposure to EE, or standard laboratory cages. The experimental design included "early" (7 weeks postgrafting) and "late" (13 weeks postgrafting) survival time points to explore the effects of exposure lengths to the three housing conditions. The morphological and cellular effects on the grafts were analyzed using immunohistochemistry, cell morphology, image analysis, and enzyme-linked immunoassay. Both the duration of the exposure and the housing conditions were seen to influence multiple parameters of grafted cell morphology. The factors acted either independently (e.g., on graft size), complementarily (e.g., on spine density), or had no distinctive effect (e.g., on lesion size) on graft development. Features of embryonic striatal grafts and their trophic milieu were influenced both by the complexity of the environmental conditions and by the length of exposure to them. The data suggest that neurorehabilitation should be a feature of clinical trials of cell transplantation in order to exploit the underlying mechanisms that promote anatomical integration of the grafted cells and maximize transplant-mediated functional recovery.
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http://dx.doi.org/10.3727/096368908787236558DOI Listing
February 2009

Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments.

Neurobiol Dis 2009 Mar 27;33(3):358-68. Epub 2008 Nov 27.

San Raffaele Scientific Institute, Milan, Italy.

In this study we analyzed the effect on behavior of a chronic exposure to brain-derived neurotrophic factor (BDNF), by analysing a mouse line overexpressing BDNF under the alphaCaMKII promoter, which drives the transgene expression exclusively to principal neurons of the forebrain. BDNF transgenic mice and their WT littermates were examined with a battery of behavioral tests, in order to evaluate motor coordination, learning, short and long-term memory formation. Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.
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http://dx.doi.org/10.1016/j.nbd.2008.11.004DOI Listing
March 2009

The corridor task: striatal lesion effects and graft-mediated recovery in a model of Huntington's disease.

Behav Brain Res 2007 May 25;179(2):326-30. Epub 2007 Feb 25.

Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue Box 911, Cardiff CF10 3US, UK.

Experimental validation of cell replacement therapy as a treatment of neurodegenerative diseases requires the demonstration of graft-mediated behavioural recovery. The Corridor task proved to be simple and efficient to conduct with a robust ipsilateral retrieval bias in our rodent Huntington's disease model. The Corridor task is a viable behavioural option, particularly to non-specialised laboratories, for the evaluation of lateralised striatal damage and the probing of alternative therapeutic strategies, including transplantation.
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http://dx.doi.org/10.1016/j.bbr.2007.02.030DOI Listing
May 2007

Morphological and cellular changes within embryonic striatal grafts associated with enriched environment and involuntary exercise.

Eur J Neurosci 2006 Dec;24(11):3223-33

Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue Box 911, Cardiff CF10 3US, UK.

Environmental enrichment (EE) and exercise have been implicated in influencing behaviour and altering neuronal processes associated with cellular morphology in both 'normal' and injured states of the CNS. Using a rodent model of Huntington's disease, we investigated whether prolonged EE or involuntary exercise can induce morphological and cellular changes within embryonic striatal transplants. Adult rats were trained on the Staircase test--requiring fine motor control to reach and collect reward pellets--prior to being lesioned unilaterally in the dorsal neostriatum with quinolinic acid. The lesioned animals received E15 whole ganglionic eminence cell suspension grafts followed by housing in EE or standard cages. Half of the animals in standard cages received daily forced exercise on a treadmill. The grafted animals showed significant functional recovery on both the Staircase test and in drug-induced rotation. Neither the housing conditions nor the training had an impact on the behaviour, with the exception of the treadmill reducing the ipsilateral drug-induced rotation observed amongst the lesioned animals. However, the animals housed in the EE had significantly increased striatal brain-derived neurotrophic factor (BDNF) levels, and graft neurons in these animals exhibited both greater spine densities and larger cell volumes. Animals on forced exercise regime had reduced BDNF levels and grafted cells with sparser spines. The study suggests that the context of the animal can affect the plasticity of transplanted cells. Appropriately exploiting the underlying, and yet unknown, mechanisms could lead the way to improved anatomical and potentially functional integration of the graft.
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http://dx.doi.org/10.1111/j.1460-9568.2006.05182.xDOI Listing
December 2006

The effects of lateralized training on spontaneous forelimb preference, lesion deficits, and graft-mediated functional recovery after unilateral striatal lesions in rats.

Exp Neurol 2006 Jun 23;199(2):373-83. Epub 2006 Feb 23.

Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue Box 911, Cardiff CF10 3US, UK.

