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The motor symptoms of Parkinson's disease (PD) are caused by the progressive loss of dopamine neurons from the substantia nigra. There are currently no treatments that can slow or reverse the neurodegeneration. To restore the lost neurons, international groups have initiated clinical trials using human embryonic or induced pluripotent stem cells (PSCs) to derive dopamine neuron precursors that are used as transplants to replace the lost neurons. Proof-of-principle experiments in the 1980s and 1990s showed that grafts of fetal ventral mesencephalon, which contains the precursors of the substantial nigra, could, under rare circumstances, reverse symptoms of the disease. Improvements in PSC technology and genomics have inspired researchers to design clinical trials using PSC-derived dopamine neuron precursors as cell replacement therapy for PD. We focus here on 4 such first-in-human clinical trials that have begun in the US, Europe, and Japan. We provide an overview of the sources of PSCs and the methods used to generate cells for transplantation. We discuss pros and cons of strategies for allogeneic, immune-matched, and autologous approaches and novel methods for overcoming rejection by the immune system. We consider challenges for safety and efficacy of the cells for durable engraftment, focusing on the genomics-based quality control methods to assure that the cells will not become cancerous. Finally, since clinical trials like these have never been undertaken before, we comment on the value of cooperation among rivals to contribute to advancements that will finally provide relief for the millions suffering from the symptoms of PD., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Huntington's disease is caused by a CAG repeat expansion in the first exon of the HTT gene, leading to the production of gain-of-toxic-function mutant huntingtin protein species and consequent transcriptional dysregulation and disrupted cell metabolism. The brunt of the disease process is borne by the striatum from the earliest disease stages, with striatal atrophy beginning approximately a decade prior to the onset of neurologic signs. Although the expanded CAG repeat in the HTT gene is necessary and sufficient to cause HD, other genes can influence the age at onset of symptoms and how they progress. Many of these modifier genes have roles in DNA repair and are likely to modulate the stability of the CAG repeat in somatic cells. Currently, there are no disease-modifying treatments for HD that can be prescribed to patients and few symptomatic treatments, but there is a lot of interest in therapeutics that can target the pathogenic pathways at the DNA and RNA levels, some of which have reached the stage of human studies. In contrast, cell therapies aim to replace key neural cells lost to the disease process and/or to support the host vulnerable striatum by direct delivery of cells to the brain. Ultimately it may be possible to combine gene and cell therapies to both slow disease processes and provide some level of neural repair. In this chapter we consider the current status of these therapeutic strategies along with their prospects and challenges., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Dysregulated cholesterol metabolism has been linked to neurodegeneration. We previously found that free, non-esterified, 7α,(25 R )26-dihydroxycholesterol (7α,26-diHC), was significantly elevated in the cerebrospinal fluid of patients with Parkinson's disease (PD). In this study we investigated the role of 7α,26-diHC in midbrain dopamine (mDA) neuron development and survival. We report that 7α,26-diHC induces apoptosis and reduces the number of mDA neurons in hESC-derived cultures and in mouse progenitor cultures. Voriconazole, an oxysterol 7α-hydroxylase (CYP7B1) inhibitor, increases the number of mDA neurons and prevents the loss of mDA neurons induced by 7α,26-diHC. These effects are specific since neither 7α,26-diHC nor voriconazole alter the number of Islet1 + oculomotor neurons. Furthermore, our results suggest that elevated 24( S ),25-epoxycholesterol, which has been shown to promote mDA neurogenesis, may be partially responsible for the effect of voriconazole on mDA neurons. These findings suggest that voriconazole, and/or other azole CYP7B1 inhibitors may have implications in PD therapy development., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: WJG and YW are listed as inventors on the patent “Kit and method for the quantitative detection of steroids” US9851368B2. WJG, EY, YW and ST are shareholders in CholesteniX Ltd., (© 2023 The Authors.)

Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5-mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2-ERK1/2 interactions., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Dopamine transmission has been implicated in motor and cognitive function. In Parkinson's disease (PD), dopamine replacement using the precursor drug L-DOPA is the predominant treatment approach, but long-term exposure leads to the onset of dyskinesias (LIDs). Chronic L-DOPA exposure has been associated with changes in gene expression and altered cortico-striatal plasticity. The aim of this research was to assess the functional consequence of long-term L-DOPA exposure on cognitive and motor function using a rodent model of PD. Across two independent experiments, we assessed the impact of chronic L-DOPA exposure, or a control D 2 R agonist, on motor and cognitive function in intact and in hemi parkinsonian rats, in the absence of drug. Abnormal involuntary movements associated with LID were measured and brain tissues were subsequently harvested for immunohistochemical analysis. Exposure to chronic L-DOPA, but not the D 2 R agonist, impaired motor and cognitive function, when animals were tested in the absence of drug. A meta-analysis of the two experiments allowed further dissociation of L-DOPA -treated rats into those that developed LIDs (dyskinetic) and those that did not develop LIDs (non-dyskinetic). This analysis revealed impaired cognitive and motor performance were evident only in dyskinetic, but not in non-dyskinetic, rats. These data reveal a functional consequence of the altered plasticity associated with LID onset and have implications for understanding symptom progression in the clinic., (© 2023. Springer Nature Limited.)

