Retrograde labeling illuminates distinct topographical organization of D1 and D2 receptor-positive neurons in the prefrontal cortex of mice

Green, Sara M.; Nathani, Sanya; Zimmerman, James J.; Fireman, David; Urs, Nikhil M.

doi:10.1101/2020.05.04.077792

Cited by 3 publications

(2 citation statements)

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“…Our studies have recently identified a possible cortico-striatal-midbrain circuit mechanism for cortical dopamine control of striatal dopamine function and behaviors (Green et al, 2020).…”

Section: Discussionmentioning

confidence: 93%

A Role for Cortical Dopamine in the Paradoxical Calming Effects of Psychostimulants

Harris

Green

Kumar

et al. 2021

Preprint

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Attention deficit hyperactivity disorder (ADHD) affects young children and manifests symptoms such as hyperactivity, impulsivity and cognitive disabilities. Psychostimulants, which are the primary treatment for ADHD, target monoamine transporters and have a paradoxical calming effect, but their mechanism of action, is unclear. Studies using the dopamine (DA) transporter (DAT) knockout mice, which have elevated striatal DA levels and are considered an animal model of ADHD, have suggested that the paradoxical calming effect of psychostimulants might be through the actions on serotonin neurotransmission. On the other hand, newer non-stimulant class of drugs such as atomoxetine and Intuniv suggest that targeting the norepinephrine (NE) system in the PFC might explain this paradoxical calming effect. We sought to decipher the mechanism of this paradoxical effect of psychostimulants through an integrated approach using ex vivo monoamine efflux experiments, monoamine transporter knockout mice, drug infusions and behavior. Our ex vivo efflux experiments reveal that NE transporter (NET) blocker desipramine elevates both norepinephrine and dopamine but not serotonin levels, in PFC tissue slices from wild-type and DAT-KO but not NET KO mice. However, serotonin (5-HT) transporter (SERT) inhibitor fluoxetine elevates only serotonin in all three genotypes. Systemic administration of both desipramine and fluoxetine but local PFC infusion of only desipramine and not fluoxetine inhibits hyperactivity in the DAT-KO mice. In contrast, pharmacological norepinephrine depletion but dopamine elevation using Nepicastat also inhibits hyperactivity in DATKO mice. Together, these data suggest that elevation of PFC dopamine and not norepinephrine or serotonin as a convergent mechanism for the paradoxical psychostimulant effects observe in ADHD therapy.

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“…Our studies have recently identified a possible cortico-striatal-midbrain circuit mechanism for cortical dopamine control of striatal dopamine function and behaviors (Green et al, 2020).…”

Section: Discussionmentioning

confidence: 93%

A Role for Cortical Dopamine in the Paradoxical Calming Effects of Psychostimulants

Harris

Green

Kumar

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Activation of D2Rs on interneurons has been shown to decrease IPSCs on pyramidal neurons (Seamans et al, 2001). D2Rs are also expressed on pyramidal neurons and their activation appears to play an excitatory role but the effect appears less robust than D1R activation (Green et al, 2020;Lançon et al, 2021). DA receptor subtype 3 (D3Rs) are also present in L2/ 3 ACC and although less is known about their direct effect on neuron excitability, they appear to play a role in gating the release of DA, NE, and ACh (Lacroix et al, 2003).…”

Section: Dysregulated Acc Major Contributor To Pathological Pain Proc...mentioning

confidence: 99%

Dysregulated neuromodulation in the anterior cingulate cortex in chronic pain

Lançon,

Séguéla

2023

Front. Pharmacol.

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Chronic pain is a significant global socioeconomic burden with limited long-term treatment options. The intractable nature of chronic pain stems from two primary factors: the multifaceted nature of pain itself and an insufficient understanding of the diverse physiological mechanisms that underlie its initiation and maintenance, in both the peripheral and central nervous systems. The development of novel non-opioidergic analgesic approaches is contingent on our ability to normalize the dysregulated nociceptive pathways involved in pathological pain processing. The anterior cingulate cortex (ACC) stands out due to its involvement in top-down modulation of pain perception, its abnormal activity in chronic pain conditions, and its contribution to cognitive functions frequently impaired in chronic pain states. Here, we review the roles of the monoamines dopamine (DA), norepinephrine (NE), serotonin (5-HT), and other neuromodulators in controlling the activity of the ACC and how chronic pain alters their signaling in ACC circuits to promote pathological hyperexcitability. Additionally, we discuss the potential of targeting these monoaminergic pathways as a therapeutic strategy for treating the cognitive and affective symptoms associated with chronic pain.

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Identification of novel BDNF-specific corticostriatal circuitries

Ehinger

Soneja

Phamluong

et al. 2021

Preprint

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BDNF is released from axon terminals originating in the cerebral cortex onto striatal neurons. Here, we characterized BDNF in the corticostriatal circuitry. First, we utilized Bdnf-Cre and Ribotag transgenic mouse lines to label BDNF-positive cells in the cortex, and detected BDNF expression in the motor cortex, medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC). Next, we used a retrograde viral tracing strategy, in combination with Bdnf-Cre knockin mice, to map the cortical outputs of BDNF neurons in the dorsal striatum. We found that the BDNF-positive prefrontal regions differentially project to the dorsal striatum. Specifically, BDNF-expressing neurons located in the mPFC project to both dorsolateral striatum (DLS) and dorsomedial striatum (DMS), and those located in the motor cortex project to the DLS. Surprisingly however, the BDNF-expressing OFC neurons differentially target the dorsal striatum depending on their mediolateral location. Specifically, the DMS is mainly innervated by the medial part of the OFC (mOFC) whereas, the DLS receives projections specifically from the ventrolateral region of the OFC (vlOFC). Next, using an anterograde viral tracing strategy, we confirmed the presence of a BDNF-specific vlOFC-DLS circuit. Finally, we show that overexpression of BDNF in the vlOFC activates TrkB signaling specifically in the DLS but not in the DMS demonstrating the functionality of this circuit. Our study uncovers a previously unknown neural circuit composed of BDNF-positive vlOFC neurons projecting to the DLS. These findings could have important implications for the role of BDNF signaling in the OFC as well as in other corticostriatal circuitries.

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Retrograde labeling illuminates distinct topographical organization of D1 and D2 receptor-positive neurons in the prefrontal cortex of mice

Cited by 3 publications

References 52 publications

A Role for Cortical Dopamine in the Paradoxical Calming Effects of Psychostimulants

A Role for Cortical Dopamine in the Paradoxical Calming Effects of Psychostimulants

Dysregulated neuromodulation in the anterior cingulate cortex in chronic pain

Identification of novel BDNF-specific corticostriatal circuitries

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