Proliferation zones in the axolotl brain and regeneration of the telencephalon

<p>Abstract</p> <p>Background</p> <p>Although the brains of lower vertebrates are known to exhibit somewhat limited regeneration after incisional or stab wounds, the Urodele brain exhibits extensive regeneration after massive tissue removal. Discovering whether and how neural progenitor cells that reside in the ventricular zones of Urodeles proliferate to mediate tissue repair in response to injury may produce novel leads for regenerative strategies. Here we show that endogenous neural progenitor cells resident to the ventricular zone of Urodeles spontaneously proliferate, producing progeny that migrate throughout the telencephalon before terminally differentiating into neurons. These progenitor cells appear to be responsible for telencephalon regeneration after tissue removal and their activity may be up-regulated by injury through an olfactory cue.</p> <p>Results</p> <p>There is extensive proliferation of endogenous neural progenitor cells throughout the ventricular zone of the adult axolotl brain. The highest levels are observed in the telencephalon, especially the dorsolateral aspect, and cerebellum. Lower levels are observed in the mesencephalon and rhombencephalon. New cells produced in the ventricular zone migrate laterally, dorsally and ventrally into the surrounding neuronal layer. After migrating from the ventricular zone, the new cells primarily express markers of neuronal differentiative fates. Large-scale telencephalic tissue removal stimulates progenitor cell proliferation in the ventricular zone of the damaged region, followed by proliferation in the tissue that surrounds the healing edges of the wound until the telencephalon has completed regeneration. The proliferative stimulus appears to reside in the olfactory system, because telencephalic regeneration does not occur in the brains of olfactory bulbectomized animals in which the damaged neural tissue simply heals over.</p> <p>Conclusion</p> <p>There is a continual generation of neuronal cells from neural progenitor cells located within the ventricular zone of the axolotl brain. Variable rates of proliferation were detected across brain regions. These neural progenitor cells appear to mediate telencephalic tissue regeneration through an injury-induced olfactory cue. Identification of this cue is our future goal.</p

Desvenlafaxine may accelerate neuronal maturation in the dentate gyri of adult male rats.

Adult hippocampal neurogenesis has been linked to the effects of anti-depressant drugs on behavior in rodent models of depression. To explore this link further, we tested whether the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine impacted adult hippocampal neurogenesis differently than its primary active SNRI metabolite desvenlafaxine. Adult male Long Evans rats (n = 5-6 per group) were fed vehicle, venlafaxine (0.5 or 5 mg) or desvenlafaxine (0.5 or 5 mg) twice daily for 16 days. Beginning the third day of drug treatment, the rats were given a daily bromodeoxyuridine (BrdU; 50 mg/kg) injection for 5 days to label dividing cells and then perfused 2 weeks after the first BrdU injection to confirm total new hippocampal cell numbers and their phenotypes. The high desvenlafaxine dose increased total new BrdU+ cell number and appeared to accelerate neuronal maturation because fewer BrdU+ cells expressed maturing neuronal phenotypes and more expressed mature neuronal phenotypes in the dentate gyri of these versus vehicle-treated rats. While net neurogenesis was not increased in the dentate gyri of rats treated with the high desvenlafaxine dose, significantly more mature neurons were detected. Our data expand the body of literature showing that antidepressants impact adult neurogenesis by stimulating NPC proliferation and perhaps the survival of neuronal progeny and by showing that a high dose of the SNRI antidepressant desvenlafaxine, but neither a high nor low venlafaxine dose, may also accelerate neuronal maturation in the adult rat hippocampus. These data support the hypothesis that hippocampal neurogenesis may indeed serve as a biomarker of depression and the effects of antidepressant treatment, and may be informative for developing novel fast-acting antidepressant strategies

High dose desvenlafaxine increases NPCproliferation and survival in the DG of rats.

<p><b>A</b>)Representative brightfield image of BrdU⁺ cellsrevealed in the dentate gyrus of a vehicle-treated rat using DAB BrdU (inbrown). Scale bar  = 50 µm. B) Stereological estimates revealed more 10–14day-old BrdU⁺ cells in the dentate gyriof DES-HI- versus vehicle-treated rats (<i>p</i> = 0.01*).</p

Antidepressant Treatment Impacts The % BrdU⁺ Cells Expressing Neuronal Markers.

<p>Table footnote. The phenotypes of at least 50 BrdU+ cells were confirmed using confocal microscopy. Percentages of BrdU+ cells co-expressing the immature neuronal marker doublecortin (DCX) and/or the mature neuronal marker neuronal nucleii (NeuN) are reported. *<i>p</i><0.05.</p

High-dose desvenlafaxine may accelerateneuronal maturation neurons in the denate gyri of adult male rats.

<p><b>A)</b> Quantification of maturing (DCX⁺and DCX⁺NeuN⁺)and mature (NeuN⁺ alone) neuronal phenotypesshowed that a significantly higher percentage of BrdU⁺cells expressed maturing versus mature phenotypes in the dentate gyri of vehicle- (p = 0.005), VEN-LO- (p = 0.00008), VEN-HI- (p = 0.009), DES-LO- (p = 0.03) treated rats but similar proportionsexpressed maturing and mature phenotypes in the dentate gyri of DES-HI-treatedrats (<i>p</i> = 0.56). Relativeto BrdU⁺ cells in vehicle-treated rats,a significantly lower proportion expressed a maturing neuronal phenotype (**p = 0.005)and more tended to express a mature neuronal phenotype (^τp = 0.08). <b>B)</b> Quantification of number of new maturing and matureneurons showed that more new maturing versus new mature neurons were foundin the dentate gyri of vehicle- (<i>p</i> = 0.03),VEN-LO- (<i>p</i> = 0.002),VEN-HI- (<i>p</i> = 0.02),DES-LO- (<i>p</i> = 0.05)treated rats but similar numbers of maturing and mature new neurons were foundin the dentate gyri of DES-HI-treated rats (<i>p</i> = 0.32)and significantly more BrdU⁺ mature neurons werefound in the dentate gyri of DES-HI versus control rats (*p = 0.02).</p

Antidepressant Treatment Impacts Total New Neuron Number.

<p>Table footnote. The total number of new BrdU⁺ cells estimated stereologically was multiplied by the % of cells expressing a DCX⁺ immature neuronal, DCX/NeuN⁺ transitioning neuronal or NeuN⁺ mature neuronal phenotype to obtain total new neuron number in the hippocampi of each rat. **<i>p</i><0.01.</p

Morphometric Analysis of BrdU/DCX+ Neurons.

<p>Morphometric Analysis of BrdU/DCX+ Neurons.</p