Light-at-night exposure affects brain development through pineal allopregnanolone-dependent mechanisms

Abstract

The molecular mechanisms by which environmental light conditions affect cerebellar development are incompletely understood. We showed that circadian disruption by light-at-night induced Purkinje cell death through pineal allopregnanolone (ALLO) activity during early life in chicks. Light-at-night caused the loss of diurnal variation of pineal ALLO synthesis during early life and led to cerebellar Purkinje cell death, which was suppressed by a daily injection of ALLO. The loss of diurnal variation of pineal ALLO synthesis induced not only reduction in pituitary adenylate cyclase-activating polypeptide (PACAP), a neuroprotective hormone, but also transcriptional repression of the cerebellar Adcyap1 gene that produces PACAP, with subsequent Purkinje cell death. Taken together, pineal ALLO mediated the effect of light on early cerebellar development in chicks.

Neuroprotective actions of cerebellar and pineal allopregnanolone on Purkinje cells

“…To investigate whether light conditions are involved in pineal allopregnanolone synthesis in juvenile birds, the birds were incubated under either a 12 hours light‐12 hours dark (LD) cycle or a 12 hours light‐12 hours dark cycle followed by exposure to light for 1 hour during the dark period (light‐at‐night). It was found the allopregnanolone concentration and synthesis are higher during the dark period in the pineal glands of LD birds than during the dark period in the pineal glands of light‐at‐night birds (Figure ). It was further found that Purkinje cell numbers are decreased in the cerebellum by light‐at‐night during (Figure ).…”

“…It was found the allopregnanolone concentration and synthesis are higher during the dark period in the pineal glands of LD birds than during the dark period in the pineal glands of light‐at‐night birds (Figure ). It was further found that Purkinje cell numbers are decreased in the cerebellum by light‐at‐night during (Figure ). It is, therefore, considered that pineal allopregnanolone contributes as an important internal factor depending on the environmental light conditions to affect cerebellar development in vertebrates.…”

“…[58][59][60] To investigate the identified putative receptors that mediate the neuroprotective action of pineal allopregnanolone, either mPRs siRNAs or isoallopregnanolone, an antagonist of allopregnanolone, were delivered into the cerebellum of chicks. It was found that silencing of mPRα increases the number of Purkinje cells that expressed active caspase-3 in the cerebellum of chicks relative to the number in the control siRNA 61 (Figure 4). Furthermore, to clarify the neuroprotective mechanisms of allopregnanolone in Purkinje cells, the effect of allopregnanolone on the expression of neuroprotective and neurotoxic factors [62][63][64][65][66][67] was investigated.…”

“…Furthermore, to clarify the neuroprotective mechanisms of allopregnanolone in Purkinje cells, the effect of allopregnanolone on the expression of neuroprotective and neurotoxic factors [62][63][64][65][66][67] was investigated. Px decreased the expression of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuroprotective factor, mRNA in the cerebellum of juvenile birds 61 (Figure 4). It was found that a daily injection of allopregnanolone in Px juvenile birds increases the expression of PACAP relative to that in Px birds 61 (Figure 4).…”

“…Px decreased the expression of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuroprotective factor, mRNA in the cerebellum of juvenile birds 61 (Figure 4). It was found that a daily injection of allopregnanolone in Px juvenile birds increases the expression of PACAP relative to that in Px birds 61 (Figure 4). Caspase-3 is a key enzyme involved in the neuroprotective action of PACAP.…”