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

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

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

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

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

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

Chapter Transplantation of Foetal Ventral Mesencephalic Grafts in Parkinson’s Disease: A Still Evolving Concept with New Regulatory Challenges

Physiological & neuro-psychology, biopsycholog

Chapter Transplantation of Foetal Ventral Mesencephalic Grafts in Parkinson’s Disease: A Still Evolving Concept with New Regulatory Challenges

Physiological & neuro-psychology, biopsycholog

Feasibility and Safety of Continuous and Chronic Bilateral Deep Brain Stimulation of the Medial Forebrain Bundle in the Naïve Sprague-Dawley Rat

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

Review: Neurorehabilitation With Neural Transplantation

Cell replacement therapy has been tested clinically in Parkinson’s disease (PD) and Huntington’s disease (HD), epilepsy, spinal cord injury, and stroke. The clinical outcomes have been variable, perhaps partly because of the differing levels of preclinical, basic experimental evidence that was available prior to the trials. The most promising results have been seen in PD trials, with encouraging ones in HD. A common feature of most trials is that they have concentrated on the biological and technical aspects of transplantation without presupposing that the outcomes might be influenced by events after the surgery. The growing evidence of plasticity demonstrated by the brain and grafts in response to environmental and training stimuli such as rehabilitation interventions has been mostly neglected throughout the clinical application of cell therapy. This review suggests that a different approach may be required to maximize recovery: postoperative experiences, including rehabilitation with explicit behavioral retraining, could have marked direct as well as positive secondary effects on the integration and function of grafted cells in the host neural system. The knowledge gained about brain plasticity following brain damage needs to be linked with what we know about promoting intrinsic recovery processes and how this can boost neurobiological and surgical strategies for repair at the clinical level. With proof of principle now established, a rich area for innovative research with profound therapeutic application is open for investigation

New Insights into In Vivo Dopamine Physiology and Neurostimulation: A Fiber Photometry Study Highlighting the Impact of Medial Forebrain Bundle Deep Brain Stimulation on the Nucleus Accumbens

New technologies, such as fiber photometry, can overcome long-standing methodological limitations and promote a better understanding of neuronal mechanisms. This study, for the first time, aimed at employing the newly available dopamine indicator (GRABDA2m) in combination with this novel imaging technique. Here, we present a detailed methodological roadmap leading to longitudinal repetitive transmitter release monitoring in in vivo freely moving animals and provide proof-of-concept data. This novel approach enables a fresh look at dopamine release patterns in the nucleus accumbens, following the medial forebrain bundle (mfb) DBS in a rodent model. Our results suggest reliable readouts of dopamine levels over at least 14 days of DBS-induced photometric measurements. We show that mfb-DBS can elicit an increased dopamine response during stimulation (5 s and 20 s DBS) compared to its baseline dopamine activity state, reaching its maximum peak amplitude in about 1 s and then recovering back after stimulation. The effect of different DBS pulse widths (PWs) also suggests a potential differential effect on this neurotransmitter response, but future studies would need to verify this. Using the described approach, we aim to gain insights into the differences between pathological and healthy models and to elucidate more exhaustively the mechanisms under which DBS exerts its therapeutic action

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

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

“The Heart Asks Pleasure First”—Conceptualizing Psychiatric Diseases as MAINTENANCE Network Dysfunctions through Insights from slMFB DBS in Depression and Obsessive–Compulsive Disorder

More than a decade ago, deep brain stimulation (DBS) of the superolateral medial forebrain bundle (slMFB), as part of the greater MFB system, had been proposed as a putative yet experimental treatment strategy for therapy refractory depression (TRD) and later for obsessive–compulsive disorders (OCD). Antidepressant and anti-OCD efficacy have been shown in open case series and smaller trials and were independently replicated. The MFB is anato-physiologically confluent with the SEEKING system promoting euphoric drive, reward anticipation and reward; functions realized through the mesocorticolimbic dopaminergic system. Growing clinical experience concerning surgical and stimulation aspects from a larger number of patients shows an MFB functionality beyond SEEKING and now re-informs the scientific rationale concerning the MFB’s (patho-) physiology. In this white paper, we combine observations from more than 75 cases of slMFB DBS. We integrate these observations with a selected literature review to provide a new neuroethological view on the MFB. We here formulate a re-interpretation of the MFB as the main structure of an integrated SEEKING/MAINTENANCE circuitry, allowing for individual homeostasis and well-being through emotional arousal, basic and higher affect valence, bodily reactions, motor programing, vigor and flexible behavior, as the basis for the antidepressant and anti-OCD efficacy