title: Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring.
abstract: 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 (12-17months 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.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Powers
authors.affiliation: Division of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Christy M
authors.initials: CM
authors.lastname: Kelley
authors.affiliation: Department of Psychology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Ramon
authors.initials: R
authors.lastname: Velazquez
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Ash
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Myla S
authors.initials: MS
authors.lastname: Strawderman
authors.affiliation: Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University Langone Medical Center, New York, NY 10962, USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Alldred
authors.affiliation: Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA; Department of Psychiatry, New York University Langone Medical Center, New York, NY 10962, USA; Department of Neuroscience & Physiology, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.affiliation: Division of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA; Department of Psychology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Strupp
mesh_terms: D000818:Animals; D001288:Attention; D066187:Basal Forebrain / Q000254:growth & development / Q000473:pathology*; D002452:Cell Count; D048429:Cell Size; D002794:Choline / Q000008:administration & dosage*; D059329:Cholinergic Neurons / Q000473:pathology; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D005260:Female; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009035:Mothers; D009929:Organ Size; D011247:Pregnancy; D011897:Random Allocation
chemical_list: D002794:Choline
keywords: 5-choice serial reaction time task; Down syndrome; basal forebrain cholinergic neurons; maternal choline supplementation; medial septal nucleus; nucleus basalis of Meynert/substantia innominata