The Stroop test is a widely used neuropsychological test measuring attention and conflict resolution, which shows sensitivity across a range of diseases, including Alzheimer's, Parkinson's and Huntington's diseases. A rodent analogue of the Stroop test, the Response-Conflict task (rRCT), allows for systematic investigation of the neural systems underpinning performance in this test. Little is known about the involvement of the basal ganglia in this neural process. The aim of this study was to use the rRCT to determine whether striatal subregions are recruited during conflict resolution processing. To achieve this, rats were exposed to Congruent or Incongruent stimuli in the rRCT and the expression patterns of the immediate early gene Zif268 were analysed throughout cortical, hippocampal and basal ganglia subregions. The results confirmed the previously reported involvement of prefrontal cortical and hippocampal regions, as well as identifying a specific role for the dysgranular (but not granular) retrosplenial cortex in conflict resolution. Finally, performance accuracy correlated significantly with reduced neural activation in the dorsomedial striatum. Involvement of the basal ganglia in this neural process has not previously been reported. These data demonstrate that the cognitive process of conflict resolution requires not only prefrontal cortical regions, but also recruits the dysgranular retrosplenial cortex and the medial region of the neostriatum. These data have implications for understanding the neuroanatomical changes that underpin impaired Stroop performance in people with neurological disorders., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The feeding-related hormone, acyl-ghrelin, protects dopamine neurones in murine 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-based models of experimental Parkinson's disease (PD). However, the potential protective effect of acyl-ghrelin on substantia nigra pars compacta (SNpc) dopaminergic neurones and consequent behavioural correlates in the more widely used 6-hydroxydopamine (6-OHDA) rat medial forebrain bundle (MFB) lesion model of PD are unknown. To address this question, acyl-ghrelin levels were raised directly by mini-pump infusion for 7 days prior to unilateral injection of 6-OHDA into the MFB with assessment of amphetamine-induced rotations on days 27 and 35, and immunohistochemical analysis of dopaminergic neurone survival. Whilst acyl-ghrelin treatment was insufficient to elevate food intake or body weight, it attenuated amphetamine-induced circling behaviour and SNpc dopamine neurone loss induced by 6-OHDA. These data support the notion that elevating circulating acyl-ghrelin may be a valuable approach to slow or impair progression of neurone loss in PD., (© 2022. The Author(s).)

Transplantation of human induced pluripotent stem cell-derived dopaminergic (iPSC-DA) neurons is a promising therapeutic strategy for Parkinson's disease (PD). To assess optimal cell characteristics and reproducibility, we evaluated the efficacy of iPSC-DA neuron precursors from two individuals with sporadic PD by transplantation into a hemiparkinsonian rat model after differentiation for either 18 (d18) or 25 days (d25). We found similar graft size and dopamine (DA) neuron content in both groups, but only the d18 cells resulted in recovery of motor impairments. In contrast, we report that d25 grafts survived equally as well and produced grafts rich in tyrosine hydroxylase-positive neurons, but were incapable of alleviating any motor deficits. We identified the mechanism of action as the extent of neurite outgrowth into the host brain, with d18 grafts supporting significantly more neurite outgrowth than nonfunctional d25 grafts. RNAseq analysis of the cell preparation suggests that graft efficacy may be enhanced by repression of differentiation-associated genes by REST, defining the optimal predifferentiation state for transplantation. This study demonstrates for the first time that DA neuron grafts can survive well in vivo while completely lacking the capacity to induce recovery from motor dysfunction. In contrast to other recent studies, we demonstrate that neurite outgrowth is the key factor determining graft efficacy and our gene expression profiling revealed characteristics of the cells that may predict their efficacy. These data have implication for the generation of DA neuron grafts for clinical application.

