Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils

It is widely believed, that environmental factors play a crucial role in the etiology and outcome of psychiatric diseases such as Attention-Deficit/Hyperactivity Disorder (ADHD). A former study from our laboratory has shown that both methylphenidate (MP) and handling have a positive effect on the dopaminergic fiber density in the prefrontal cortex (PFC) of early traumatized gerbils (Meriones unguiculatus). The current study was performed to investigate if enriched environment during MP application has an additional influence on the dopaminergic and GABAergic fiber densities in the PFC and amygdala in this animal model

Ontogeny of the dopamine innervation in the nucleus accumbens of gerbils

Lesting J, Neddens J, Teuchert-Noodt G. Ontogeny of the dopamine innervation in the nucleus accumbens of gerbils. BRAIN RESEARCH. 2005;1066(1-2):16-23.The postnatal maturation of immunohistochemically stained dopamine (DA) fibres was quantitatively examined in the core and shell subareas of the nucleus accumbens (NAC) of gerbils. Animals of different ages, ranging from juvenile [postnatal day (PD) 14, 30] to adolescent (PD70), adult (PD90, PD180, PD360) and ageing (PD540, PD720) were analysed. The timescale of the maturation of the accumbal DA innervation was regionally different, probably due to the different origin of DA fibres in the mesencephalon. Both the accumbal core, with DA afferents arising from the lateral ventral tegmental area (VTA) and the substantia nigra pars compacta, as well as the accumbal shell, with DA afferents arising from the medial VTA, show moderate DA fibre densities at PD14. The core displayed a significant decrease of the DA fibre density up to PD30 and a subsequent significant increase between PD70 and 90, whereas the shell solely showed an augmentation of the DA innervation between PD70 and 90. Our data suggest that the different maturation of the DA innervation in core and shell might reflect differences in the development of motor and limbic functions, mediated by the nigrostriate and the mesolimbic system, respectively. (c) 2005 Published by Elsevier B.V

Alteration in the GABAergic network of the prefrontal cortex in a potential animal model of psychosis

Brummelte S, Neddens J, Teuchert-Noodt G. Alteration in the GABAergic network of the prefrontal cortex in a potential animal model of psychosis. Journal of Neural Transmission. 2007;114(5):539-547

Hemisphere-specific effects on serotonin but not dopamine innervation in the nucleus accumbens of gerbils caused by isolated rearing and a single early methamphetamine challenge

Lesting J, Neddens J, Busche A, Teuchert-Noodt G. Hemisphere-specific effects on serotonin but not dopamine innervation in the nucleus accumbens of gerbils caused by isolated rearing and a single early methamphetamine challenge. BRAIN RESEARCH. 2005;1035(2):168-176.The aim of this study was twofold: We examined whether serotonin (5-HT) and dopamine (DA) innervations of the nucleus accumbens are lateralised and whether the environment or the combination with an early pharmacological impact might interfere with the postnatal maturation of the monoaminergic innervation. Male gerbils were assigned to either enriched rearing (ER) or isolated rearing (IR). Animals from both rearing conditions additionally received a single dose of either methamphetamine [MA (50 mg/kg ip)] or saline on postnatal day 14. DA and 5-HT fibres of the adult animals (postnatal day 90-110) were immunocytochemically stained and fibre densities were quantified in nucleus accumbens core and shell of both the left and right hemisphere. Our data demonstrate that the DA and 5-HT innervation is not lateralised in saline-treated animals of both rearing conditions. IR increases the DA fibre density in both hemispheres of saline controls, whereas an additional MA treatment reverses this effect. In both ER and IR groups, MA provokes an excessive 5-HT fibre in growth of only the right hemisphere. The combination of IR with MA induces right-side asymmetries of the 5-HT fibre density in both the core and shell. From the data obtained, we conclude that the maturation of the monoaminergic innervation of the nucleus accumbens is vulnerable to postnatal stimuli. The subtle "innervation imbalance" observed in our studies is consistent with previously reported effects in other brain regions of this animal model and may be causative for behavioural disturbances. (c) 2005 Elsevier B.V. All rights reserved

Developmentally induced imbalance of dopaminergic fibre densities in limbic brain regions of gerbils (Meriones unguiculatus)

Busche A, Polascheck D, Lesting J, Neddens J, Teuchert-Noodt G. Developmentally induced imbalance of dopaminergic fibre densities in limbic brain regions of gerbils (Meriones unguiculatus). JOURNAL OF NEURAL TRANSMISSION. 2004;111(4):451-463.It is well established that epigenetic factors influence the maturation of neurotransmitter systems. Social isolation as well as an early intervention with methamphetamine (MA) lead to a diminished maturation of dopaminergic (DA) fibres in cortical and striatal areas in the brain of Mongolian gerbils. The aim of this study was to prove whether isolated rearing (IR) and the application of a single dose of MA on postnatal day 14 affect the maturation of DA fibres in caudal limbic areas. Therefore the DA fibre densities were quantified in the dorsolateral and ventrolateral entorhinal cortex (EC), the ventral subiculum (SUB) and in three amygdala nuclei - the basolateral (BLA), the lateral (LA) and the central (CA) nucleus. Our results showed that IR and an early MA application led to an increase of DA fibre densities in various caudal limbic areas. Whereas the BLA was affected by both IR and MA, the LA and the medial left CA were only influenced by MA in IR animals. The DA fibre surplus in the ventrolateral EC was significant in MA treated ER and IR animals in the left and right hemisphere, respectively. The SUB and the dorsolateral EC remained unaffected by both epigenetic factors. Altogether, the BLA seems to be the area which responds most sensitively to IR and MA. Previous studies in our laboratory showed a suppressive maturation of DA fibres in the prefrontal cortex (PFC) and nucleus accumbens (NAC) induced by the same set of epigenetic factors. Thus, due to the close functional connection between the PFC and limbic areas, it could be assumed that the suppressive maturation of prefrontal DA fibres implicates an enhancement of DA innervation densities in caudal limbic areas. Imbalances in the morphology and physiology of the different DA projections are suggested here to be crucial in the aetiology of schizophrenia

