There is increasing evidence that brain-derived neurotrophic factor (BDNF) plays a crucial role in Alzheimer's disease (AD) pathology. A number of studies demonstrated that AD patients exhibit reduced BDNF levels in the brain and the blood serum, and in addition, several animal-based studies indicated a potential protective effect of BDNF against Aβ-induced neurotoxicity. In order to further investigate the role of BDNF in the etiology of AD, we created a novel mouse model by crossing a well-established AD mouse model (APP/PS1) with a mouse exhibiting a chronic BDNF deficiency (BDNF(+/-)). This new triple transgenic mouse model enabled us to further analyze the role of BDNF in AD in vivo. We reasoned that in case BDNF has a protective effect against AD pathology, an AD-like phenotype in our new mouse model should occur earlier and/or in more severity than in the APP/PS1-mice. Indeed, the behavioral analysis revealed that the APP/PS1-BDNF(+/-)-mice show an earlier onset of learning impairments in a two-way active avoidance task in comparison to APP/PS1- and BDNF(+/-)-mice. However in the Morris water maze (MWM) test, we could not observe an overall aggrevated impairment in spatial learning and also short-term memory in an object recognition task remained intact in all tested mouse lines. In addition to the behavioral experiments, we analyzed the amyloid plaque pathology in the APP/PS1 and APP/PS1-BDNF(+/-)-mice and observed a comparable plaque density in the two genotypes. Moreover, our results revealed a higher plaque density in prefrontal cortical compared to hippocampal brain regions. Our data reveal that higher cognitive tasks requiring the recruitment of cortical networks appear to be more severely affected in our new mouse model than learning tasks requiring mainly sub-cortical networks. Furthermore, our observations of an accelerated impairment in active avoidance learning in APP/PS1-BDNF(+/-)-mice further supports the hypothesis that BDNF deficiency amplifies AD-related cognitive dysfunctions.

Work in various animal models has demonstrated that cognitive training in infancy has a greater effect on adult cognitive performance than pretraining in adulthood. Since the underlying synaptic mechanisms are unclear, the aim of this study was to test the working hypothesis that associative training "preshapes" synaptic circuits in the developing infant brain and thereby improves learning in adulthood. Using a two-way active avoidance (TWA) paradigm, we found that avoidance training during infancy, even though the infant rats were not capable to learn a successful avoidance strategy, improves avoidance learning in adulthood. On the neuroanatomical level we show here for the first time that infant TWA training in the ventromedial prefrontal cortex suppresses developmental spine formation. In contrast in the lateral orbitofrontal cortex, developmental spine pruning is suppressed, possibly by "tagging" activated synapses, which thereby are protected from being eliminated. Moreover, we demonstrate that infant TWA training alters learning-induced synaptic plasticity in the adult brain. The synaptic and dendritic changes correlate with specific behavioral parameters. Taken together, these results support the working hypothesis that infant cognitive training interferes with developmental reorganization and maturation of dendritic spines and thereby "optimizes" prefrontal neuronal circuits for adult learning.

β-Carbolines (BCs) belong to the heterogenous family of carbolines, which have been found exogenously, that is, in various fruits, meats, tobacco smoke, alcohol and coffee, but also endogenously, that is, blood, brain and CSF. These exogenous and endogenous BCs and some of their metabolites can exert neurotoxic effects, however, an unexpected stimulatory effect of 9-methyl-β-carboline (9-me-BC) on dopaminergic neurons in primary mesencephalic cultures was recently discovered. The aim of the present study was to extend our knowledge on the stimulatory effects of 9-me-BC and to test the hypothesis that 9-me-BC may act as a cognitive enhancer. We found that 10 days (but not 5 days) of pharmacological treatment with 9-me-BC (i) improves spatial learning in the radial maze, (ii) elevates dopamine levels in the hippocampal formation, and (iii) results after 10 days of treatment in elongated, more complex dendritic trees and higher spine numbers on granule neurons in the dentate gyrus of 9-me-BC-treated rats. Our results demonstrate that beyond its neuroprotective/neurorestorative and anti-inflammatory effects, 9-me-BC acts as a cognitive enhancer in a hippocampus-dependent task, and that the behavioral effects may be associated with a stimulatory impact on hippocampal dopamine levels and dendritic and synaptic proliferation.

