TY - JOUR
T1 - Maternal choline supplementation in a mouse model of Down syndrome
T2 - Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring
AU - Powers, Brian E.
AU - Kelley, Christy M.
AU - Velazquez, Ramon
AU - Ash, Jessica A.
AU - Strawderman, Myla S.
AU - Alldred, Melissa J.
AU - Ginsberg, Stephen D.
AU - Mufson, Elliott J.
AU - Strupp, Barbara J.
N1 - Funding Information:
This work was supported by National Institute of Child Health and Human Development , grant number HD057564 (to BJS, EJM, SDG); National Institute on Aging , grant numbers AG014449 (to EJM, SDG), AG043375 (EJM & SDG), and AG107617 (SDG); the Alzheimer’s Association , grant number IIRG-12-237253 (to SDG); and the National Institute of Health , grant number HD45224 .
Publisher Copyright:
© 2016 IBRO
PY - 2017/1/6
Y1 - 2017/1/6
N2 - The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs). Our prior studies demonstrated that maternal choline supplementation (MCS) improves attention and spatial cognition in Ts65Dn offspring, normalizes hippocampal neurogenesis, and lessens BFCN degeneration in the medial septal nucleus (MSN). Here we determined whether (i) BFCN degeneration contributes to attentional dysfunction, and (ii) whether the attentional benefits of perinatal MCS are due to changes in BFCN morphology. Ts65Dn dams were fed either a choline-supplemented or standard diet during pregnancy and lactation. Ts65Dn and disomic (2N) control offspring were tested as adults (12–17 months of age) on a series of operant attention tasks, followed by morphometric assessment of BFCNs. Ts65Dn mice demonstrated impaired learning and attention relative to 2N mice, and MCS significantly improved these functions in both genotypes. We also found, for the first time, that the number of BFCNs in the nucleus basalis of Meynert/substantia innominata (NBM/SI) was significantly increased in Ts65Dn mice relative to controls. In contrast, the number of BFCNs in the MSN was significantly decreased. Another novel finding was that the volume of BFCNs in both basal forebrain regions was significantly larger in Ts65Dn mice. MCS did not normalize any of these morphological abnormalities in the NBM/SI or MSN. Finally, correlational analysis revealed that attentional performance was inversely associated with BFCN volume, and positively associated with BFCN density. These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD.
AB - The Ts65Dn mouse model of Down syndrome (DS) and Alzheimer's disease (AD) exhibits cognitive impairment and degeneration of basal forebrain cholinergic neurons (BFCNs). Our prior studies demonstrated that maternal choline supplementation (MCS) improves attention and spatial cognition in Ts65Dn offspring, normalizes hippocampal neurogenesis, and lessens BFCN degeneration in the medial septal nucleus (MSN). Here we determined whether (i) BFCN degeneration contributes to attentional dysfunction, and (ii) whether the attentional benefits of perinatal MCS are due to changes in BFCN morphology. Ts65Dn dams were fed either a choline-supplemented or standard diet during pregnancy and lactation. Ts65Dn and disomic (2N) control offspring were tested as adults (12–17 months of age) on a series of operant attention tasks, followed by morphometric assessment of BFCNs. Ts65Dn mice demonstrated impaired learning and attention relative to 2N mice, and MCS significantly improved these functions in both genotypes. We also found, for the first time, that the number of BFCNs in the nucleus basalis of Meynert/substantia innominata (NBM/SI) was significantly increased in Ts65Dn mice relative to controls. In contrast, the number of BFCNs in the MSN was significantly decreased. Another novel finding was that the volume of BFCNs in both basal forebrain regions was significantly larger in Ts65Dn mice. MCS did not normalize any of these morphological abnormalities in the NBM/SI or MSN. Finally, correlational analysis revealed that attentional performance was inversely associated with BFCN volume, and positively associated with BFCN density. These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD.
KW - 5-choice serial reaction time task
KW - Down syndrome
KW - basal forebrain cholinergic neurons
KW - maternal choline supplementation
KW - medial septal nucleus
KW - nucleus basalis of Meynert/substantia innominata
UR - http://www.scopus.com/inward/record.url?scp=84998816172&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84998816172&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2016.11.001
DO - 10.1016/j.neuroscience.2016.11.001
M3 - Article
C2 - 27840230
AN - SCOPUS:84998816172
SN - 0306-4522
VL - 340
SP - 501
EP - 514
JO - Neuroscience
JF - Neuroscience
ER -