Developmental neuroplasticity and the origin of neurodegenerative diseases.

OBJECTIVES: Neurodegenerative diseases like Alzheimer's and Parkinson's Disease, marked by characteristic protein aggregations, are more and more accepted to be synaptic disorders and to arise from a combination of genetic and environmental factors. In this review we propose our concept that neuroplasticity might constitute a link between early life challenges and neurodegeneration. METHODS: After introducing the general principles of neuroplasticity, we show how adverse environmental stimuli during development impact adult neuroplasticity and might lead to neurodegenerative processes. RESULTS: There are significant overlaps between neurodevelopmental and neurodegenerative processes. Proteins that represent hallmarks of neurodegeneration are involved in plastic processes under physiological conditions. Brain regions - particularly the hippocampus - that retain life-long plastic capacities are the key targets of neurodegeneration. Neuroplasticity is highest in young age making the brain more susceptible to external influences than later in life. Impacts during critical periods have life-long consequences on neuroplasticity and structural self-organization and are known to be common risk factors for neurodegenerative diseases. CONCLUSIONS: Several lines of evidence support a link between developmental neuroplasticity and neurodegenerative processes later in life. A deeper insight into these processes is necessary to design strategies to mitigate or even prevent neurodegenerative pathologies.

Amelioration of psychiatric symptoms through exposure to music individually adapted to brain rhythm disorders - a randomised clinical trial on the basis of fundamental research.

INTRODUCTION: This pilot study examined, whether long-term exposure of psychiatric patients to music that was individually adapted to brain rhythm disorders associated with psychoticism could act to ameliorate psychiatric symptoms. METHODS: A total of 50 patients with various psychiatric diagnoses were randomised in a 1:1 ratio to listen to CDs containing either music adapted to brain rhythm anomalies associated with psychoticism - measured via a specific spectral analysis - or standard classical music. Participants were instructed to listen to the CDs over the next 18 months. Psychiatric symptoms in both groups were assessed at baseline and at 4, 8 and 18 months, using the Brief Symptom Inventory (BSI). RESULTS: At 18 months, patients in the experimental group showed significantly decreased BSI scores compared to control patients. Intriguingly, this effect was not only seen for symptoms of psychoticism and paranoia but also for anxiety, phobic anxiety and somatisation. CONCLUSIONS: Exposure to the adapted music was effective in ameliorating psychotic, anxiety and phobic anxiety symptoms. Based on the theories of neuroplasticity and brain rhythms, it can be hypothesised that this intervention may be enhancing brain-rhythm synchronisation and plasticity in prefrontal-hippocampal circuits that are implicated in both psychosis/paranoia and anxiety/phobic anxiety.

Synaptic remodeling in the dentate gyrus, CA3, CA1, subiculum, and entorhinal cortex of mice: effects of deprived rearing and voluntary running.

Hippocampal cell proliferation is strongly increased and synaptic turnover decreased after rearing under social and physical deprivation in gerbils (Meriones unguiculatus). We examined if a similar epigenetic effect of rearing environment on adult neuroplastic responses can be found in mice (Mus musculus). We examined synaptic turnover rates in the dentate gyrus, CA3, CA1, subiculum, and entorhinal cortex. No direct effects of deprived rearing on rates of synaptic turnover were found in any of the studied regions. However, adult wheel running had the effect of leveling layer-specific differences in synaptic remodeling in the dentate gyrus, CA3, and CA1, but not in the entorhinal cortex and subiculum of animals of both rearing treatments. Epigenetic effects during juvenile development affected adult neural plasticity in mice, but seemed to be less pronounced than in gerbils.

Synapse plasticity in motor, sensory, and limbo-prefrontal cortex areas as measured by degrading axon terminals in an environment model of gerbils (Meriones unguiculatus).