First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy. Here, we consider some of these outstanding questions, including our understanding of the interaction between anti-Parkinsonian medication and the neural transplant, the impact of the cell therapy on cognitive or neuropsychiatric symptoms of PD, the role of neuroinflammation in the therapeutic process and the development of graft-induced dyskinesias. We identify questions that are currently pertinent to the field that require further exploration, and pave the way for a more holistic understanding of this neural repair strategy for treatment of PD., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Advanced therapeutic medicinal products (ATMPs), including cell and gene therapies, are in development for Parkinson's disease (PD). In many cases, the goal is to replace the lost dopamine (DA), which is anticipated to improve motor dysfunctions associated with DA loss. However, it is less clear the extent to which these therapeutic interventions may impact on the wide range of cognitive symptoms that manifest as the disease progresses. Although the accepted perception is that cognitive symptoms are predominately non-DAergic in origin, in this commentary, it is argued that several, specific cognitive processes, such as habit formation, working memory and reward processing, have been reported to be DA-dependent. Furthermore, there is evidence of DAergic medications modulating these behaviours in PD patients. Finally, the potential for cell and gene ATMPs to influence these symptoms is considered. It is concluded that DA replacement through ATMPs is likely to improve certain DA-dependent symptoms, but only sparse clinical data are currently available and the ability to precisely titrate DA transmission is likely to be complex., Competing Interests: The author declares no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Background: The risk of graft-induced dyskinesias (GIDs) presents a major challenge in progressing cell transplantation as a therapy for Parkinson's disease. Current theories implicate the presence of grafted serotonin neurons, hotspots of dopamine release, neuroinflammation and established levodopa-induced dyskinesia., Objective: To elucidate the mechanisms of GIDs., Methods: Neonatally desensitized, dopamine denervated rats received intrastriatal grafts of human embryonic stem cells (hESCs) differentiated into either ventral midbrain dopaminergic progenitor (vmDA) (n = 15) or ventral forebrain cells (n = 14)., Results: Of the eight rats with surviving grafts, two vmDA rats developed chronic spontaneous GIDs, which were observed at 30 weeks post-transplantation. GIDs were inhibited by D 2 -like receptor antagonists and not affected by 5-HT1A/1B/5-HT6 agonists/antagonists. Grafts in GID rats showed more microglial activation and lacked serotonin neurons., Conclusions: These findings argue against current thinking that rats do not develop spontaneous GID and that serotonin neurons are causative, rather indicating that GID can be induced in rats by hESC-derived dopamine grafts and, critically, can occur independently of both previous levodopa exposure and grafted serotonin neurons. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Huntington's disease (HD) is a hereditary, neurodegenerative disorder characterized by a triad of symptoms: motor, cognitive and psychiatric. HD is caused by a genetic mutation, expansion of the CAG repeat in the huntingtin gene, which results in loss of medium spiny neurons (MSNs) of the striatum. Cell replacement therapy (CRT) has emerged as a possible therapy for HD, aiming to replace those cells lost to the disease process and alleviate its symptoms. Initial pre-clinical studies used primary fetal striatal cells to provide proof-of-principal that CRT can bring about functional recovery on some behavioral tasks following transplantation into HD models. Alternative donor cell sources are required if CRT is to become a viable therapeutic option and human pluripotent stem cell (hPSC) sources, which have undergone differentiation toward the MSNs lost to the disease process, have proved to be strong candidates. The focus of this chapter is to review work conducted on the functional assessment of animals following transplantation of hPSC-derived MSNs. We discuss different ways that graft function has been assessed, and the results that have been achieved to date. In addition, this chapter presents and discusses challenges that remain in this field., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cell therapeutics have entered into an exciting era, with first-in-person clinical trials underway for Parkinson's disease and novel cell therapies in development for other neurodegenerative diseases. In the hope of ensuring successful translation of these novel cell products to the clinic, a significant amount of preclinical work continues to be undertaken. Rodent models of neural transplantation are required to thoroughly assess the survival, safety and efficacy of novel therapeutics. It is critical to produce robust and reliable preclinical data, in order to increase the likelihood of clinical success. As a result, significant effort has been driven into generating ever more relevant model systems, from genetically modified disease models to mice with humanized immune systems. Despite this, several challenges remain in the quest to assess human cells in the rodent brain long-term. Here, with a focus on models of Parkinson's and Huntington's disease, we discuss key considerations for choosing an appropriate rodent model for neural transplantation. We also consider the challenges associated with long-term survival and assessment of functional efficacy in these models, as well as the need to consider the clinical relevance of the model. While the choice of model will be dependent on the scientific question, by considering the caveats associated with each model, we identify opportunities to optimize the preclinical assessment and generate reliable data on our novel cell therapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Early CNS transplantation studies used foetal derived cell products to provide a foundation of evidence for functional recovery in preclinical studies and early clinical trials. However, it was soon recognised that the practical limitations of foetal tissue make it unsuitable for widespread clinical use. Considerable effort has since been directed towards producing target cell phenotypes from pluripotent stem cells (PSCs) instead, and there now exist several publications detailing the differentiation and characterisation of PSC-derived products relevant for transplantation in Huntington's disease (HD). In light of this progress, we ask if foetal tissue transplantation continues to be justified in HD research. We argue that (i) the extent to which accurately differentiated target cells can presently be produced from PSCs is still unclear, currently making them undesirable for studying wider CNS transplantation issues; (ii) foetal derived cells remain a valuable tool in preclinical research for advancing our understanding of which products produce functional striatal grafts and as a reference to further improve PSC-derived products; and (iii) until PSC-derived products are ready for human trials, it is important to continue using foetal cells to gather clinical evidence that transplantation is a viable option in HD and to use this opportunity to optimise practical parameters (such as trial design, clinical practices, and delivery strategies) to pave the way for future PSC-derived products., Competing Interests: The authors declare that there are no competing interests associated with the manuscript., (© 2021 The Author(s).)

The basal ganglia are implicated in a wide range of motor, cognitive and behavioral activities required for normal function. This region is predominantly affected in Huntington's disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD ( n = 64) and healthy controls ( n = 21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behavior, and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson's correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behavior, and function. The MBT provides a valid, sensitive, and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials.

