Optogenetic stimulation of ventral tegmental area dopaminergic neurons in a female rodent model of depression: The effect of different stimulation patterns.

Major depressive disorder is one of the most common mental disorders, and more than 300 million of people suffer from depression worldwide. Recent clinical trials indicate that deep brain stimulation of the superolateral medial forebrain bundle (mfb) can have rapid and long-term antidepressant effects in patients with treatment-resistant depression. However, the mechanisms of action are elusive. In this study, using female rats, we demonstrate the antidepressant effects of selective optogenetic stimulation of the ventral tegmental area's dopaminergic (DA) neurons passing through the mfb and compare different stimulation patterns. Chronic mild unpredictable stress (CMUS) induced depressive-like, but not anxiety-like phenotype. Short-term and long-term stimulation demonstrated antidepressant effect (OSST) and improved anxiolytic effect (EPM), while long-term stimulation during CMUS induction prevented depressive-like behavior (OSST and USV) and improved anxiolytic effect (EPM). The results highlight that long-term accumulative stimulation on DA pathways is required for antidepressant and anxiolytic effect.

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

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.

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

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.

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

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.

In Search for a Pathogenesis of Major Depression and Suicide-A Joint Investigation of Dopamine and Fiber Tract Anatomy Focusing on the Human Ventral Mesencephalic Tegmentum: Description of a Workflow.

Major depressive disorder (MDD) is prevalent with a high subjective and socio-economic burden. Despite the effectiveness of classical treatment methods, 20-30% of patients stay treatment-resistant. Deep Brain Stimulation of the superolateral branch of the medial forebrain bundle is emerging as a clinical treatment. The stimulation region (ventral tegmental area, VTA), supported by experimental data, points to the role of dopaminergic (DA) transmission in disease pathology. This work sets out to develop a workflow that will allow the performance of analyses on midbrain DA-ergic neurons and projections in subjects who have committed suicide. Human midbrains were retrieved during autopsy, formalin-fixed, and scanned in a Bruker MRI scanner (7T). Sections were sliced, stained for tyrosine hydroxylase (TH), digitized, and integrated into the Montreal Neurological Institute (MNI) brain space together with a high-resolution fiber tract atlas. Subnuclei of the VTA region were identified. TH-positive neurons and fibers were semi-quantitatively evaluated. The study established a rigorous protocol allowing for parallel histological assessments and fiber tractographic analysis in a common space. Semi-quantitative readings are feasible and allow the detection of cell loss in VTA subnuclei. This work describes the intricate workflow and first results of an investigation of DA anatomy in VTA subnuclei in a growing naturalistic database.

Reserpine-induced rat model for depression: Behavioral, physiological and PET-based dopamine receptor availability validation.

BACKGROUND: Reserpine (RES), a Vesicular Monoamine Transporter 2 (VMAT2) inhibitor agent, has been used in preclinical research for many years to create animal models for depression and to test experimental antidepressant strategies. Nevertheless, evidence of the potential use and validity of RES as a chronic pharmacological model for depression is lacking, and there are no comprehensive studies of the behavioral effects in conjunction with molecular outcomes. METHODS: Experiment 1. Following baseline behavior testing sensitive to depression-like phenotype and locomotion (Phase 1), 27 Sprague-Dawley (SD) rats received i.p. either vehicle solution (0.0 mg/kg), low (0.2 mg/kg) or high (0.8 mg/kg) RES dose for 20 days using a pre-determined schedule and reassessed for behavioral phenotypes (Phase 2). After 10 days washout period, and a final behavioral assessment (Phase 3), the brains were collected 16 days after the last injection for mRNA-expression assessment. Experiment 2. In a similar timetable as in Experiment 1 but without the behavioral testing, 12 SD rats underwent repetitive dopamine D2/3 receptor PET scanning with [18F]DMFP following each Phase. The binding potential (BPND) of [18F]DMFP was quantified by kinetic analysis as a marker of striatal D2/3R availability. Weight and welfare were monitored throughout the study. RESULTS: Significant, dose-dependent weight loss and behavioral deficits including both motor (hypo-locomotion) and non-motor behavior (anhedonia, mild anxiety and reduced exploration) were found for both the low and high dose groups with significant decrease in D2R mRNA expression in the accumbal region for the low RES group after Phase 3. Both RES treated groups showed substantial increase in [18F]DMFP BPND (in line with dopamine depletion) during Phase 2 and 3 compared to baseline and Controls. CONCLUSIONS: The longitudinal design of the study demonstrated that chronic RES administration induced striatal dopamine depletion that persisted even after the wash-out period. However, the behavior phenotype observed were transient. The data suggest that RES administration can induce a rodent model for depression with mild face validity.