Still little is known about naturally occurring synaptogenesis in the adult neocortex and related impacts of epigenetic influences. We therefore investigated (pre)synaptic plasticity in various cortices of adult rodents, visualized by secondary lysosome accumulations (LA) in remodeling axon terminals. Twenty-two male gerbils from either enriched (ER) or impoverished rearing (IR) were used for quantification of silver-stained LA. ER-animals showed rather low LA densities in most primary fields, whereas barrel and secondary/associative cortices exhibited higher densities and layer-specific differences. In IR-animals, these differences were evened out or even inverted. Basic plastic capacities might be linked with remodeling of local intrinsic circuits in the context of cortical map adaptation in both IR- and ER-animals. Frequently described disturbances due to IR in multiple corticocortical and extracortical afferent systems, including the mesocortical dopamine projection, might have led to maladaptations in the plastic capacities of prefronto-limbic areas, as indicated by different LA densities in IR- compared with ER-animals.

Developmental effects on dopamine projections and hippocampal cell proliferation in the rodent model of postweaning social and physical deprivation can be triggered by brief changes of environmental context.

Periadolescence is a critical period during which environmental stimuli modulate developmental neural plasticity. This includes the density of mesolimbic dopamine (DA) projections and the mitotic dynamic in the hippocampal dentate gyrus, both involved in central structures for emotional and cognitive functioning. Behavioural tests suggest that even short periods of stimulation can have lasting developmental effects on cognitive and emotional measures. We therefore exposed animals kept in isolation to brief daily context changes during periadolescence (postnatal days 30-60). We assessed the effects on neural development after animals had reached adulthood at postnatal day 90 by measuring the density of dopamine fibres in the medial prefrontal cortex (PFC), nucleus accumbens (core and shell), olfactory tubercle, and amygdala (basolateral and central), and by labelling mitoses in the dentate gyrus by BrdU. In experimental animals as compared to deprived controls, dopamine fibre densities were increased in the PFC and basolateral amygdala, decreased in the central amygdala, but not altered in the ventral striatum. Hippocampal cell proliferation was decreased. These results show that even a low level of experimental sensory stimulation during periadolescence triggers neural developmental processes, with lasting effects into adulthood.

Effect of postnatal methamphetamine trauma and adolescent methylphenidate treatment on adult hippocampal neurogenesis in gerbils.

Methylphenidate (e.g. Ritalin) is the most common drug used in the treatment of attention-deficit hyperactivity disorder. However, only a few studies have investigated the neuroanatomical long-term effects of this treatment. Prolonged application of methylphenidate during adolescence causes alterations in dopaminergic fiber or receptor densities in adult rodents. This study was conducted to investigate the effects of adolescent methylphenidate treatment on adult hippocampal neurogenesis in male gerbils (Meriones unguiculatus). Animals were first treated with either a single methamphetamine challenge on postnatal day 14 (to cause a disturbance in the dopaminergic system, to mimic the disturbed dopaminergic system seen in ADHD children) or saline and then received a daily oral application of 5 mg/kg methylphenidate or water from postnatal day 30-60 or were left undisturbed. On postnatal 90 gerbils were injected with bromodeoxyuridine (BrdU, a DNA synthesis marker) and sacrificed seven days later. Results reveal that the pretreatment with methamphetamine causes a decrease in the number of BrdU-positive cells in the dentate gyrus. Methylphenidate treatment however did not cause any differences in the number of labelled cells in any group. This implies that, despite methylphenidate's efficiency in inducing changes in the dopaminergic system and associated areas, it might be less effective in altering neurogenesis in the hippocampus.

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. Animals received a single early dose of methamphetamine (MA; 50 mg/kg; i.p.) on postnatal day (PD) 14, which is known to cause multiple changes in the subsequent development of several neurotransmitter systems including the dopaminergic systems, and were then treated with oral daily applications of MP (5 mg/kg) from PD30-60. Animals treated this way were either transferred to an enriched environment after weaning (on PD30) or were kept under impoverished rearing conditions. There was no effect of an enriched environment on the dopaminergic or GABAergic fiber density neither in the PFC nor in the amygdala. With regard to former studies these results underline the particular impact of MP in the treatment of ADHD.

Inverse relationship between adult hippocampal cell proliferation and synaptic rewiring in the dentate gyrus.

