Permanent improvement in deficient sensory inhibition in DBA/2 mice with increased perinatal choline

Medical Research, Veterans Affairs Medical Center, 1055 Clermont Avenue, Denver, CO 80220, USA.
Psychopharmacology (Impact Factor: 3.88). 07/2008; 198(3):413-20. DOI: 10.1007/s00213-008-1170-3
Source: PubMed


Schizophrenia patients and certain inbred mouse strains (i.e., DBA/2) show deficient sensory inhibition which has been linked to reduced numbers of hippocampal alpha7 nicotinic receptors and to underlying polymorphisms in the promoter region for the alpha7 gene. Increasing maternal dietary choline, a selective alpha7 agonist, during gestation has been shown to produce long-term changes in adult offspring behavior (i.e., improved learning and memory in rats).
The objective of this study is to improve sensory inhibition in DBA/2 mice through maternal choline supplementation.
DBA/2 dams were placed on normal (1.1 g/kg) or supplemented (5 g/kg) choline diet throughout gestation and lactation. Offspring were placed on normal diet at weaning and were assessed for sensory inhibition parameters at adulthood. Evoked EEG responses to identical paired auditory stimuli were compared. At the end of the study, the brains were collected for autoradiographic assessment of hippocampal levels of alpha-bungarotoxin binding to visualize alpha7 nicotinic receptors.
Offspring mice which were choline supplemented during gestation showed significantly improved sensory inhibition compared to mice gestated on the normal choline diet. The improvement was produced by a significant reduction in the response to the second stimulus, demonstrating improved inhibition to that stimulus. There was a concurrent increase in alpha7 receptor numbers in both the CA1 and dentate gyrus regions of the hippocampus suggesting that this increase may be responsible for the improved inhibition.
These data show that gestational choline supplementation produces permanent improvement in a deficit associated with schizophrenia and may have implications for human prenatal nutrition.

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    • "First, perinatal choline supplementation facilitates alpha7*-dependent brain inhibitory function in infants [21]. Similarly , rodent studies demonstrate that supplementing dams during pregnancy and lactation permanently increases offspring levels of hippocampal alpha7* nAChRs and facilitates hippocampal function [22] [23] [24] [25] [26] [27]. In addition, perinatal choline protects the nervous system against a host of developmental insults [28] [29] [30] [31] [32]. "
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    ABSTRACT: Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress.
    Behavioural brain research 03/2014; 271. DOI:10.1016/j.bbr.2014.03.031 · 3.03 Impact Factor
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    • "ding in the hippocampus of DBA / 2 mice . Regionally , both the dentate gyrus and area CA1 showed statisti - cally significant increases for supplemented mice over those gestated on normal choline levels . n = 12 for normal choline , n = 11 for supplemented , data are mean ± SEM , * p < . 05 , * * p < . 01 . Source : copied with per - mission from Stevens et al . , 2008a , Figure 3"
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    ABSTRACT: The onset of diagnostic symptomology for neuropsychiatric diseases is often the end result of a decades-long process of aberrant brain development. Identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal. However, there are few models for how this goal might be achieved. This review uses the development of a psychophysiological correlate of attentional deficits in schizophrenia to propose a developmental model with translational primary prevention implications. Review of genetic and neurobiological studies suggests that an early interaction between alpha7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Therapeutic implications, including perinatal dietary choline supplementation, are discussed.
    Journal of Child Psychology and Psychiatry 11/2009; 51(5):535-49. DOI:10.1111/j.1469-7610.2009.02187.x · 6.46 Impact Factor
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    • "Furthermore, perinatal choline supplementation can alter behavior and neurochemistry following a variety of developmental disorders, including the alleviation of behavioral abnormalities associated with fetal alcohol syndrome in Sprague–Dawley rats (Thomas et al., 2000, 2004, 2007; Wagner and Hunt, 2006), and the attenuation of some of the motor deficits observed in a Mecp21 lox mouse model of Rhett syndrome (Nag et al., 2008; Nag and Berger- Sweeney, 2007). A recent report also demonstrates that prenatal choline supplementation improves sensory gating in a DBA/2 mouse model of schizophrenia that exhibits reduced numbers of hippocampal α7 nicotinic ACh receptors (Stevens et al., 2008). Consequently, it was of interest in the present study to investigate the effects of prenatal choline availability on the types of hippocampal gamma oscillations that have been shown to be sensitive to the modification of hippocampal α7 nicotinic ACh receptors (Cobb and Davies, 2005; Dani and Bertrand, 2007; Maggi et al., 2001). "
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    ABSTRACT: Choline supplementation of the maternal diet has long-term facilitative effects on spatial and temporal memory processes in the offspring. To further delineate the impact of early nutritional status on brain and behavior, we examined effects of prenatal-choline availability on hippocampal oscillatory frequency bands in 12 month-old male and female rats. Adult offspring of time-pregnant dams that were given a deficient level of choline (DEF=0.0 g/kg), sufficient choline (CON=1.1 g/kg) or supplemental choline (SUP=3.5 g/kg) in their chow during embryonic days (ED) 12-17 were implanted with an electroencephalograph (EEG) electrode in the hippocampal dentate gyrus in combination with an electromyograph (EMG) electrode patch implanted in the nuchal muscle. Five consecutive 8-h recording sessions revealed differential patterns of EEG activity as a function of awake, slow-wave sleep (SWS) and rapid-eye movement (REM) sleep states and prenatal choline status. The main finding was that SUP rats displayed increased power levels of gamma (30-100 Hz) band oscillations during all phases of the sleep/wake cycle. These findings are discussed within the context of a general review of neuronal oscillations (e.g., delta, theta, and gamma bands) and synchronization across multiple brain regions in relation to sleep-dependent memory consolidation in the hippocampus.
    Brain Research 10/2008; 1237:176-94. DOI:10.1016/j.brainres.2008.08.077 · 2.84 Impact Factor
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