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Retrograde adenoviral vector targeting of nociresponsive pontospinal noradrenergic neurons in the rat in vivo.

ABSTRACT: The spinal dorsal horn receives a dense innervation of noradrenaline-containing fibers that originate from pontine neurons in the A5, locus coeruleus (LC), and A7 cell groups. These pontospinal neurons are believed to constitute a component of the endogenous analgesic system. We used an adenoviral vector with a catecholaminergic-selective promoter (AVV-PRS) to retrogradely label the noradrenergic neurons projecting to the lumbar (L4-L5) dorsal horn with enhanced green fluorescent protein (EGFP) or monomeric red fluorescent protein (mRFP). Retrogradely labeled neurons (145 +/- 12, n = 14) were found in A5-12%, LC-80% and A7-8% after injection of AVV-PRS-EGFP to the dorsal horn of L4-L5. These neurons were immunopositive for dopamine beta-hydroxylase, indicating that they were catecholaminergic. Retrograde labeling was optimal 7 days after injection, persisted for over 4 weeks, and was dependent on viral vector titer. The spinal topography of the noradrenergic projection was examined using EGFP- and mRFP-expressing adenoviral vectors. Pontospinal neurons provide bilateral innervation of the cord and there was little overlap in the distribution of neurons projecting to the cervical and lumbar regions. The axonal arbor of the pontospinal neurons was visualized with GFP immunocytochemistry to show projections to the inferior olive, cerebellum, thalamus, and cortex but not to the hippocampus or caudate putamen. Formalin testing evoked c-fos expression in these pontospinal neurons, suggesting that they were nociresponsive (A5-21%, LC-16%, and A7-26%, n = 8). Thus, we have developed a viral vector-based strategy to selectively, retrogradely target the pontospinal noradrenergic neurons that are likely to be involved in the descending control of nociception.

SUBMITTER: Howorth PW

PROVIDER: S-EPMC2659361 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Retrograde adenoviral vector targeting of nociresponsive pontospinal noradrenergic neurons in the rat in vivo.

Howorth Patrick W PW Teschemacher Anja G AG Pickering Anthony E AE

The Journal of comparative neurology 20090101 2

The spinal dorsal horn receives a dense innervation of noradrenaline-containing fibers that originate from pontine neurons in the A5, locus coeruleus (LC), and A7 cell groups. These pontospinal neurons are believed to constitute a component of the endogenous analgesic system. We used an adenoviral vector with a catecholaminergic-selective promoter (AVV-PRS) to retrogradely label the noradrenergic neurons projecting to the lumbar (L4-L5) dorsal horn with enhanced green fluorescent protein (EGFP) ...[more]

PMID: 19003793

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Project description:Noradrenaline is a neurotransmitter involved in general arousal, selective attention, memory, inflammation, and neurodegeneration. The purpose of this work was to delineate noradrenergic neurons in vivo by T1-weighted MRI with magnetization transfer (MT). In the brainstem of human and mice, MRI identified the locus coeruleus, dorsal motor vagus nucleus, and nucleus tractus solitarius. Given (1) the long T1 and low magnetization transfer ratio for the noradrenergic cell groups compared to other gray matter, (2) significant correlation between MT MRI signal intensity and proton density, and (3) no correlation between magnetization transfer ratio (or R1) and iron, copper, or manganese in human brain, the high MRI signal of the noradrenergic neurons must be attributed to abundant water protons interacting with any T1-shortening paramagnetic ions in active cells rather than to specific T1-shortening molecules. The absence of a high MRI signal from the locus coeruleus of Ear2(-/-) mice lacking noradrenergic neurons confirms that cell bodies of noradrenergic neurons are the source of the bright MRI appearance. The observation of this high signal in DBH(-/-) mice, in 3-week-old mice, and in mice under hyperoxia/hypercapnia/hypoxia together with the general absence of neuromelanin (NM) in noradrenergic neurons of young rodents further excludes that it is due to NM, dopamine β-hydroxylase, their binding to paramagnetic ions, blood inflow, or hemoglobin. Instead, these findings indicate a high density of water protons whose T1 is shortened by paramagnetic ions as the relevant source of the high MRI signal. In the brain of APP/PS1/Ear2(-/-) mice, a transgenic model of Alzheimer's disease, MRI detected noradrenergic neuron loss in the locus coeruleus. Proton magnetic resonance spectroscopy revealed that a 60-75% reduction of noradrenaline is responsible for a reduction of N-acetylaspartate and glutamate in the hippocampus as well as for a shortening of the water proton T2 in the frontal cortex. These results suggest that a concurrent shortage of noradrenaline in Alzheimer's disease accelerates pathologic processes such as inflammation and neuron loss.

Dataset Information

Retrograde adenoviral vector targeting of nociresponsive pontospinal noradrenergic neurons in the rat in vivo.

Publications

Retrograde adenoviral vector targeting of nociresponsive pontospinal noradrenergic neurons in the rat in vivo.

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