In Huntington's disease (HD), the medium spiny projection neurons of the neostriatum degenerate early in the course of the disease. While genetic mutant models of HD provide an excellent resource for studying the molecular and cellular effects of the inherited polyQ huntingtin mutation, they do not typically present with overt atrophy of the basal ganglia, despite this being a major pathophysiological hallmark of the disease. By contrast, excitotoxic lesion models, which use quinolinic acid to specifically target the striatal projection neurons, are employed to study the functional consequences of striatal atrophy and to investigate potential therapeutic interventions that target the neuronal degeneration. This chapter provides a detailed guide to the generation of excitotoxic lesion models of HD in rats.

Stem cell treatments for neurodegenerative diseases are expected to reach clinical trials soon. Most of the approaches currently under development involve transplantation of immature progenitors that subsequently undergo phenotypic and functional maturation in vivo, and predicting the long-term graft outcome already at the progenitor stage remains a challenge. Here, we took an unbiased approach to identify predictive markers expressed in dopamine neuron progenitors that correlate with graft outcome in an animal model of Parkinson's disease through gene expression analysis of >30 batches of grafted human embryonic stem cell (hESC)-derived progenitors. We found that many of the commonly used markers did not accurately predict in vivo subtype-specific maturation. Instead, we identified a specific set of markers associated with the caudal midbrain that correlate with high dopaminergic yield after transplantation in vivo. Using these markers, we developed a good manufacturing practice (GMP) differentiation protocol for highly efficient and reproducible production of transplantable dopamine progenitors from hESCs., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Huntington's disease (HD) is an incurable neurodegenerative disorder which causes a triad of motor, cognitive and psychiatric disturbances. Cognitive disruptions are a core feature of the disease, which significantly affect daily activities and quality of life, therefore cognitive training interventions present an exciting therapeutic intervention possibility for HD. We aimed to determine if specific cognitive training, in an operant task of attention, modifies the subsequent behavioural and neuropathological phenotype of the Hdh(Q111) mouse model of HD. Three testing groups comprising both Hdh(Q111) mice and wildtype controls were used. The first group received cognitive training in an operant task of attention at 4months of age. The second group received cognitive training in a comparable non-attentional operant task at 4months of age, and the third group were control animals that did not receive cognitive training. All groups were then tested in an operant task of attention at 12months of age. Relative to naïve untrained mice, both wildtype and Hdh(Q111) mice that received cognitive training in the operant task of attention demonstrated an increased number of trials initiated, greater accuracy, and fewer 'time out' errors. A specific improvement in response time performance was observed in Hdh(Q111) mice, relative to naïve untrained Hdh(Q111) mice. Relative to the group that received comparable training in a non-attentional task, both wildtype and Hdh(Q111) mice that received attentional training demonstrated superior accuracy in the task and made fewer 'time out' errors. Despite significant behavioural change, in both wildtype and Hdh(Q111) mice that had received cognitive training, no significant changes in neuropathology were observed between any of the testing groups. These results demonstrate that attentional cognitive training implemented at a young age significantly improves attentional performance, at an older age, in both wildtype and Hdh(Q111) mice. Attentional cognitive training also improved motor performance in Hdh(Q111) mice, thus leading to the conclusion that cognitive training can improve disease symptoms in a mouse model of HD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Although rheumatoid arthritis (RA) is a disease of articular joints, patients often suffer from co-morbid neuropsychiatric changes, such as anxiety, that may reflect links between heightened systemic inflammation and abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we apply behavioral neuroscience methods to assess the impact of antigen-induced arthritis (AIA) on behavioral performance in wild type (WT) and interleukin-10 deficient ( Il10 -/- ) mice. Our aim was to identify limb-specific motor impairments, as well as neuropsychological responses to inflammatory arthritis., Methods: Behavioral testing was performed longitudinally in WT and Il10 -/- mice before and after the induction of arthritic joint pathology. Footprint analysis, beam walking and open field assessment determined a range of motor, exploratory and anxiety-related parameters. Specific gene changes in HPA axis tissues were analyzed using qPCR., Results: Behavioral assessment revealed transient motor and exploratory impairments in mice receiving AIA, coinciding with joint swelling. Hind limb coordination deficits were independent of joint pathology. Behavioral impairments returned to baseline by 10 days post-AIA in WT mice. Il10 -/- mice demonstrated comparable levels of swelling and joint pathology as WT mice up to 15 days post-AIA, but systemic differences were evident in mRNA expression in HPA axis tissues from Il10 -/- mice post-AIA. Interestingly, the behavioral profile of Il10 -/- mice revealed a significantly longer time post-AIA for activity and anxiety-related behaviors to recover., Conclusions: The novel application of sensitive behavioral tasks has enabled dissociation between behaviors that occur due to transient joint-specific pathology and those generated by more subtle systemic alterations that manifest post-AIA., Competing Interests: Competing Interests The author(s) declare that they have no competing interests. The authors report no conflicting interests.