The ability of striatal embryonic grafts to promote functional recovery on complex behavioral tasks depends on various factors, including the amount of striatal-like tissue within the grafts and the duration of post-graft training. However, how the innate paw bias of animals is affected by experience, or influences recovery following injury, is less known. Here, we have examined the effects of intrinsic side bias and lateralized limb use training on spontaneous forelimb preference and graft-mediated functional recovery in a skilled reaching task in a rodent model of Huntington's disease. Naïve rats were assessed on their baseline paw preferences when reaching between the bars of their cage to retrieve sugar pellets from a tray attached outside. Next, rats were lesioned unilaterally in the lateral dorsal striatum with quinolinic acid, and 7-10 days later, half of the animals were given suspension grafts prepared from E15 whole ganglionic eminence implanted into the lesioned striatum. The animals then received extensive unilateral training, either ipsi- or contralateral to the side of the lesion and graft in separate subgroups, on the 'staircase' task until asymptotic performance was obtained. As reported previously, the grafts alleviated lesion-induced deficits in retrieving pellets from the contralateral staircase. Spontaneous biases were then reassessed in the cage-reaching task. Irrespective of whether the animal received ipsilateral or contralateral staircase training, the unilateral lesions induced a significant shift in spontaneous bias towards the ipsilateral paw. Grafted animals showed a similar shift in bias if staircase training was given to the ipsilateral paw but showed no change in spontaneous bias (similar to controls) if they had received contralateral training during the post-transplantation period. The results suggest that striatal grafts can alleviate lesion-induced changes in their spontaneous side preferences, but only if they receive extensive training in the use of the contralateral limb, compatible with the notion that recovery is use-dependent.
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http://dx.doi.org/10.1016/j.expneurol.2005.12.033DOI Listing
June 2006

Environmental enrichment affects striatal graft morphology and functional recovery.

Eur J Neurosci 2004 Jan;19(1):159-68

Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue Box 911, Cardiff CF10 3US, UK.

Environmental conditions and behavioural experience can affect neuronal function and morphology. It is less well known whether such factors also influence the growth, integration and functional recovery provided by neural grafts placed within the damaged brain. Here we report on the effects of differential housing conditions on striatal graft morphology and functional recovery after striatal lesions. Rats were pretrained on a skilled bilateral forelimb task, the staircase test, and lesioned unilaterally in the lateral dorsal striatum with quinolinic acid. One group of lesioned animals was given suspension grafts of E15 whole ganglionic eminence implanted into the lesioned striatum. Following transplantation, the animals were housed either in standard cages (four per cage) or in enriched environment housing conditions (10 per cage) with tunnels, ladders and increased living space available for exploration, social interaction and play. The differentially housed animals were retested on the skilled staircase test at two separate time points. Repeated testing, environmental enrichment and transplantation positively influenced behavioural recovery. Partial recovery was observed bilaterally amongst the grafted animals in both housing conditions. Nevertheless, the grafted animals housed in the enriched environment performed significantly better in the final test compared with all of the other experimental groups. The grafts survived equally well under both housing conditions but the grafts of animals housed in the enriched environment contained larger projection neurons and were somewhat better reinnervated by dopaminergic afferents. An increased level of striatal brain-derived neurotrophic factor was observed in the control animals housed under the enriched compared with the standard conditions. The results indicate that an enriched environment can affect both graft function and graft morphology through as yet unknown mechanisms.
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http://dx.doi.org/10.1111/j.1460-9568.2004.03105.xDOI Listing
January 2004

Motor training effects on recovery of function after striatal lesions and striatal grafts.

Exp Neurol 2003 Nov;184(1):274-84

Brain Repair Group, School of Biosciences, Cardiff University, Museum Avenue Box 911, Cardiff CF10 3US, Wales, UK.

Environment, training, and experience can influence plasticity and recovery of function after brain damage. However, it is less well known whether, and how, such factors influence the growth, integration, and functional recovery provided by neural grafts placed within the brain. To explore this process, rats were pretrained on the skilled staircase test, then lesioned unilaterally in the lateral dorsal striatum with quinolinic acid. Half of the animals were given suspension grafts prepared from E15 whole ganglionic eminence implanted into the lesioned striatum. For the following 5 months, half of the animals in each group were trained daily in a bilateral manual dexterity task. Then, 23 weeks after surgery, all animals were retested on the staircase test. The grafts promoted recovery in the reaching task, irrespective of the additional dexterity training, and within the trained group recovery was proportional to the volume of the striatal-like tissue in the graft, suggesting that training influenced the pattern of graft-induced functional recovery. The additional training also benefited the rats with lesions alone, raising their performance close to level of the grafted groups. In separate tests of rotation, the grafts reduced drug-induced ipsilateral turning in response to both amphetamine and apomorphine, an effect that was greater in the grafted rats given extra training. The results suggest that both nonspecific motor training and cell transplantation can contribute to recovery of lost function in tests of spontaneous and skilled lateralized motor function after striatal damage, and that these two factors interact in a task-specific manner.
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http://dx.doi.org/10.1016/s0014-4886(03)00028-1DOI Listing
November 2003