Molecular basis for catecholaminergic neuron diversity

Rinat Neuroscience, 3155 Porter Drive, Palo Alto, CA 94304, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2004; 101(38):13891-6. DOI: 10.1073/pnas.0405340101
Source: PubMed


Catecholaminergic neurons control diverse cognitive, motor, and endocrine functions and are associated with multiple psychiatric and neurodegenerative disorders. We present global gene-expression profiles that define the four major classes of dopaminergic (DA) and noradrenergic neurons in the brain. Hypothalamic DA neurons and noradrenergic neurons in the locus coeruleus display distinct group-specific signatures of transporters, channels, transcription, plasticity, axon-guidance, and survival factors. In contrast, the transcriptomes of midbrain DA neurons of the substantia nigra and the ventral tegmental area are closely related with <1% of differentially expressed genes. Transcripts implicated in neural plasticity and survival are enriched in ventral tegmental area neurons, consistent with their role in schizophrenia and addiction and their decreased vulnerability in Parkinson's disease. The molecular profiles presented provide a basis for understanding the common and population-specific properties of catecholaminergic neurons and will facilitate the development of selective drugs.

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    • "The ascending DA projections comprise 2 major systems supported by anatomical descriptions and recent molecular descriptions of global-gene expression diversity [6]. The nigrostriatal system projects predominantly from the substantia nigra pars compata to the dorsal putamen and caudate nucleus (dorsal striatum) and globus pallidus. "
    Dataset: Mehta2006

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    • "We opted for a 96.96 dynamic array to evaluate 96 cells, each for the expression of 96 key genes, an approach used previously to discriminate stem cell identities (Buganim et al., 2012; Guo et al., 2010). We selected 96 gene candidates based on reported differential expression between SNc and VTA (Chung et al., 2005; Greene et al., 2005; Grimm et al., 2004), with a positive bias toward genes with validated midbrain mRNA expression as shown by in situ hybridization in public databases (Table S1). In addition, we evaluated the expression of housekeeping genes (Actb, Gapdh, and Hprt), genes linked to PD (Atp13a2, Lrrk2, Park2, Park7, Pink1, and Snca), as well as validated DA neuronal markers (Ddc, Th, Slc6a3, and Slc18a2). "
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    ABSTRACT: Effective approaches to neuropsychiatric disorders require detailed understanding of the cellular composition and circuitry of the complex mammalian brain. Here, we present a paradigm for deconstructing the diversity of neurons defined by a specific neurotransmitter using a microfluidic dynamic array to simultaneously evaluate the expression of 96 genes in single neurons. With this approach, we successfully identified multiple molecularly distinct dopamine neuron subtypes and localized them in the adult mouse brain. To validate the anatomical and functional correlates of molecular diversity, we provide evidence that one Vip+ subtype, located in the periaqueductal region, has a discrete projection field within the extended amygdala. Another Aldh1a1+ subtype, located in the substantia nigra, is especially vulnerable in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Overall, this rapid, cost-effective approach enables the identification and classification of multiple dopamine neuron subtypes, with distinct molecular, anatomical, and functional properties.
    Cell Reports 11/2014; 9(3):930-43. DOI:10.1016/j.celrep.2014.10.008 · 8.36 Impact Factor
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    • "Are all cells within these nuclei equally responsive to genetic and environmental insult, or is it possible that cells with different terminal fields are differentially susceptible to certain forms of stressors? For example, evidence suggests that in Alzheimer’s and Parksinson’s diseases, LC neurons degenerate selectively (Gesi et al., 2000; Grimm et al., 2004; Weinshenker, 2008; Szot et al., 2010; McMillan et al., 2011; Miguelez et al., 2011). It may be that such degeneration targets LC-PFC projection neurons specifically and that this selective degeneration plays a role in the cognitive decline associated with these diseases. "
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    ABSTRACT: Cognitive functions associated with prefrontal cortex (PFC), such as working memory and attention, are strongly influenced by catecholamine [dopamine (DA) and norepinephrine (NE)] release. Midbrain dopaminergic neurons in the ventral tegmental area and noradrenergic neurons in the locus coeruleus are major sources of DA and NE to the PFC. It is traditionally believed that DA and NE neurons are homogeneous with highly divergent axons innervating multiple terminal fields and once released, DA and NE individually or complementarily modulate the prefrontal functions and other brain regions. However, recent studies indicate that both DA and NE neurons in the mammalian brain are heterogeneous with a great degree of diversity, including their developmental lineages, molecular phenotypes, projection targets, afferent inputs, synaptic connectivity, physiological properties, and behavioral functions. These diverse characteristics could potentially endow DA and NE neurons with distinct roles in executive function, and alterations in their responses to genetic and epigenetic risk factors during development may contribute to distinct phenotypic and functional changes in disease states. In this review of recent literature, we discuss how these advances in DA and NE neurons change our thinking of catecholamine influences in cognitive functions in the brain, especially functions related to PFC. We review how the projection-target specific populations of neurons in these two systems execute their functions in both normal and abnormal conditions. Additionally, we explore what open questions remain and suggest where future research needs to move in order to provide a novel insight into the cause of neuropsychiatric disorders related to DA and NE systems.
    Frontiers in Neural Circuits 05/2014; 8. DOI:10.3389/fncir.2014.00053 · 3.60 Impact Factor
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