Background: Patients suffering from Parkinson's disease (PD) display cognitive and neuropsychiatric dysfunctions, especially with disease progression. Although these impairments have been reported to impact more heavily upon a patient's quality of life than any motor dysfunctions, there are currently no interventions capable of adequately targeting these non-motor deficits., Objectives: Utilizing a rodent model of PD, we investigated whether cell replacement therapy, using intrastriatal transplants of human-derived ventral mesencephalic (hVM) grafts, could alleviate cognitive and neuropsychiatric, as well as motor, dysfunctions., Methods: Rats with unilateral 6-hydroxydopamine lesions to the medial forebrain bundle were tested on a complex operant task that dissociates motivational, visuospatial and motor impairments sensitive to the loss of dopamine. A subset of lesioned rats received intrastriatal hVM grafts of ~9 weeks gestation. Post-graft, rats underwent repeated drug-induced rotation tests and were tested on two versions of the complex operant task, before post-mortem analysis of the hVM tissue grafts., Results: Post-graft behavioural testing revealed that hVM grafts improved non-motor aspects of task performance, specifically visuospatial function and motivational processing, as well as alleviating motor dysfunctions., Conclusions: We report the first evidence of human VM cell grafts alleviating both non-motor and motor dysfunctions in an animal model of PD. This intervention, therefore, is the first to improve cognitive and neuropsychiatric symptoms long-term in a model of PD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Huntington's disease (HD) is a debilitating, genetically inherited neurodegenerative disorder that results in early loss of medium spiny neurons from the striatum and subsequent degeneration of cortical and other subcortical brain regions. Behavioral changes manifest as a range of motor, cognitive, and neuropsychiatric impairments. It has been established that replacement of the degenerated medium spiny neurons with rat-derived fetal whole ganglionic eminence (rWGE) tissue can alleviate motor and cognitive deficits in preclinical rodent models of HD. However, clinical application of this cell replacement therapy requires the use of human-derived (hWGE), not rWGE, tissue. Despite this, little is currently known about the functional efficacy of hWGE. The aim of this study was to directly compare the ability of the gold standard rWGE grafts, against the clinically relevant hWGE grafts, on a range of behavioral tests of motor function. Lister hooded rats either remained as unoperated controls or received unilateral excitotoxic lesions of the lateral neostriatum. Subsets of lesioned rats then received transplants of either rWGE or hWGE primary fetal tissue into the lateral striatum. All rats were tested postlesion and postgraft on the following tests of motor function: staircase test, apomorphine-induced rotation, cylinder test, adjusting steps test, and vibrissae-evoked touch test. At 21 weeks postgraft, brain tissue was taken for histological analysis. The results revealed comparable improvements in apomorphine-induced rotational bias and the vibrissae test, despite larger graft volumes in the hWGE cohort. hWGE grafts, but not rWGE grafts, stabilized behavioral performance on the adjusting steps test. These results have implications for clinical application of cell replacement therapies, as well as providing a foundation for the development of stem cell-derived cell therapy products.

Although episodic memory deficits are the most conspicuous cognitive change in patients with Alzheimer's disease (AD), patients also display alterations in emotional expression, including anxiety and impaired conditioned fear behaviours. The neural circuitry underlying emotional learning is known to involve the amygdala and hippocampus, although the precise impact of amyloid pathology on the interaction between these brain regions remains unclear. Recent evidence suggests that Tg2576 mice, which express a human amyloid precursor protein (APP) mutation associated with early-onset AD, demonstrate normal acquisition of conditioned freezing to auditory and contextual stimuli paired with footshock. However, examination of the expression of c-Fos revealed altered neural network activity in transgenic mice. In the present study we examined the effects of the APP mutation on the expression of c-Fos following the retrieval of emotional memories. To this end, stimulus-induced cellular activity was measured by analysing expression of the immediate-early gene c-Fos after the retrieval of auditory or contextual fear memories. To characterize regional interdependencies of c-Fos expression, structural equation modelling was used to compare patterns of neural network activity. Consistent with previous findings, Tg2576 mice displayed reduced freezing elicited by the auditory stimulus but not by the conditioning context. Interestingly, the analysis of c-Fos expression revealed that the APPswe mutation disrupted dentate gyrus and amygdala function, as well as altering the influence of these regions on the neural network dynamics activated during context memory retrieval. These results provide novel insight into the influence of excess amyloid production on neural network activity during memory retrieval., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Despite recent recognition of the complexity of the motor and nonmotor dysfunctions that manifest in Parkinson's disease, the propensity of drugs to alleviate the dopamine-dependent symptoms in the 6-hydroxydopamine rat model is still typically being assessed using relatively simple measures of motor function. We investigated the ability of the D2 agonist, bromocriptine, to ameliorate impairments in a more complex operant task, which simultaneously assessed both motor and nonmotor deficits. Rats were trained on a lateralized choice reaction time task that has previously been found to be sensitive to dopamine depletion. One subgroup of rats was then given unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. Once they exhibited stable postlesion deficits, the rats in the lesion group were administered bromocriptine (1.25 mg/kg) 120 min before testing. Bromocriptine induced a transient improvement in motor function but most notably produced a persistent improvement in the accuracy of performance in the task. The improvement in response initiation and selection persisted on testing in the absence of bromocriptine and was not reversed by the D2 antagonist, raclopride (0.2 mg/kg). These results may reflect a conditioning effect of bromocriptine on operant behaviour.

