Abstract
The development of individual organs and the whole organism is under the control by morphogenetic factors over the critical period of morphogenesis. This study was aimed to test our hypothesis that the developing brain operates as an endocrine organ during morphogenesis, in rats during the perinatal period (Ugrumov in Neuro Chem 35:837–850, 2010). Norepinephrine, which is a morphogenetic factor, was used as a marker of the endocrine activity of the developing brain, although it is also secreted by peripheral organs. In this study, it was first shown that the concentration of norepinephrine in the peripheral blood of neonatal rats is sufficient to ensure the morphogenetic effect on the peripheral organs and the brain itself. Using pharmacological suppression of norepinephrine production in the brain, but not in peripheral organs, it was shown that norepinephrine is delivered from the brain to the general circulation in neonatal rats, that is, during morphogenesis. In fact, even partial suppression of norepinephrine production in the brain of neonatal rats led to a significant decrease of norepinephrine concentration in plasma, suggesting that at this time the brain is an important source of circulating norepinephrine. Conversely, the suppression of the production of norepinephrine in the brain of prepubertal rats did not cause a change in its concentration in plasma, showing no secretion of brain-derived norepinephrine to the bloodstream after morphogenesis. The above data support our hypothesis that morphogenetic factors, including norepinephrine, are delivered from the developing brain to the bloodstream, which occurs only during the critical period of morphogenesis.
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Abbreviations
- DHBA:
-
Dihydroxybenzylamine
- DBH:
-
Dopamine ß-hydroxylase
- E:
-
Embryonic day
- HPLC-ED:
-
High performance liquid chromatography with electrochemical detection
- 6-OHDA:
-
6-Hydroxydopamine
- ICH:
-
Immunocytochemistry
- NE:
-
Norepinephrine
- PBS:
-
Phosphate buffer saline
- P:
-
Postnatal day
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Funding
This research was supported by the Russian Science Foundation: Grants № 14-15-01122 and № 17-14-01422 for the study of the brain-blood barrier permeability in newborn and adult rats, respectively.
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MVU created the concept and design of the study, interpreted the experimental data; ARM, YON, NSB, AYS performed experiments, analyzed and interpreted biochemical data; LKD carried out immunohistochemistry and image analysis, prepared figures. All authors have approved the final manuscript and agree to be accountable for all aspects of the work.
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Appendices
Appendix 1
The content of norepinephrine (NE) and dopamine (DA) in peripheral organs in rats on postnatal days 3 (P3) and P31 24 h after: (1) intraventricular injection of 6-hydroxydopamine (6-OHDA) at the dose of 7.5 µg on P2 and 150 µg on P30, or 0.9% NaCl in both age groups (control); (2) subcutaneous injection of 6-OHDA at the dose of 150 µg, or 0.9% NaCl (control) on P30