Adult neurogenesis is a key feature of the hippocampal dentate gyrus (DG). Neurogenesis is accompanied by synaptogenesis as new cells become integrated into the circuitry of the hippocampus. However, little is known to what extent the embedding of new neurons rewires the pre-existing network. Here we investigate synaptic rewiring in the DG of gerbils (Meriones unguiculatus) under different rates of adult cell proliferation caused by different rearing conditions as well as juvenile methamphetamine treatment. Surprisingly, we found that an increased cell proliferation reduced the amount of synaptic rewiring. To help explain this unexpected finding, we developed a novel model of dentate network formation incorporating neurogenesis and activity-dependent synapse formation and remodelling. In the model, we show that homeostasis of neuronal activity can account for the inverse relationship between cell proliferation and synaptic rewiring.

Early preweaning methamphetamine and postweaning rearing conditions interfere with the development of peripheral stress parameters and neural growth factors in gerbils.

Adrenal steroid hormones and neuronal growth factors are two interacting systemic factors that mediate the environment's influence on the brain's structure and function. In order to further elucidate their role and relationship in the effects of early stressful experience and isolated rearing (IR), this study measured blood corticosterone titres and relative adrenal weights and assessed nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) concentrations in brain regions of both hemispheres of young adult Mongolian gerbils injected on postnatal day 14 with a single high dose of methamphetamine (MA) or saline and raised after weaning either in an enriched or an impoverished environment. Irrespective of MA challenge, IR decreased corticosterone titres to about half, but increased relative adrenal weights. BDNF concentrations were decreased by IR in saline-injected animals in the left prefrontal and parietal cortices and right entorhinal and hippocampal cortices, and in the subcortical regions of both hemispheres. NGF concentrations were unaltered by IR in saline-injected animals, but increased in MA challenged animals in the entorhinal/hippocampal cortices and subcortical areas of both hemispheres. MA application induced shifts of the lateral asymmetry in NGF contents in prefrontal and entorhinal cortices. The results suggest that an early pharmacological traumatization can set a switch for further brain development, and that growth factor concentrations might possibly be influenced by peripheral stress hormones.

Administration of oral methylphenidate during adolescence prevents suppressive development of dopamine projections into prefrontal cortex and amygdala after an early pharmacological challenge in gerbils.

The enduring effects of postweaning subchronic methylphenidate (MP) treatment and/or previous early preweaning methamphetamine (MA) application on dopamine (DA) fiber density were investigated in multiple cortical and subcortical areas of the gerbil brain. The study aimed to explore three questions: (1) is the development of DA fiber innervation in control animals sensitive to a clinically relevant subchronic treatment with MP? (2) Is the development of DA fiber innervation in the forebrain altered by a single early MA challenge? (3) If so, might the subsequent institution of a therapeutically relevant MP application scheme interfere with such early induced alternative developmental trajectories for DA fiber innervation? For this purpose, gerbils pretreated both with saline and MA (50 mg/kg, i.p.) on day 14 received either H(2)O or MP (5 mg/kg) orally on days 30 to 60. On day 90, DA fibers were immunohistochemically detected and quantified. As a result, MP on its own did not have any significant influence on the postnatal development of the DA fiber systems, whereas it prevented a previously MA triggered suppressive development of DA fiber innervation in the prefrontal cortex and amygdala complex (30% less fiber innervation in both areas). Thus, MP prevented previously initiated miswiring of DA fibers from actually being implemented in the gerbil forebrain. During earlier studies, rather complex miswiring has been documented in response to an early preweaning MA challenge. This miswiring was associated with functional deficits resembling some of the symptoms of patients with ADHD. Therefore, morphogenetic properties of MP need further attention.

Density of dopaminergic fibres in the prefrontal cortex of gerbils is sensitive to aging.

Mesencephalic dopamine (DA) projections are essential for cognitive and behavioral functions and believed to play a critical role during development and aging. The dopaminergic afferents of the rodent prefrontal cortex (PFC) show an extremely prolonged maturation which is very sensitive to epigenetic challenges. However, less is known about the long-term maturation and aging of these DA axons. Therefore, immunohistochemically stained DA fibres were quantitatively examined in the PFC of the Mongolian gerbil (Meriones unguiculatus) ranging from 6 to 24 months of age. Results show a decrease in DA fibre densities in the superficial layers of the PFC in 24 month old animals compared to 6 and 12 months.

