Behavioural Compensation after Dopamine Grafts in Brain

Iversen, Susan D.; Dunnett, S. B.; Stenevi, Ulf; Björklund, Anders

doi:10.1007/978-1-349-07431-0_17

Cited by 8 publications

(10 citation statements)

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“…The dopamine (DA) molecule is a major CNS neurotransmitter that has been the focus of extensive study due to its prominent involvement in core behavioral processes – including motor control, motivation, learning, and memory – and contribution to several neuropsychiatric disorders – including Parkinson’s disease, schizophrenia, and drug addiction (Iversen et al, 2010). DA influences behavioral output by modulating basal ganglia circuit function.…”

Section: Introductionmentioning

confidence: 99%

Endocannabinoid modulation of dopamine neurotransmission

et al. 2017

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Dopamine (DA) is a major catecholamine neurotransmitter in the mammalian brain that controls neural circuits involved in the cognitive, emotional, and motor aspects of goal-directed behavior. Accordingly, perturbations in DA neurotransmission play a central role in several neuropsychiatric disorders. Somewhat surprisingly given its prominent role in numerous behaviors, DA is released by a relatively small number of densely packed neurons originating in the midbrain. The dopaminergic midbrain innervates numerous brain regions where extracellular DA release and receptor binding promote short- and long-term changes in postsynaptic neuron function. Striatal forebrain nuclei receive the greatest proportion of DA projections and are a predominant hub at which DA influences behavior. A number of excitatory, inhibitory, and modulatory inputs orchestrate DA neurotransmission by controlling DA cell body firing patterns, terminal release, and effects on postsynaptic sites in the striatum. The endocannabinoid (eCB) system serves as an important filter of afferent input that acts locally at midbrain and terminal regions to shape how incoming information is conveyed onto DA neurons and to output targets. In this review, we aim to highlight existing knowledge regarding how eCB signaling controls DA neuron function through modifications in synaptic strength at midbrain and striatal sites, and to raise outstanding questions on this topic.

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Section: Introductionmentioning

confidence: 99%

Endocannabinoid modulation of dopamine neurotransmission

et al. 2017

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“…Midbrain dopaminergic (mDA) neurons in this group are implicated in emotional behavior, motivational functions, and reward mechanisms (2)(3)(4). On the other hand, SNc neurons mainly project to the dorsal striatum and regulate motor function (5). mDA neurons are of major interest in biomedical research because degeneration of SNc mDA neurons is the hallmark of Parkinson's disease (6).…”

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confidence: 99%

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

Pristerà

Lin

Kaufmann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice. We show that deletion of Foxa1/2 results in down-regulation of tyrosine hydroxylase, the rate-limiting enzyme of dopamine (DA) biosynthesis, specifically in dopaminergic neurons of the substantia nigra pars compacta (SNc). In addition, DA synthesis and striatal DA transmission were reduced after Foxa1/2 deletion. Furthermore, the burst-firing activity characteristic of SNc mDA neurons was drastically reduced in the absence of FOXA1/2. These molecular and functional alterations lead to a severe feeding deficit in adult Foxa1/2 mutant mice, independently of motor control, which could be rescued by L-DOPA treatment. FOXA1/2 therefore control the maintenance of molecular and physiological properties of SNc mDA neurons and impact on feeding behavior in adult mice.FOXA1 | FOXA2 | dopamine | burst firing | feeding M ost dopaminergic (DAergic) neurons in the adult midbrain are grouped in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). VTA and SNc neurons have been classically linked to diverse functions and different projection targets (1). VTA neurons project to the ventral striatum, cortical areas, and limbic structures. Midbrain dopaminergic (mDA) neurons in this group are implicated in emotional behavior, motivational functions, and reward mechanisms (2-4). On the other hand, SNc neurons mainly project to the dorsal striatum and regulate motor function (5). mDA neurons are of major interest in biomedical research because degeneration of SNc mDA neurons is the hallmark of Parkinson's disease (6). In addition, mDA neuron dysfunction is associated with cognitive impairment, motivational deficits, addiction, and drug abuse (7-10). The identification of factors that maintain dopamine (DA) function in developed adult neurons may contribute to the understanding of the mechanisms supporting the homeostasis of mDA neurons and therefore help in identifying therapeutic targets to treat disorders arising from dysfunctional mDA neurons.FOXA1 and FOXA2 (FOXA1/2) are members of the wingedhelix/forkhead transcription factors, which share over 95% homology between mice and humans (11). FOXA1/2 are so-called "pioneer proteins" that, by binding to tightly condensed chromatin in promoters and enhancer regions, facilitate access of other transcription factors (12, 13). FOXA1/2 regulate the development of diverse organs, including the lung, liver, pancreas, prostate, and kidneys (14). We have also found that FOXA1/2 play a crucial role in the generation of mDA neurons during early and late development, regulating both their specification and dif...

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“…Many types of studies related to disorders including drug abuse, schizophrenia, Parkinson’s disease, and perhaps eating disorders, attention deficithyperactivity disorder, Tourette’s syndrome, and Lesch-Nyhan syndrome, which may involve dopaminergic systems (Iversen et al, 2009) could be enhanced through this use of this model, as compared to the use of mDA neurons in isolation. For example, hPSC-derived mDA neurons have been used as a model of MPP+ toxicity and GDNF protection (Zeng et al, 2006), but MPP+ toxicity is known to involve the fine terminal arborization of mDA terminals in the striatum, which occur only in the presence of appropriate synaptic targets of mDA neurons as well (Feuerstetin et al, 1988), and thus such studies might be enhanced.…”

Section: Discussionmentioning

confidence: 99%

A new technique for modeling neuronal connectivity using human pluripotent stem cells

Lee

Bendriem

Freed

2015

RNN

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PurposeWe describe a technique for independently differentiating neocortical and mesencephalic dopaminergic (mDA) neurons from a single human pluripotent stem cell (hPSC) line, and subsequently allowing the two cell types to interact and form connections.MethodsDopaminergic and neocortical progenitors were differentiated in separate vessels, then separately seeded into the inner and outer compartments of specialized cell culture vessels designed for in vitro studies of wound healing. Cells were further differentiated using dopamine-specific and neocortex-specific trophic factors, respectively. The barrier was then removed, and differentiation was continued for three weeks in the presence of BDNF.ResultsAfter three weeks of differentiation, neocortical and mDA cell bodies largely remained in the areas into which they had been seeded, and the gap between the mDA and neocortical neuron populations could still be discerned. Abundant tyrosine hydroxylase (TH)-positive projections had extended from the area of the inner chamber to the outer chamber neocortical area.ConclusionsWe have developed a hPSC-based system for producing connections between neurons from two brain regions, neocortex and midbrain. Future experiments could employ modifications of this method to examine connections between any two brain regions or neuronal subtypes that can be produced from hPSCs in vitro.

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Behavioural Compensation after Dopamine Grafts in Brain

Cited by 8 publications

References 0 publications

Endocannabinoid modulation of dopamine neurotransmission

Endocannabinoid modulation of dopamine neurotransmission

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

A new technique for modeling neuronal connectivity using human pluripotent stem cells

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