Generation of a DAT-P2A-Flpo mouse line for intersectional genetic targeting of dopamine neuron subpopulations

Kramer, Daniel J.; Aisenberg, Erin; Kosillo, Polina; Friedmann, Drew; Stafford, David; Lee, Angus Yiu-Fai; Luo, Liqun; Hockemeyer, Dirk; Ngai, John; Bateup, Helen S.

doi:10.1016/j.celrep.2021.109123

Cited by 17 publications

(12 citation statements)

References 76 publications

(154 reference statements)

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“…mRNA translation is subject to multiple modulatory factors, and mRNA existence does not ensure a high level of protein expression. Consistent with our results, a study showed that the tdTomato+ neurons located in the periaqueductal region in DAT-Cre::Ai14 were TH-negative ( Cardozo Pinto et al, 2019 ; Kramer et al, 2021 ). We ruled out the off-target expression of Cre-recombinase in DAT-Cre mice, showing that these TH-negative neurons were VIP neurons expressing DAT mRNA.…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with this report, we have found that a part of DAT DR-PAG neurons is VIP neurons lacking TH in this study. Dissociation of the DAT and TH expression in the DR-PAG region was also reported by Kramer et al (2021) . We have shown, DAT DR-PAG neurons consist of TH neurons and VIP/VGlut2 neurons, therefore, to elucidate the fine roles of DA neurons or DAT neurons in the DR-PAG region, precise genetic separation of neural subgroups must be required.…”

Section: Discussionsupporting

confidence: 52%

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Histochemical Characterization of the Dorsal Raphe-Periaqueductal Grey Dopamine Transporter Neurons Projecting to the Extended Amygdala

Zhao

Ito

Soko

et al. 2022

eNeuro

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The dorsal raphe (DR) nucleus contains many tyrosine hydroxylase (TH)-positive neurons which are regarded as dopaminergic (DA) neurons. These DA neurons in the DR and periaqueductal gray (PAG) region (DA DR-PAG neurons) are a subgroup of the A10 cluster, which is known to be heterogeneous. This DA population projects to the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) and has been reported to modulate various affective behaviors. To characterize, the histochemical features of DA DR-PAG neurons projecting to the CeA and BNST in mice, the current study combined retrograde labeling with Fluoro-Gold (FG) and histological techniques, focusing on TH, dopamine transporter (DAT), vasoactive intestinal peptide (VIP), and vesicular glutamate transporter 2 (VGlut2). To identify putative DA neurons, DAT-Cre::Ai14 mice were used. It was observed that DAT DR-PAG neurons consisted of the following two subpopulations: TH+/VIP– and TH–/VIP+ neurons. The DAT+/TH–/VIP+ subpopulation would be non-DA noncanonical DAT neurons. Anterograde labeling of DAT DR-PAG neurons with AAV in DAT-Cre mice revealed that the fibers exclusively innervated the lateral part of the CeA and the oval nucleus of the BNST. Retrograde labeling with FG injections into the CeA or BNST revealed that the two subpopulations similarly innervated these regions. Furthermore, using VGlut2-Cre::Ai14 mice, it was turned out that the TH–/VIP+ subpopulations innervating both CeA and BNST were VGlut2-positive neurons. These two subpopulations of DAT DR-PAG neurons, TH+/VIP– and TH–/VIP+, might differentially interfere with the extended amygdala, thereby modulating affective behaviors.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 52%

Histochemical Characterization of the Dorsal Raphe-Periaqueductal Grey Dopamine Transporter Neurons Projecting to the Extended Amygdala

Zhao

Ito

Soko

et al. 2022

eNeuro

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“…Previous studies used alternative approaches to overcome the limitations of a single-model approach in whole-brain image segmentation. Some excluded deeper, more densely innervated areas from analysis 41 . Others combined probability maps from different segmentation methods by extracting the maximum probability for each pixel 42 .…”

Section: Resultsmentioning

confidence: 99%

Brain-wide projections and differential encoding of prefrontal neuronal classes underlying learned and innate threat avoidance