Tomographic tract tracing and data driven approaches to unravel complex 3D fiber anatomy of DBS relevant prefrontal projections to the diencephalic-mesencephalic junction in the marmoset.

BACKGROUND: Understanding prefrontal cortex projections to diencephalic-mesencephalic junction (DMJ), especially to subthalamic nucleus (STN) and ventral mesencephalic tegmentum (VMT) helps our comprehension of Deep Brain Stimulation (DBS) in major depression (MD) and obsessive-compulsive disorder (OCD). Fiber routes are complex and tract tracing studies in non-human primate species (NHP) have yielded conflicting results. The superolateral medial forebrain bundle (slMFB) is a promising target for DBS in MD and OCD. It has become a focus of criticism owing to its name and its diffusion weighted-imaging based primary description. OBJECTIVE: To investigate DMJ connectivity in NHP with a special focus on slMFB and the limbic hyperdirect pathway utilizing three-dimensional and data driven techniques. METHODS: We performed left prefrontal adeno-associated virus - tracer based injections in the common marmoset monkey (n = 52). Histology and two-photon microscopy were integrated into a common space. Manual and data driven cluster analyses of DMJ, subthalamic nucleus and VMT together, followed by anterior tract tracing streamline (ATTS) tractography were deployed. RESULTS: Typical pre- and supplementary motor hyperdirect connectivity was confirmed. The advanced tract tracing unraveled the complex connectivity to the DMJ. Limbic prefrontal territories directly projected to the VMT but not STN. DISCUSSION: Intricate results of tract tracing studies warrant the application of advanced three-dimensional analyses to understand complex fiber-anatomical routes. The applied three-dimensional techniques can enhance anatomical understanding also in other regions with complex fiber anatomy. CONCLUSION: Our work confirms slMFB anatomy and enfeebles previous misconceptions. The rigorous NHP approach strengthens the role of the slMFB as a target structure for DBS predominantly in psychiatric indications like MD and OCD.

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

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.

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.

"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.

Diverging prefrontal cortex fiber connection routes to the subthalamic nucleus and the mesencephalic ventral tegmentum investigated with long range (normative) and short range (ex-vivo high resolution) 7T DTI.

Uncertainties concerning anatomy and function of cortico-subcortical projections have arisen during the recent years. A clear distinction between cortico-subthalamic (hyperdirect) and cortico-tegmental projections (superolateral medial forebrain bundle, slMFB) so far is elusive. Deep Brain Stimulation (DBS) of the slMFB (for major depression, MD and obsessive compulsive disorders, OCD) has on the one hand been interpreted as actually involving limbic (prefrontal) hyperdirect pathways. On the other hand slMFB's stimulation region in the mesencephalic ventral tegmentum is said to impact on other structures too, going beyond the antidepressant (or anti OCD) efficacy of sole modulation of the cortico-tegmental reward-associated pathways. We have here used a normative diffusion MRT template (HCP, n = 80) for long-range tractography and augmented this dataset with ex-vivo high resolution data (n = 1) in a stochastic brain space. We compared this data with histological information and used the high resolution ex-vivo data set to scrutinize the mesencephalic tegmentum for small fiber pathways present. Our work resolves an existing ambiguity between slMFB and prefrontal hyperdirect pathways which-for the first time-are described as co-existent. DBS of the slMFB does not appear to modulate prefrontal hyperdirect cortico-subthalamic but rather cortico-tegmental projections. Smaller fiber structures in the target region-as far as they can be discerned-appear not to be involved in slMFB DBS. Our work enfeebles previous anatomical criticism and strengthens the position of the slMFB DBS target for its use in MD and OCD.

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

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.

Enhanced adenosine A1 receptor and Homer1a expression in hippocampus modulates the resilience to stress-induced depression-like behavior.

Resilience to stress is critical for the development of depression. Enhanced adenosine A1 receptor (A1R) signaling mediates the antidepressant effects of acute sleep deprivation (SD). However, chronic SD causes long-lasting upregulation of brain A1R and increases the risk of depression. To investigate the effects of A1R on mood, we utilized two transgenic mouse lines with inducible A1R overexpression in forebrain neurons. These two lines have identical levels of A1R increase in the cortex, but differ in the transgenic A1R expression in the hippocampus. Switching on the transgene promotes robust antidepressant and anxiolytic effects in both lines. The mice of the line without transgenic A1R 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 A1R 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 A1R 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.

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

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.

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

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.

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

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.

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

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.

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.

Rehabilitation training in neural restitution.

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.