Aberrant striatal function results in an array of physiological symptoms, including impaired consummatory and regulatory behaviours, which can lead to weight loss and dehydration. It was hypothesised, therefore, that cell loss in the neostriatum may contribute to altered fluid intake by regulating physiological signals related to dehydration status. To test this theory, rats with lesions of the lateral neostriatum and sham controls underwent a series of physiological challenges, including the experimental induction of intracellular and intravascular dehydration. No baseline differences in prandial or non-prandial drinking were observed, nor were differences in locomotor activity evident between groups. Furthermore, intracellular dehydration increased water intake in lesion rats in a manner comparable to sham rats. Interestingly, a specific impairment was evident in lesion rats after subcutaneous injection of poly-ethylene glycol was used to induce intravascular dehydration, such that lesion rats failed to adapt their water intake to this physiological change. The results suggest that the striatal lesions resulted in regulatory dysfunction by impairing motivational control over compensatory ingestive behaviour after intravascular hydration, while the physiological signals related to dehydration remain intact. Loss of these cells in neurodegenerative disorders, such Huntington's disease, may contribute to regulatory changes evident in the course of the disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Unilateral infusion of 6-hydroxydopamine into the nigro-striatal pathway in the rat is the most common dopamine lesion model of Parkinson's disease. In the present study, we explore the impact of near complete unilateral loss of dopamine along the nigro-striatal pathway and subsequent cell replacement therapy in a choice reaction time task in rats, with assessment of spatial responding towards either side of the body (ipsilateral or contralateral to the lesion) on alternate days. Results indicated a stable contralateral deficit in response accuracy, reaction times and motor function for 50 consecutive days of testing, with no signs of recovery or compensation. All lesioned rats developed a near-hole bias and displayed prolonged movement and reaction times when responses had to be directed towards a distal response location on the side of the body contralateral to the lesion, as well as a smaller ipsilateral impairment in response accuracy and movement times. Grafts of dopamine-rich tissue into the denervated striatum improved some, but not all, of the deficits induced by the lesion. Specifically, grafted rats performed at a similar level to control animals when assessed on the ipsilateral side, they demonstrated a partial restitution of their ability to respond to far contralateral stimuli, and they exhibited a marked reduction in the time to complete all lateralised responses on both sides. The present characterisation of the task and the effects of cell replacement via primary fetal mesencephalic tissue demonstrate restorative properties in alleviating the marked spatial response bias induced by unilateral loss of dopamine., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Medium-sized spiny neurons (MSNs) are the only neostriatum projection neurons, and their degeneration underlies some of the clinical features of Huntington's disease. Using knowledge of human developmental biology and exposure to key neurodevelopmental molecules, human pluripotent stem (hPS) cells were induced to differentiate into MSNs. In a feeder-free adherent culture, ventral telencephalic specification is induced by BMP/TGFβ inhibition and subsequent SHH/DKK1 treatment. The emerging FOXG1(+)/GSX2(+) telencephalic progenitors are then terminally differentiated, resulting in the systematic line-independent generation of FOXP1(+)/FOXP2(+)/CTIP2(+)/calbindin(+)/DARPP-32(+) MSNs. Similar to mature MSNs, these neurons carry dopamine and A2a receptors, elicit a typical firing pattern and show inhibitory postsynaptic currents, as well as dopamine neuromodulation and synaptic integration ability in vivo. When transplanted into the striatum of quinolinic acid-lesioned rats, hPS-derived neurons survive and differentiate into DARPP-32(+) neurons, leading to a restoration of apomorphine-induced rotation behavior. In summary, hPS cells can be efficiently driven to acquire a functional striatal fate using an ontogeny-recapitulating stepwise method that represents a platform for in vitro human developmental neurobiology studies and drug screening approaches.

Restoration of the damaged central nervous system is a vast challenge. However, there is a great need for research into this topic, due to the prevalence of central nervous system disorders and the devastating impact they have on people's lives. A number of strategies are being examined to achieve this goal, including cell replacement therapy, enhancement of endogenous plasticity and the recruitment of endogenous neurogenesis. The current chapter reviews this topic within the context of Parkinson's disease, Huntington's disease and stroke. For each disease exogenous cell therapies are discussed including primary (foetal) cell transplants, neural stem cells, induced pluripotent stem cells and marrow stromal cells. This chapter highlights the different mechanistic approaches of cell replacement therapy versus cells that deliver neurotropic factors, or enhance the endogenous production of these factors. Evidence of exogenously transplanted cells functionally integrating into the host brain, replacing cells, and having a behavioural benefit are discussed, along with the ability of some cell sources to stimulate endogenous neuroprotective and restorative events. Alongside exogenous cell therapy, the role of endogenous neurogenesis in each of the three diseases is outlined and methods to enhance this phenomenon are discussed.

