Retrograde Labeling Illuminates Distinct Topographical Organization of D1 and D2 Receptor-Positive Pyramidal Neurons in the Prefrontal Cortex of Mice

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

doi:10.1523/eneuro.0194-20.2020

Cited by 12 publications

(6 citation statements)

References 51 publications

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“…Thus, our data provide a mechanistic insight into possible mechanisms of the paradoxical calming effects of psychostimulants and highlight a predominant role for cortical DA in this phenomenon. Our previous studies have identified a possible cortico-striatal-midbrain circuit involved in cortical DA control of striatal DA function and behaviors 26 . Future studies elucidating the circuit mechanisms regulated by this cortical DA-dependent phenomenon will provide a possible platform for studying the regulation of striatal DA dysfunction, which is a pathological feature of multiple neurological and psychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

A role for cortical dopamine in the paradoxical calming effects of psychostimulants

Harris

Green

Kumar

et al. 2022

Sci Rep

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Psychostimulants have a paradoxical calming effect in the treatment of attention deficit hyperactivity disorder (ADHD), but their mechanism of action is unclear. Studies using dopamine (DA) transporter (DAT) knockout (KO) mice have suggested that the paradoxical calming effect of psychostimulants might occur through actions on serotonin (5-HT) neurotransmission. However, newer non-stimulant drugs, such as atomoxetine and guanfacine, suggest that targeting the norepinephrine (NE) system in the prefrontal cortex (PFC) might explain this paradoxical calming effect. Thus, we sought to clarify the mechanism of this paradoxical action of psychostimulants. Our ex vivo efflux experiments reveal that the NE transporter (NET) blocker desipramine elevates both norepinephrine (NE) and dopamine (DA), but not 5-HT levels, in PFC tissue slices from wild-type (WT) and DAT-KO, but not NET-KO mice. However, the 5-HT transporter (SERT) inhibitor fluoxetine elevates only 5-HT in all three genotypes. Systemic administration of desipramine or fluoxetine inhibits hyperactivity in DAT-KO mice, whereas local PFC infusion of desipramine alone produced this same effect. In contrast, pharmacological NE depletion and DA elevation using nepicastat also inhibits hyperactivity in DAT-KO mice. Together, these data suggest elevation of PFC DA and not NE or 5-HT, as a convergent mechanism for the paradoxical effects of psychostimulants observed in ADHD therapy.

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Section: Discussionmentioning

confidence: 99%

A role for cortical dopamine in the paradoxical calming effects of psychostimulants

Harris

Green

Kumar

et al. 2022

Sci Rep

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“…DRN–projecting CART neurons were identified by a cre-dependent retrograde tracing approach as reported previously [28]. AAVrg-hsyn-DIO-EGFP was injected in the DRN of CART-cre x Ai14 reporter mice.…”

Section: Methodsmentioning

confidence: 99%

A new insight into the role of CART peptide in serotonergic function and anxiety

Balasubramanian,

Wang,

Ismail

et al. 2024

Preprint

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Cocaine and amphetamine-regulated transcript (CART) peptide has been established as a contributor to anxiogenic behavior. Genetic mutations in the CART gene are associated with anxiety and depression, and increased CART expression has been reported in suicide victims. Extensive research has focused on the role of CART peptide in mesolimbic neurocircuitry, but its involvement in the dorsal raphe nucleus (DRN) and serotonin (5HT) system remains unexplored. Here we demonstrate that CART processes are proximal to 5HTDRN neurons and that microinjection of CART (55-102) peptide into the DRN has an anxiogenic effect in mice. Furthermore, central CART administration reduced cfos activation in 5HT neurons of the ventral DRN, which is a putative reward/anti-stress circuit. The inhibitory effect of CART on 5HTDRN neuronal function and local 5HT release is further demonstrated with in vivo fiber photometry coupled with calcium and 5HT biosensors and by mass spectrometry. Moreover, using Credependent retrograde tracing, we observed DRN projecting CART neurons in the Edinger Westphal nucleus (EW), nucleus accumbens (NAc), and various hypothalamic nuclei including the ventromedial hypothalamus (VMH). Interestingly, based on ex vivo electrophysiological recordings, acute stress increased excitability in DRN projecting CART neurons located in the EW, but not in the VMH or NAc. This suggests that the stress may promote anxiety-like behavior by activating the EW CART-5HT DRN circuit that ultimately inhibits 5HT transmission. In sum, understanding the intricate dynamics of the CARTergic and 5HTergic systems proves crucial in addressing 5HT-related dysfunctions, providing invaluable insights into both health and disease.

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“…It is well known that the OFC projects to the dorsal striatum (Gremel and Costa, 2013;Gremel et al, 2016;Zimmermann et al, 2017). Previous studies showed that the DMS receives input from the mOFC (Gourley et al, 2016;Green et al, 2020). The DMS plays an important role for goal directed behavior (Vandaele et al, 2019) and BDNF in the mOFC is essential to sustain goal-sensitive action in mice (Gourley et al, 2016).…”

Section: Characterization Of Corticostriatal Bdnf Neuronsmentioning

confidence: 99%

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 Pyramidal Neurons in the Prefrontal Cortex of Mice

Cited by 12 publications

References 51 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

A new insight into the role of CART peptide in serotonergic function and anxiety

Identification of novel BDNF-specific corticostriatal circuitries

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