Postnatal maturation of cortical serotonin lateral asymmetry in gerbils is vulnerable to both environmental and pharmacological epigenetic challenges

Neddens J, Dawirs RR, Bagorda F, Busche A, Horstmann S, Teuchert-Noodt G. Postnatal maturation of cortical serotonin lateral asymmetry in gerbils is vulnerable to both environmental and pharmacological epigenetic challenges. BRAIN RESEARCH. 2004;1021(2):200-208.Long-term effects of postnatal differential rearing conditions and/or early meth amphetamine (MA) application on serotonin (5-HT) fibre density were investigated in several cortical areas of both hemispheres of gerbils. The aim of this study was twofold: (1) Is the 5-HT fibre innervation of the cerebral cortex lateralised, and (2) if so, do postnatal environmental conditions and/or an early drug challenge interfere with development of 5-HT cerebral asymmetries? For that purpose, male gerbils were reared either under semi-natural or restricted environmental and social conditions, under both conditions once (on postnatal day 14) being treated with either a single dose of MA (50 mg/kg, i.p.) or saline. On postnatal day 110, 5-HT fibres were immunohistochemically stained and innervation densities quantified in prefrontal cortex, insular cortex, frontal cortex, parietal cortex, and entorhinal cortex. It was found that (1) 5-HT innervation in the cerebral cortex was clearly lateralised; (2) direction and extent of this asymmetry were not uniformly distributed over the different areas investigated; (3) both early methamphetamine challenge and rearing condition differentially interfered with adult 5-HT cerebral asymmetry; (4) combining MA challenge with subsequent restricted rearing tended to reverse the effects of MA on 5-HT cerebral asymmetry in some of the cortical areas investigated; and (5) significant responses in 5-HT cerebral asymmetry only occurred in prefrontal and entorhinal association cortices. The present findings suggest that the ontogenesis of cortical laterality is influenced by epigenetic factors and that disturbances of the postnatal maturation of lateralised functions may be associated with certain psychopathological behaviours. (C) 2004 Elsevier B.V. All rights reserved

Epigenetic factors differentially influence postnatal maturation of serotonin (5-HT) innervation in cerebral cortex of gerbils: interaction of rearing conditions and early methamphetamine challenge

Neddens J, Bagorda F, Busche A, et al. Epigenetic factors differentially influence postnatal maturation of serotonin (5-HT) innervation in cerebral cortex of gerbils: interaction of rearing conditions and early methamphetamine challenge. DEVELOPMENTAL BRAIN RESEARCH. 2003;146(1-2):119-130.The effects of disjunctive environmental deprivation combined with a single methamphetamine (MA) challenge on postnatal maturation of the serotonin (5-HT) innervation pattern in cerebral cortex of gerbils were studied. Gerbils were assigned to either enriched (ER) or impoverished (M) environmental rearing conditions. On postnatal day I 10, 5-HT was immunostained. The 5-HT innervation pattern of the brain was qualitatively evaluated and provided in graphic form. The densities of 5-HT fibres were quantified in areas of prefrontal, insular, frontal, parietal, and entorhinal cortices of the right hemisphere using digital image analysis. The early MA challenge led to an overshoot of the fibre density in medial and orbital prefrontal cortex and entorhinal cortex of ER animals. IR animals mostly resisted MA effects except of a restraint of the innervation of the insular cortex. In comparison to enriched rearing, restricted rearing caused overshoot maturation of 5-HT innervation in insular and entorhinal cortices. The present data provide evidence for a region-specific postnatal vulnerability of the maturing 5-HT innervation, namely in association cortices. In contrast, both sensory and motor cortices showed no significant changes at all. The results are discussed in context with previously presented findings of alterations of the cortical dopamine innervation depending on both epigenetic factors. In conclusion, both experimental variables together give new insight into raphe-cortical plasticity that may contribute to a better understanding of the role of 5-HT fibre systems in structural maturation of the cortex. Postnatal environment may be involved in individual vulnerability of a variety of mental disorders during adolescence and aging. (C) 2003 Elsevier B.V. All rights reserved

Large-Scale Oral Treatment Study with the Four Most Promising D3-Derivatives for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is associated with the aggregation of the amyloid β protein (Aβ). Aβ oligomers are currently thought to be the major neurotoxic agent responsible for disease development and progression. Thus, their elimination is highly desirable for therapy development. Our therapeutic approach aims at specific and direct elimination of toxic Aβ oligomers by stabilizing Aβ monomers in an aggregation-incompetent conformation. We have proven that our lead compound “D3”, an all d-enantiomeric-peptide, specifically eliminates Aβ oligomers in vitro. In vivo, D3 enhances cognition and reduces plaque load in several transgenic AD mouse models. Here, we performed a large-scale oral proof of concept efficacy study, in which we directly compared four of the most promising D3-derivatives in transgenic mice expressing human amyloid precursor protein with Swedish and London mutations (APPSL), transgenic mice, to identify the most effective compound. RD2 and D3D3, both derived from D3 by rational design, were discovered to be the most effective derivatives in improving cognition in the Morris water maze. The performance of RD2- and D3D3-treated mice within the Morris water maze was significantly better than placebo-treated mice and, importantly, nearly as good as those of non-transgenic littermates, suggesting a complete reversal of the cognitive deficit of APPSL mice