Dysfunction of the neostriatum, a primary feature of several neurodegenerative disorders, including Parkinson's disease and Huntington's disease, has been found to result in impaired localisation of, and reaction to, contralateral stimuli. On the basis of previous findings, it is hypothesised that, with increasing eccentricity of the response option, striatal cell loss may impair response localisation at the furthest levels of eccentricity, whereas dopamine (DA) depletion may not impact adversely upon responses executed in this extrapersonal space. In order to elucidate more fully the function of the striatum, the present study examined the differential impact of unilateral DA depletion or excitoxic lesion on response execution in ipsilateral and contralateral space at up to four levels of eccentricity. The results confirmed that, after both types of striatal dysfunction, the sensory ability to detect stimuli remains intact, whereas the ability to direct responses in absolute contralateral space is impaired. Distinct differences in the profiles of impairment were, however, evident, with a marked increase in response omissions observed after DA depletion, which may reflect decreased motivational processing, and recovery of function observed in rats with excitotoxic lesions, which suggests the ability to re-learn. Furthermore, the data demonstrate that, after cell loss, responding in near contralateral space is controlled by competing striata, whereas responding in extrapersonal space relies on the contralateral hemisphere. These results have implications for understanding the role of the striatum in egocentrically defined response localisation, as well as for unravelling the behavioural impact of striatal cell loss or aberrant DA transmission observed in neurodegenerative diseases., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Improvements in modelling Parkinson's disease in rodents contribute to the advancement of scientific knowledge and open innumerable pathways for the development of new therapeutic interventions. In a recent article in this journal, Decressac and co-workers present an interesting comparison between two classic 6-hydroxydopamine (6-OHDA) models and the more recently established rodent model of Parkinson's disease induced by over-expression of α-synuclein using adeno-associated viral vectors. As expected, injections of 6-OHDA result in extensive loss of dopamine associated with pronounced motor deficits. Interestingly, over-expression of α-synuclein in the substantia nigra pars compacta also results in a considerable loss of dopamine as well as motor impairments. Both the level of dopamine loss and the motor deficits seen after α-synuclein over-expression were similar in extent to that seen after intrastriatal injections of 6-OHDA, but the temporal profile of degeneration and the development of motor deficits were progressive, more closely mimicking the clinical condition. This commentary offers further insights into the differences between these two rodent models, and asks how well they each replicate idiopathic PD. In addition, the translational relevance, reliability, and predictive value of this more recently developed AAV α-synuclein model are considered., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The neural circuitry underlying emotional learning and memory is known to involve both the amygdala and hippocampus. Both of these structures undergo anatomical and functional changes during the course of Alzheimer's disease. The present study used expression of the immediate early gene c-Fos to examine the effect of amyloid-induced synaptic pathology on neural activity in the hippocampus and amygdala immediately following Pavlovian fear conditioning. Tg2576 mice underwent cued fear conditioning and the regional interdependencies of c-Fos expression in the hippocampus and the amygdala were assessed using structural equation modelling. Tg2576 mice displayed normal acquisition of conditioned freezing to a punctate auditory cue paired with shock. However, the analysis of c-Fos expression indicated abnormal regional activity in the hippocampal dentate gyrus of Tg2576 mice. Structural equation modelling also supported the view that activity within the amygdala was independent of hippocampal activity in Tg2576 mice (unlike control mice) and regional interaction between the dentate gyrus and CA3 region was disrupted. The results provide novel insight into the effects of excess amyloid production on brain region interdependencies underpinning emotional learning., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The unilateral 6-hydroxydopamine mouse lesion models of Parkinson's disease have received increasing attention in recent years, but comparison of the different lesion models was largely focused at a histological level. An extensive behavioural comparison between different mouse models on tests of motor function has yet to be carried out, to pin point tests that accurately discriminate between different extents of dopaminergic depletion. In the present study we examine the consequences of injection of the toxin at three sites along the nigrostriatal tract (substantia nigra, medial forebrain bundle, and striatum) on a broad range of simple motor tasks, and on the dopaminergic pathology. All lesion groups demonstrated marked behavioural deficits and displayed distinct profiles of degeneration along the nigrostriatal dopamine pathway. Tests that correlated closely with the level of substantia nigra cell loss included the corridor, cylinder and balance beam tests, the rotarod, inverted cage lid and three types of rotational assessment (spontaneous, amphetamine-induced and apomorphine-induced). Specific tasks are identified which are capable of distinguishing a near-complete lesion, with amphetamine rotation, corridor and cylinder tests showing the highest correlations with levels of nigral cell loss. Performance in the different behavioural tests was associated with distinct profiles of cell loss in the SN and VTA. We provide a comprehensive behavioural assessment of lesion-induced deficits in mouse models of PD, which should facilitate selection of the most appropriate lesion model and most sensitive behavioural tests for use in future studies investigating therapeutic interventions., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) has long been considered predominantly to be a "movement disorder," and it is only relatively recently that nonmotor symptoms of PD have been recognized to be a major concern to patients. Consequently, there has been surprisingly little investigation into the feasibility of utilizing cell replacement therapies to ameliorate any of the nonmotor dysfunctions of PD. In this chapter, we identify nonmotor