Postnatal development of GABA and calbindin cells and fibers in the prefrontal cortex and basolateral amygdala of gerbils (Meriones unguiculatus).

The postnatal maturation of immunohistochemically stained gamma-amino-butyric acid (GABA) and calbindin (CB) cells and fibers were quantitatively examined in the prefrontal cortex (PFC) and the basolateral amygdala (BLA) of the Mongolian gerbil (Meriones unguiculatus). Animals of different ages, ranging from juvenile (postnatal day (PD)14, PD20, PD30), to adolescent (PD70), adult (PD180, PD540) and aged (PD720) were analyzed. Results reveal an increase in GABAergic fiber densities between PD14-20 in the PFC and the BLA with a concomitant decrease in cell density. After PD70 GABA fiber density slightly decreases again in the BLA, while there is a further slow but significant increase in the PFC between PD70 and PD540. Fibers immunoreactive for the calcium binding-protein CB, which is predominantly localized in particular GABAergic subpopulations, also accumulate between PD14 and PD20 in the PFC and BLA, while a concomitant decrease in cell density is only seen in the BLA. Both areas reveal a decrease of CB cells between PD30 and PD70, which parallels with a decrease of CB fibers in the PFC. However, there is no particular 'aging-effect' in the fiber or cell densities of GABA or CB in any of the investigated areas in old animals. In conclusion, we here demonstrate long-term dynamics in cell and fiber densities of the GABAergic system until late in development which might correspond to the prolonged maturation of other neuroanatomical and functional systems.

Postnatal development of dopamine innervation in the amygdala and the entorhinal cortex of the gerbil (Meriones unguiculatus).

Dopamine (DA) projections from the mesencephalon are believed to play a critical role during development and are essential for cognitive and behavioral functions. Since the postnatal maturation patterns of these projections differ substantially between various brain regions, cortical, limbic or subcortical areas might exhibit varying vulnerabilities concerning developmental disorders. The dopaminergic afferents of the rodent prefrontal cortex show an extremely prolonged maturation which is very sensitive to epigenetic challenges. However, less is known about the development of the DA innervation of caudal limbic areas. Therefore, immunohistochemically stained DA fibers were quantitatively examined in the basolateral (BLA) and central amygdaloid nucleus (CE) and the ventrolateral entorhinal cortex (EC) of the Mongolian gerbil (Meriones unguiculatus). Animals of different ages, ranging from juvenile [postnatal day (PD) 14, 20, 30)] to adolescent (PD70), adult (6, 18 months) and aged (24 months), were analyzed. Results show a significant increase of fibers between PD14 and PD20 in the BLA and lateral part of the CE, with a trend for a subsequent decline in fiber densities until PD30. The EC and medial part of the CE showed no developmental changes. Interestingly, none of the investigated areas showed significant reductions of DA fibers during aging.

A theoretical network model to analyse neurogenesis and synaptogenesis in the dentate gyrus.

We describe a strongly biologically motivated artificial neural network approach to model neurogenesis and synaptic turnover as it naturally occurs for example in the hippocampal dentate gyrus (DG) of the developing and adult mammalian and human brain. The results suggest that cell proliferation (CP) has not only a functional meaning for computational tasks and learning but is also relevant for maintaining homeostatic stability of the neural activity. Moderate rates of CP buffer disturbances in input activity more effectively than networks without or very high CP. Up to a critical mark an increase of CP enhances synaptogenesis which might be beneficial for learning. However, higher rates of CP are rather ineffective as they destabilize the network: high CP rates and a disturbing input activity effect a reduced cell survival. By these results the simulation model sheds light on the recurrent interdependence of structure and function in biological neural networks especially in hippocampal circuits and the interacting morphogenetic effects of neurogenesis and synaptogenesis.

Long-term effects of a single adult methamphetamine challenge: minor impact on dopamine fibre density in limbic brain areas of gerbils.

