GABAergic control of substantia nigra dopaminergic neurons

Tepper, James M.; Lee, Christian R.

doi:10.1016/s0079-6123(06)60011-3

Cited by 207 publications

(197 citation statements)

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“…Burst firing in mDA neurons is dependent on afferent inputs (50), as demonstrated by ex vivo midbrain preparations, which lack the burst-firing component (51). One major contributor to the burst firing displayed by mDA neurons is the glutamatergic input (52,53), although GABAergic innervation can also modulate burst firing (54). It is tempting to hypothesize that the absence of burst firing is due to altered control of inputs to mDA neurons.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…2). The neurons were classified as either GABAergic (GABA, n ϭ 580) or dopaminergic (DA, n ϭ 86) based on their waveforms (Wilson, 2004;Tepper and Lee, 2007). To verify that the long-duration spike waveforms are indeed from DA neurons, we compared firing rates before and after the injection of quinpirole, a D 2 -like dopamine receptor agonist (1 mg/kg, i.p.…”

Section: Trainingmentioning

confidence: 99%

“…The substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia, a set of subcortical nuclei critical for action selection and instrumental learning (Redgrave et al, 1999a;Yin and Knowlton, 2006;Hikosaka, 2007;Yin, 2010). The neurons from the SNr project to downstream motor control structures, releasing GABA and providing tonic inhibition of target structures (Hikosaka, 2007;Tepper and Lee, 2007). Previous work on eye movements in monkeys has shown that these neurons pause at the time of voluntary saccades, thus disinhibiting tonically active motor control circuits downstream (Hikosaka, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of Action Selection and Timing in Substantia Nigra Neurons

Fan¹,

Rossi²,

Yin³

2012

J. Neurosci.

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The timing of actions is critical for adaptive behavior. In this study we measured neural activity in the substantia nigra as mice learned to change their action duration to earn food rewards. We observed dramatic changes in single unit activity during learning: both dopaminergic and GABAergic neurons changed their activity in relation to behavior to reflect the learned instrumental contingency and the action duration. We found the emergence of "action-on" neurons that increased firing for the duration of the lever press and mirrorimage "action-off" neurons that paused at the same time. This pattern is especially common among GABAergic neurons. The activity of many neurons also reflected confidence about the just completed action and the prospect of reward. Being correlated with the relative duration of the completed action, their activity could predict the likelihood of reward collection. Compared with the GABAergic neurons, the activity of dopaminergic neurons was more commonly modulated by the discriminative stimulus signaling the start of each trial, suggesting that their phasic activity reflected sensory salience rather than any reward prediction error found in previous work. In short, these results suggest that (1) nigral activity is highly plastic and modified by the learning of the instrumental contingency; (2) GABAergic output from the substantia nigra can simultaneously inhibit and disinhibit downstream structures, while the dopaminergic output also provide bidirectional modulation of the corticostriatal circuits; (3) dopaminergic and GABAergic neurons show similar task-related activity, although DA neurons are more responsive to the trial start signal.

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“…Removal of inhibition in such conditions evokes a classical disinhibition burst (the disinhibition model of burst generation is well known and described in e.g. [35,[47][48][49] [35]. In this example, the simulated DA neuron is tonically active at 1.5 Hz during tonic co-activation of NMDA and GABA receptors (g NMDA = 16.9 m S/cm 2 , g GABA = 5mS/cm 2 ).…”

Section: Compensatory Action Of Asynchronous Nmda and Gaba Inputsmentioning

confidence: 99%

Dopamine neurons change the type of excitability in response to stimuli

Morozova

Zakharov²,

Gutkin

et al. 2016

Preprint

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The dynamics of neuronal excitability determine the neuron's response to stimuli, its synchronization and resonance properties and, ultimately, the computations it performs in the brain. We investigated the dynamical mechanisms underlying the excitability type of dopamine (DA) neurons, using a conductance-based biophysical model, and its regulation by intrinsic and synaptic currents. Calibrating the model to reproduce low frequency tonic firing results in N-methyl-D-aspartate (NMDA) excitation balanced by γ-Aminobutyric acid (GABA)-mediated inhibition and leads to type I excitable behavior characterized by a continuous decrease in firing frequency in response to hyperpolarizing currents. Furthermore, we analyzed how excitability type of the DA neuron model is influenced by changes in the intrinsic current composition. A subthreshold sodium current is necessary for a continuous frequency decrease during application of a negative current, and the low-frequency "balanced" state during simultaneous activation of NMDA and GABA receptors. Blocking this current switches the neuron to type II characterized by the abrupt onset of repetitive firing. Enhancing the anomalous rectifier Ih current also switches the excitability to type II. Key characteristics of synaptic conductances that may be observed in vivo also change the type of excitability: a depolarized γ-Aminobutyric acid receptor (GABAR) reversal potential or coactivation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) leads to an abrupt frequency drop to zero, which is typical for type II excitability. Coactivation of N-methyl-D-aspartate receptors (NMDARs) together with AMPARs and GABARs shifts the type I/II boundary toward more hyperpolarized GABAR reversal potentials. To better understand how altering each of the aforementioned currents leads to changes in excitability profile of DA neuron, we provide a thorough dynamical analysis. Collectively, these results imply that type I excitability in dopamine neurons might be important for low firing rates and fine-tuning basal dopamine levels, while switching excitability to type II during NMDAR and AMPAR activation may facilitate a transient increase in dopamine concentration, as type II neurons are more amenable to synchronization by mutual excitation. Author SummaryDopamine neurons play a central role in guiding motivated behaviors. However, complete understanding of computations these neurons perform to encode rewarding and salient stimuli is still forthcoming. Network connectivity influences neural responses to stimuli, but so do intrinsic excitability properties of individual neurons, as such properties define synchronization qualities and neural coding strategy. We investigated the excitability type of the DA neuron and found that, depending on the synaptic and intrinsic current composition, DA neurons can switch from type I to type II excitability. In short, without synaptic inputs or under balanced excitatory and inhibitory inputs DA neurons exhibits type I excitability, w...

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GABAergic control of substantia nigra dopaminergic neurons

Cited by 207 publications

References 127 publications

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

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

Mechanisms of Action Selection and Timing in Substantia Nigra Neurons

Dopamine neurons change the type of excitability in response to stimuli

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