Intraventricular injection | Subcutaneous injection | ||||||
|---|---|---|---|---|---|---|---|
Age | Postnatal day 3 | Postnatal day 31 | Postnatal day 31 | ||||
Substance/Organ | NE (ng), DA (ng) | Control (NaCl) | 6-OHDA (7.5 µg) | Control (NaCl) | 6-OHDA (150 µg) | Control (NaCl) | 6-OHDA (150 µg) |
Adrenals | NE | 126.62 ± 11.3 | 114.91 ± 9.51 | 1323.3 ± 98.41 | 1513.82 ± 122.54 | 1765.7 ± 236.33 | 1828.43 ± 127.46 |
DA | 5.38 ± 0.36 | 4.15 ± 0.47 | 74.9 ± 10.93 | 64.22 ± 4.14 | 65.42 ± 10.07 | 95.79 ± 10.76 | |
Duodenum | NE | 4.86 ± 0.68 | 5.19 ± 0.85 | 187.84 ± 13.32 | 162.75 ± 12.82 | 218.41 ± 16.55 | 207.95 ± 14.47 |
DA | 0.23 ± 0.05 | 0.23 ± 0.08 | 4.99 ± 0.63 | 6.46 ± 0.69 | 6.54 ± 0.2 | 8 ± 0.16 | |
Heart | NE | 3.98 ± 0.4 | 3.25 ± 0.15 | 288.56 ± 20.44 | 277.82 ± 20.66 | 177.36 ± 7.62 | 149.02 ± 21.41 |
DA | 0.2 ± 0.07 | 0.15 ± 0.06 | 5.23 ± 0.66 | 4.97 ± 0.59 | 2.42 ± 0.25 | 3.46 ± 0.59 | |
Appendix 2
The content of norepinephrine (NE) and dopamine (DA) in peripheral organs in rats on postnatal days 3 (P3) and P31, 25 h after the administration, first subcutaneously GBR 12,909 (40 mg/kg), and then after 1 h, of 6-hydroxydopamine (6-OHDA) at the dose of 7.5 μg on P2 or 150 μg on P30 intraventricularly; control animals received 0.9% NaCl in both age groups
Age | Postnatal day 3 | Postnatal day 31 | |||
|---|---|---|---|---|---|
Substance/Organ | NE, DA (ng) | Control (Nacl) | GBR and 6-OHDA | Control (Nacl) | GBR and 6-OHDA |
Adrenals | NE | 128.04 ± 15.46 | 122.5 ± 14.61 | 1909.9 ± 149.85 | 1808.54 ± 238.12 |
DA | 6.09 ± 0.84 | 3.89 ± 0.35 | 97.27 ± 20.89 | 76.4 ± 14.89 | |
Duodenum | NE | 3.33 ± 0.32 | 2.8 ± 0.3 | 197.94 ± 10.31 | 175.6 ± 27.96 |
DA | 0.41 ± 0.05 | 0.38 ± 0.05 | 4.21 ± 0.57 | 3.59 ± 0.74 | |
Heart | NE | 2.81 ± 0.3 | 3.17 ± 0.3 | 339.92 ± 23.65 | 284.26 ± 37.57 |
DA | 0.18 ± 0.05 | 0.17 ± 0.06 | 5.99 ± 1.24 | 7.53 ± 0.6 | |
Appendix 3
The content of norepinephrine (NE) in the brain, peripheral organs, and the concentration of NE in plasma in rats on postnatal days 3 (P3) and P31, 24 h after a subcutaneous injection of GBR 12,909 or 0.9% NaCl (control)
Age | Postnatal day 3 | Postnatal day 31 | |||
|---|---|---|---|---|---|
Substance/Organ | NE | Control (NaCl) | GBR 12,909 | Control (NaCl) | GBR 12,909 |
Brain | NE (ng) | 58.94 ± 2.17 | 63.51 ± 3.19 | 521.37 ± 28.4 | 436.99 ± 22.68 |
Adrenals | NE (ng) | 118.85 ± 6.5 | 124.14 ± 17.49 | 1483.29 ± 285.21 | 1757.96 ± 277.55 |
Duodenum | NE (ng) | 6.04 ± 1.26 | 4.74 ± 1.06 | 115.44 ± 2.86 | 122.05 ± 10.95 |
Heart | NE (ng) | 7.04 ± 0.6 | 5.34 ± 0.54 | 210.47 ± 8.73 | 249.53 ± 25.53 |
Plasma | NE (ng/ml) | 3.21 ± 0.76 | 4.71 ± 0.97 | 3.04 ± 0.72 | 3.58 ± 0.4 |
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Murtazina, A.R., Nikishina, Y.O., Bondarenko, N.S. et al. Developing brain as a source of circulating norepinephrine in rats during the critical period of morphogenesis. Brain Struct Funct 224, 3059–3073 (2019). https://doi.org/10.1007/s00429-019-01950-5
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DOI: https://doi.org/10.1007/s00429-019-01950-5