impairments associated predominately with dopaminergic dysmodulation, evaluate the few emerging studies that have identified a role for dopamine and nigral transplantation in nonmotor performance, and consider a number of outstanding questions and considerations dominating the field of nigral transplantation today. Preliminary results obtained from rodent models of PD, despite being limited in number, give clear indications of graft effects on striatal processing beyond the simple activation of motor output and promise a major, exciting, and fruitful new avenue of research for the next decade. We can now consider the prospect of rewriting the opportunities for treating patients, with new stem cell sources to be complemented by new targets for therapeutic benefit., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Amyloid-β (Aβ) is cleaved from amyloid precursor protein (APP) predominantly after APP has trafficked through the secretory pathway and then become re-internalised by endocytosis. Clathrin-mediated and, more recently, clathrin-independent endocytosis have both been implicated in this process. Furthermore, endocytic abnormalities have been identified in cases of Alzheimer's disease (AD), however, the relevance of these changes to the aetiology of the disease remains unclear. We therefore examined the expression of proteins related to these endocytic processes in the cortex of Tg2576 mice that overexpress the Swedish mutation in APP, and consequently overexpress Aβ, to determine if there were any changes in their associated pathways. We identified significant increases in the levels of clathrin, dynamin and PICALM, all proteins intimately involved with the clathrin-mediated endocytic pathway, in the transgenic animals. However, levels of proteins associated with flotillin or caveolin-mediated endocytic pathways remained unchanged. These results emphasise the importance of clathrin-mediated endocytosis in the aetiology of AD and reinforce the results of the recent GWAS studies that identified genes for clathrin-mediated endocytosis as susceptibility genes for AD. Such studies in transgenic mice will allow us to learn more about the role of clathrin-mediated endocytosis in AD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Subregions of the neostriatum have been dissociated according to their role in specific aspects of instrumental and Pavlovian learning. While the dorsomedial striatum is critical for the acquisition of goal-directed behaviours, the dorsolateral striatum has been shown to be necessary for the formation of habits. The ventrolateral subregion of the neostriatum (VLS), which supports a distinct cortical-subcortical circuitry, has not, however, been investigated within these paradigms. Thus, to determine whether the VLS is involved in the formation of action-outcome associations, Experiment 1 used a sensory specific devaluation procedure to assess the role of the VLS in the acquisition of goal-directed instrumental behaviours. Experiment 2 examined the ability of VLS lesion rats to form Pavlovian-outcome associations and to adjust responses according to the current incentive value of the reward by using a Pavlovian approach task, while Experiment 3 assessed the development and expression of habitual responding. Results indicated an intact ability of both sham and VLS lesion rats to form instrumental action-outcome associations and to use such representations to direct behaviour according to the incentive value of the outcome. VLS lesion rats equally demonstrated intact development of habitual lever press responses, which were shown to be impervious to lithium chloride devaluation treatment. VLS lesion rats did, however, demonstrate aberrant goal-directed responding to a Pavlovian auditory stimulus after outcome specific devaluation treatment. Thus, these results indicate that the VLS is necessary for utilising a representation of a Pavlovian stimulus-outcome association to direct behaviour according to the current incentive value of a reward., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The onset of Alzheimer's disease (AD) is often accompanied by changes in emotion, motivation, and goal-directed behavior. The production of beta-amyloid is thought to be a major and early contributor to the pathogenesis of AD. The present study tested the hypothesis that amyloid pathology present in the amygdala, frontal cortex, and hippocampus of Tg2576 mice would disrupt the development of instrumental- and/or Pavlovian-outcome associations. The results showed that both instrumental- and Pavlovian-conditioned behaviors were sensitive to outcome devaluation (Experiments 1 & 2) and that Pavlovian cues influenced goal-directed actions associated with the same outcome (Experiment 2) in Tg2576 mice. In contrast, context mediated Pavlovian-conditioned behaviors in aged (Experiment 3a) but not young (Experiment 3b) Tg2576 mice were insensitive to outcome devaluation. Aged Tg2576, nevertheless, successfully acquired a simple context discrimination at the same rate as control mice. We conclude that amyloid pathology in aged Tg2576 mice may specifically disrupt context-outcome associations supported by the hippocampus and/or its interaction with the amygdala.

Due to the relative success of therapeutic interventions aimed at treating the overt motor symptoms evident in Parkinson's disease (PD), a greater appreciation of the non-motor aspects of the disease has emerged in recent time. Indeed, evidence suggests that impairments in emotional processing, behavioural control and cognitive function may emerge early in the onset of the disease. Decades of experimental research have seen the development of diverse animal models, all of which have aimed to mimic the characteristic features of the disease process including the dopaminergic neural cell loss, the molecular neuropathology and the concomitant behavioural impairments. The following review provides an overview of the use of animal, particularly rodent, models in the quest to obtain a greater understanding of the role of corticostriatal dopamine in cognitive and neuropsychiatric functions. Given the limitations of using the available rodent models of PD, including altered motor and motivational function, it has become necessary to employ a range of techniques to eke out the precise function of this neurotransmitter in corticostriatal function. Combinations of lesion and pharmacological studies have allowed the assessment of dopamine depletion and precise receptor populations in the learning or expression of a range of executive functions, which has gained us considerable insight into the relationship between the neuropathology that occurs in PD and the resulting impairments in cognitive and neuropsychiatric function.