Striosome–dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons

Crittenden, Jill R.; Tillberg, Paul W; Riad, Michael H.; Shima, Yasuyuki; Gerfen, Charles R.; Curry, Jeffrey; Housman, David E.; Nelson, Sacha B.; Boyden, Edward S.; Graybiel, Ann M.

doi:10.1073/pnas.1613337113

Cited by 127 publications

(179 citation statements)

References 59 publications

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“…The MOR in GABAergic forebrain neurons, therefore, is implicated in motivation for heroin rather than heroin reward. This is in accordance with recent evidence that striatonigral fibers originating from striosomes, and receiving inputs from cortical regions related to motivational control, form a specialized integrative unit within the mesocorticolimbic dopamine circuit (63) and that striatal MORs are specifically expressed in striosomal compartments (7). Further, Dlx-MOR mice also showed enhanced motivation to gain palatable food.…”

Section: Discussionsupporting

confidence: 92%

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Charbogne

Gardon

Martín‐García

et al. 2017

Biological Psychiatry

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BACKGROUND Mu opioid receptors (MORs) are central to pain control, drug reward and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in GABAergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. METHODS We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in GABAergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology and microdialysis, probed neuronal activation by c-Fos immunohistochemistry and resting state-functional magnetic resonance imaging, and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. RESULTS Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area (VTA), local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. CONCLUSIONS Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus beyond a well-established role in reward processing, operating at the level of local VTA neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors.

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Section: Discussionsupporting

confidence: 92%

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Charbogne

Gardon

Martín‐García

et al. 2017

Biological Psychiatry

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“…To detect the striosome and matrix compartments, we used BAC transgenic mice (Gong et al, 2007) with an enhanced GFP reporter for the matrix-enriched signaling molecule, CalDAG-GEFI (Kawasaki et al, 1998; Crittenden et al, 2016). The compartmental selectivity of CalDAG-GEFI-GFP expression followed gradients across the striatum, with the compartmental borders being easiest to identify in the central and lateral parts of the caudoputamen (Figures 2A–C).…”

Section: Resultsmentioning

confidence: 99%

Striatal Cholinergic Interneurons Modulate Spike-Timing in Striosomes and Matrix by an Amphetamine-Sensitive Mechanism

et al. 2017

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The striatum is key for action-selection and the motivation to move. Dopamine and acetylcholine release sites are enriched in the striatum and are cross-regulated, possibly to achieve optimal behavior. Drugs of abuse, which promote abnormally high dopamine release, disrupt normal action-selection and drive restricted, repetitive behaviors (stereotypies). Stereotypies occur in a variety of disorders including obsessive-compulsive disorder, autism, schizophrenia and Huntington's disease, as well as in addictive states. The severity of drug-induced stereotypy is correlated with induction of c-Fos expression in striosomes, a striatal compartment that is related to the limbic system and that directly projects to dopamine-producing neurons of the substantia nigra. These characteristics of striosomes contrast with the properties of the extra-striosomal matrix, which has strong sensorimotor and associative circuit inputs and outputs. Disruption of acetylcholine signaling in the striatum blocks the striosome-predominant c-Fos expression pattern induced by drugs of abuse and alters drug-induced stereotypy. The activity of striatal cholinergic interneurons is associated with behaviors related to sensory cues, and cortical inputs to striosomes can bias action-selection in the face of conflicting cues. The neurons and neuropil of striosomes and matrix neurons have observably separate distributions, both at the input level in the striatum and at the output level in the substantia nigra. Notably, cholinergic axons readily cross compartment borders, providing a potential route for local cross-compartment communication to maintain a balance between striosomal and matrix activity. We show here, by slice electrophysiology in transgenic mice, that repetitive evoked firing patterns in striosomal and matrix striatal projection neurons (SPNs) are interrupted by optogenetic activation of cholinergic interneurons either by the addition or the deletion of spikes. We demonstrate that this cholinergic modulation of projection neurons is blocked in brain slices taken from mice exposed to amphetamine and engaged in amphetamine-induced stereotypy, and lacking responsiveness to salient cues. Our findings support a model whereby activity in striosomes is normally under strong regulation by cholinergic interneurons, favoring behavioral flexibility, but that in animals with drug-induced stereotypy, this cholinergic signaling breaks down, resulting in differential modulation of striosomal activity and an inability to bias action-selection according to relevant sensory cues.

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“…It is estimated that a single SN DA neuron can innervate 2.7% of the total striatal volume, synapsing with up to 75,000 medium spiny neurons [55,56]. Furthermore, our understanding of DA neuron function itself is continually evolving with the advent of more sensitive tools [57,58]. The selective nature of mitophagy, as distinct from non-selective general macro-autophagy cannot be understated.…”

Section: Discussionmentioning

confidence: 99%

PINK1 and Parkin: emerging themes in mitochondrial homeostasis

McWilliams

Muqit

2017

Current Opinion in Cell Biology

266

235

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The Parkinson's disease (PD)-associated protein kinase, PTEN-induced putative kinase1 (PINK1), and ubiquitin E3 ligase Parkin, function in a common signalling pathway known to regulate mitochondrial network homeostasis and quality control, including mitophagy. The multistep activation of this pathway, as well as an unexpected convergence between the post-translational modifications of ubiquitylation and phosphorylation, has added breadth to our understanding of cellular damage responses during human disease. In concert with these new insights in signal transduction, unique modalities and signatures of vertebrate mitophagy have been unravelled in vivo for the very first time. The cell biology of mammalian mitophagy, and the roles of PINK1-Parkin signalling in vivo have emerged to be more complex than previously thought.

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Striosome–dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons

Cited by 127 publications

References 59 publications

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

Striatal Cholinergic Interneurons Modulate Spike-Timing in Striosomes and Matrix by an Amphetamine-Sensitive Mechanism

PINK1 and Parkin: emerging themes in mitochondrial homeostasis

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