BACKGROUND: The aim of the study was to test long-term effects of (+)-methamphetamine (MA) on the dopamine (DA) innervation in limbo-cortical regions of adult gerbils, in order to understand better the repair and neuroplasticity in disturbed limbic networks. METHODS: Male gerbils received a single high dose of either MA (25 mg/kg i.p.) or saline on postnatal day 180. On postnatal day 340 the density of immunoreactive DA fibres and calbindin and parvalbumin cells was quantified in the right hemisphere. RESULTS: No effects were found in the prefrontal cortex, olfactory tubercle and amygdala, whereas the pharmacological impact induced a slight but significant DA hyperinnervation in the nucleus accumbens. The cell densities of calbindin (CB) and parvalbumin (PV) positive neurons were additionally tested in the nucleus accumbens, but no significant effects were found. The present results contrast with the previously published long-term effects of early postnatal MA treatment that lead to a restraint of the maturation of DA fibres in the nucleus accumbens and prefrontal cortex and a concomitant overshoot innervation in the amygdala. CONCLUSION: We conclude that the morphogenetic properties of MA change during maturation and aging of gerbils, which may be due to physiological alterations of maturing vs. mature DA neurons innervating subcortical and cortical limbic areas. Our findings, together with results from other long-term studies, suggest that immature limbic structures are more vulnerable to persistent effects of a single MA intoxication; this might be relevant for the assessment of drug experience in adults vs. adolescents, and drug prevention programs.

Influence of methylphenidate on brain development--an update of recent animal experiments.

Methylphenidate (MPH) is the most commonly used drug to treat attention deficit/hyperactivity disorder (ADHD) in children effectively and safely. In spite of its widespread application throughout one of the most plastic and sensitive phases of brain development, very little is known to date about its long-term effects on brain structure and function. Hence, this short review updates the influence of MPH on brain development, since recent human and animal studies suggest that MPH alters the dopaminergic system with long-term effects beyond the termination of treatment.Animal studies imply that the effects of MPH may depend on the neural responder system: Whereas structural and functional parameters are improved by MPH in animals with psychomotor impairments, they remain unaltered or get worse in healthy controls. While recent behavioural studies do not fully support such a differential effect of MPH in ADHD, the animal studies certainly prompt for further investigation of this issue. Furthermore, the abuse of MPH, when (rarely) intravenously applied, may even impair the maturation of dopaminergic fibres in subcortical brain areas. This argues for careful clinical assessment and diagnostics of ADHD symptomatology not only in conjunction with the prescription of MPH. Hence, one should be assured that MPH is only given to children with clear ADHD symptomatology leading to psychosocial impairment. The animal data suggest that under these conditions MPH is supportive for brain development and the related behaviour in children with ADHD.

Ontogeny of the dopamine innervation in the nucleus accumbens of gerbils.

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.

Offer and demand: proliferation and survival of neurons in the dentate gyrus.

The proliferation and survival of new cells in the dentate gyrus of mammals is a complex process that is subject to numerous influences, presenting a confusing picture. We suggest regarding these processes on the level of small networks, which can be simulated in silico and which illustrate in a nutshell the influences that proliferating cells exert on plasticity and the conditions they require for survival. Beyond the insights gained by this consideration, we review the available literature on factors that regulate cell proliferation and neurogenesis in the dentate gyrus in vivo. It turns out that the rate of cell proliferation and excitatory afferents via the perforant path interactively determine cell survival, such that the best network stability is achieved when either of the two is increased whereas concurrent activation of the two factors lowers cell survival rates. Consequently, the mitotic activity is regulated by systemic parameters in compliance with the hippocampal network's requirements. The resulting neurogenesis, in contrast, depends on local factors, i.e. the activity flow within the network. In the process of cell differentiation and survival, each cell's spectrum of afferent and efferent connections decides whether it will integrate into the network or undergo apoptosis, and it is the current neuronal activity which determines the synaptic spectrum. We believe that this framework will help explain the biology of dentate cell proliferation and provide a basis for future research hypotheses.

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.

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.

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

Long-term effects of postnatal differential rearing conditions and/or early methamphetamine (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.