Restorative effect of estrogen on basal forebrain cholinergic neurons
The basal forebrain cholinergic (BFC) system is one of the most important neurotransmitter systems in the brain. It has received much attention in the past two decades, primarily for its role in learning, memory, attention and behavior. The BFC system has also been reported to be particularly vulnerable in neurodegenerative diseases, such as in Alzheimer’s disease (AD). The gonadal steroid, estrogen, is an essential contributor in controlling the vulnerability of the BFC system. Besides its classical or genomic mechanism, estrogen is known to have non-classical actions on intracellular signaling pathways. In this study, we investigated the ameliorative effects of estrogen treatment and the role of non-classical estrogen actions on BFC neurons in a neurodegenerative mouse model, in vivo. N-methyl-D-aspartate (NMDA) was injected unilaterally into the substantia innominata - nucleus basalis magnocellularis (SI-NBM) complex of the basal forebrain to elicit cholinergic cell death in the injected area and thus fiber loss in the ipsilateral cortex. An acute treatment of 17β-estradiol (E2) after the NMDA-induced lesion restored the ipsilateral cholinergic fiber density in the cortex in a time- and dose-dependent manner. Conversely, it did not have any effect on the cholinergic cell loss in the SI-NBM. The ameliorative action of E2 on cholinergic fiber loss was detected in both intact and gonadectomized young male and female mice, but not in aged animals. The E2-induced cholinergic fiber density restoration was also absent in neuron-specific estrogen receptor α (ERα) knockout mice. Selective blockade of the mitogen activated protein kinase (MAPK) and protein kinase A (PKA) pathways prevented E2’s ability to restore the cholinergic fiber density. Furthermore, activation of non-classical estrogen signaling by a non-classical pathway activator (estren) induced E2-like fiber restoration. Our findings demonstrate that estrogen restores the cholinergic fiber density in the cortex through a non-classical signaling mechanism after the loss of subcortical cholinergic input. Similar restorative effects were observed in young animals, irrespective of sex or endogenous estrogen levels. These observations reveal a critical role for non-classical estrogen signaling via ERα and MAPK-PKA pathways in BFC neurons, in vivo. Taken together, our study discloses important aspects relating to the vulnerability of the BFC system in neurodegenerative processes, such as AD or traumatic brain injury and might shed light on future medical treatments through the use of non-classical estrogen pathway activators.
Advisor: Ábrahám, István
Degree Name: Doctor of Philosophy
Degree Discipline: Physiology
Publisher: University of Otago
Keywords: estrogen; cholinergic; basal forebrain; neurodegeneration; non-classical; signaling pathway
Research Type: Thesis