Gongwer

Klune

Enos

et al. 2022

Preprint

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Long-range axonal projections provide the foundation for functional connectivity between brain regions and are critical in the modulation of behavior. Descending projections from medial prefrontal cortex (mPFC) to various target regions regulate critical behavioral functions including decision making, social behavior and mood. While specific mPFC projections have distinct behavioral roles, individual mPFC projection neurons can also innervate multiple target regions. Yet how mPFC projection neurons divide their axons across the brain is poorly understood. In this study, we mapped the axon collaterals of mPFC neurons that project to nucleus accumbens (NAc), ventral tegmental area (VTA), or contralateral mPFC (cmPFC) in mice. We used tissue clearing and light sheet fluorescence microscopy to visualize the 3-D structure of axonal arbors across the intact brain. While machine learning can automate analysis of axons in images of cleared tissue, it is challenging to train a model that generalizes to all axonal structures because the appearance of axons varies by target region. In this study, we present DeepTraCE (Deep learning-based image Tracing with Combined-model Enhancement), a new strategy for axon segmentation and quantification in images of cleared tissue. DeepTraCE is based on the deep-learning framework TRAILMAP; it achieves highly accurate axon detection by combining multiple machine learning models that are each applied to different brain regions. Using DeepTraCE, we find that cmPFC, NAc, and VTA-projecting mPFC neurons represent largely separable classes with unique axon collaterals in cortical, olfactory, and thalamic regions, respectively.

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“…Recent gene profiling studies have identified several distinct sub-populations of DA neurons defined by their unique transcriptional signature (Poulin et al, 2014;La Manno et al, 2016;Hook et al, 2018;Kramer et al, 2018;Saunders et al, 2018;Tiklová et al, 2019;Poulin et al, 2020). Mouse models are being developed to allow intersectional genetic targeting of these newly defined dopaminergic populations to better understand their anatomical connectivity, functional properties and behavioral roles (Poulin et al, 2018;Kramer et al, 2021). Such approaches will enable a more fine-grained understanding of dopaminergic functions in both health and disease.…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models

Kosillo

Bateup

2021

Front. Neural Circuits

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by altered social interaction and communication, and repetitive, restricted, inflexible behaviors. Approximately 1.5-2% of the general population meet the diagnostic criteria for ASD and several brain regions including the cortex, amygdala, cerebellum and basal ganglia have been implicated in ASD pathophysiology. The midbrain dopamine system is an important modulator of cellular and synaptic function in multiple ASD-implicated brain regions via anatomically and functionally distinct dopaminergic projections. The dopamine hypothesis of ASD postulates that dysregulation of dopaminergic projection pathways could contribute to the behavioral manifestations of ASD, including altered reward value of social stimuli, changes in sensorimotor processing, and motor stereotypies. In this review, we examine the support for the idea that cell-autonomous changes in dopaminergic function are a core component of ASD pathophysiology. We discuss the human literature supporting the involvement of altered dopamine signaling in ASD including genetic, brain imaging and pharmacologic studies. We then focus on genetic mouse models of syndromic neurodevelopmental disorders in which single gene mutations lead to increased risk for ASD. We highlight studies that have directly examined dopamine neuron number, morphology, physiology, or output in these models. Overall, we find considerable support for the idea that the dopamine system may be dysregulated in syndromic ASDs; however, there does not appear to be a consistent signature and some models show increased dopaminergic function, while others have deficient dopamine signaling. We conclude that dopamine dysregulation is common in syndromic forms of ASD but that the specific changes may be unique to each genetic disorder and may not account for the full spectrum of ASD-related manifestations.

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Generation of a DAT-P2A-Flpo mouse line for intersectional genetic targeting of dopamine neuron subpopulations

Cited by 17 publications

References 76 publications

Histochemical Characterization of the Dorsal Raphe-Periaqueductal Grey Dopamine Transporter Neurons Projecting to the Extended Amygdala

Histochemical Characterization of the Dorsal Raphe-Periaqueductal Grey Dopamine Transporter Neurons Projecting to the Extended Amygdala

Brain-wide projections and differential encoding of prefrontal neuronal classes underlying learned and innate threat avoidance

Dopaminergic Dysregulation in Syndromic Autism Spectrum Disorders: Insights From Genetic Mouse Models

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