Molecular basis for catecholaminergic neuron diversity

Abstract

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.C atecholaminergic (CA) neurons producing the neurotransmitters dopamine (DA) and noradrenalin (NA) are organized in anatomically discrete groups and constitute Ϸ1 of 10 7 cells in the vertebrate CNS (1, 2). The most prominent groups of DA neurons reside in the substantia nigra (SN; A9 cell group; Ϸ10,000 neurons in the rat) and the ventral tegmental area (VTA; A10; Ϸ25,000 neurons) of the midbrain. The SN neurons provide the nigrostriatal ascending inputs to the telencephalon and comprise a key component of the extrapyramidal motor system controlling postural reflexes and initiation of movement. DA neurons in the adjacent VTA give rise to mesocortical and mesolimbic pathways that are implicated in control of emotional balance, reward-associated behavior, attention, and memory. Additional groups of DA neurons reside in the medial zona incerta of the hypothalamus (A13; Ϸ900 neurons) and participate in the regulation of endocrine functions. The largest collection of NA neurons resides in the pontine locus coeruleus (LC; Ϸ1,500 neurons). These neurons form a modulatory projection system to most CNS areas and contribute to the regulation of emotional status, sensory perception, arousal, sleepwake patterns, and most autonomic functions.Consistent with their varied functions, the CA neurons are associated with multiple neurodegenerative, psychiatric, and endocrine disorders. Selective degeneration of DA neurons in the SN but not in the VTA or the hypothalamus leads to Parkinson's disease (PD) (3-7), whereas abnormal function of the VTA DA neurons has been linked to schizophrenia, attention deficit, addiction, and hyperactivity disorders (8-11). In addition, dysfunction of hypothalamic DA neurons can cause hyperprolactinemia, an endocrine disorder of the reproductive system (12), whereas changes in the activity of the NA system have been linked to depression as well as sleep disorders (13,14).The drugs currently available for therapy reflec...

Cellular Excitability and the Regulation of Functional Neuronal Identity: From Gene Expression to Neuromodulation

“…Ongoing work aims to identify mechanisms that control activity and differential vulnerability of DA midbrain neurons, upstream and downstream from K-ATP channels, by analyzing gene expression of individual electrophysiologically characterized DA neurons from SN and VTA via microarray strategies. This single-cell approach complements and improves the specificity of recent elegant microarray studies using pools of microdissected SN and VTA DA neurons for global transcriptome comparison (Grimm et al, 2004;Chung et al, 2005;Greene et al, 2005).…”

Improved RNA preservation for immunolabeling and laser microdissection

“…Target cells need to be identified and while it is possible in some cases to do this morphologically (e.g., Lobsiger et al 2007), when this is not possible, a cell-specific label must be employed. This can be achieved either by immunolabeling or using cell-specific promoters to drive expression of fluorescent proteins (Grimm et al 2004;Lobo et al 2006). The latter approach obviates the need for an immunolabeling step but limits investigations to the availability of transgenic mice with appropriate cell-specific promoter-marker protein combinations.…”

“…Rapid immunolabeling procedures have been developed in an attempt to overcome this problem (Fend et al 1999;Gjerdrum et al 2004), but these have been inadequately validated with regard to RNA integrity. Usually the qualitative presence of PCR product or ribosomal RNA is reported as the only evidence of RNA preservation (Grimm et al 2004). Furthermore, rapid procedures may not result in sufficient labeling for all antibodies, compromising the ability to reliably identify the cell of interest.…”

Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools

“…The VTA neurons project to the prefrontal cortex, amygdala, and nucleus accumbens, circuits involved in emotional and cognitive functions (1,2). In addition to the anatomical and functional differences, transcriptome as well as marker analyses of neurons in mDA clusters have also revealed some molecular differences (2)(3)(4)(5). Finally, neurons in the SNpc are selectively lost in Parkinson's disease (PD) patients (6,7), as well as in various genetic mouse models (8)(9)(10)(11), further highlighting the physiological diversity of mDA.…”