A growing body of evidence highlights the impact of the early social environment for the adequate development of brain and behavior in animals and humans. Disturbances of this environment were found to be both maladaptive and adaptive to emotional and cognitive function. Using the semi-precocial, biparental rodent Octodon degus, we aimed to examine (i) the impact of age (juvenile/adult), sex (male/female), and (ii) "motivation" to solve the task (by applying increasing foot-shock-intensities) on two-way active avoidance (TWA) learning in socially reared degus, and (iii) whether early life stress inoculation by 1h daily parental separation during the first three weeks of life has maladaptive or adaptive consequences on cognitive function as measured by TWA learning. Our results showed that (i) juvenile degus, unlike altricial rats of the same age, can successfully learn the TWA task comparable to adults, and (ii) that learning performance improves with increasing "task motivation", irrespective of age and sex. Furthermore, we revealed that (iii) stress inoculation improves avoidance learning, particularly in juvenile males, quantitatively and qualitatively depending on "task motivation". In conclusion, the present study describes for the first time associative learning in O. degus and its modulation by early life stress experience as an animal model to study the underlying mechanisms of learning and memory in the stressed and unstressed brain. Although, stress is commonly viewed as being maladaptive, our data indicate that early life stress inoculation triggers developmental cascades of adaptive functioning, which may improve cognitive and emotional processing of stressors later in life.

A growing body of evidence supports the hypothesis that juvenile cognitive training shapes neural networks and behavior, and thereby determines the adult´s capacity for learning and memory. In particular, we have shown that infant rats, even though they do not develop an active avoidance strategy in a two-way active avoidance task, show as adults accelerated learning in the same learning task. This indicates that a memory trace was formed in the infant rats, which most likely is recruited during adult training. To identify the learning conditions, which are essential prerequisites to form this memory trace in infancy or adolescence, we investigated the critical impact of: (i) age, (ii) CS–UCS contingency, and (iii) pre-training intensity on this facilitating effect. We observed: (i) an age-dependent improvement of avoidance learning, (ii) that the beneficial impact of infant or adolescent pre-training on adult learning increases with the age at pre-training, (iii) that CS–UCS contingency during infant pre-training was most efficient to accelerate adult learning, (iv) that pre-training intensity (i.e. number of pre-training trials) was positively correlated with the pre-training induced acceleration of adult learning, and (v) that infant rats, compared to adolescent rats, need a higher training intensity to show learning improvement as adults. These results indicate that infant rats develop a goal-oriented escape strategy, which during adult training is replaced by an avoidance strategy, facilitated by the recruitment of the CS–UCS association, which has been learned during infant training. Based on these results the future challenge will be to identify the specific contribution of prefronto-limbic circuits in infant and adult learning in relation to their functional maturation.

The temporal dissociation between early information acquisition and output of complex behaviors is a common principle during development. Thus, although infant rats are not able to generate sufficient avoidance behavior during two-way active avoidance (TWA) training they obviously deposit a certain, "memory trace" (Schable, Poeggel, Braun, & Gruss, 2007). The ontogeny of learning is probably mirrored by the maturing functionality of different basal forebrain regions.Two of the basal forebrain regions involved in TWA learning are the medial septum/diagonal band of Broca (MS/DB), which is essential for the encoding and retrieval of memory and the lateral septum (LS) that plays a role in the generation of behavior.Mapping 2-fluoro-deoxy-glucose utilization in freely behaving animals, the aim of this study was to assess the functional recruitment of the MS/DB and LS in infant (P17-P21) and adolescent (P38-P42) rats during the first (acquisition) and fifth (retrieval) TWA training.Metabolic activity in the MS/DB was similar in both age groups during acquisition and retrieval indicating that this region is already mature in the infant rat. In contrast, metabolic activity in the LS was generally lower in the infant rats suggesting that this region is not yet fully functional during PI 7 and P21. This insufficient recruitment may be one reason for the poor TWA performance of infant rats.Finally, the LS displayed significantly higher activity during acquisition than during retrieval indicating that the highest amount of energy is consumed during the initial learning phase. (C) 2009 Elsevier Inc. All rights reserved.

The Coffin-Lowry syndrome, a rare syndromic form of X-linked mental retardation, is caused by loss-of-function mutations in the hRSK2 (RPS6KA3) gene. To further investigate RSK2 (90-kDa ribosomal S6 kinase) implication in cognitive processes, a mrsk2_KO mouse has previously been generated as an animal model of Coffin-Lowry syndrome. The aim of the present study was to identify possible neurochemical dysregulation associated with the behavioral and morphological abnormalities exhibited by mrsk2_KO mice. A cortical dopamine level increase was found in mrsk2_KO mice that was accompanied by an over-expression of dopamine receptor of type 2 and the dopamine transporter. We also detected an increase of total and phosphorylated extracellular regulated kinase that may be responsible for the increased level of tyrosine hydroxylase phosphorylation also observed. By taking into consideration previously reported data, our results strongly suggest that the dopaminergic dysregulation in mrsk2_KO mice may be caused, at least in part, by tyrosine hydroxylase hyperactivity. This cortical hyperdopaminergia may explain some non-cognitive but also cognitive alterations exhibited by mrsk2_KO mice.

Following our hypothesis that juvenile emotional and/or cognitive experience should affect learning performance at preweaning age as well as adulthood, the present study in female Wistar rats aimed to examine the impact of (i) avoidance training at preweaning age, (ii) exposure to repeated maternal separation, (iii) the combination of both, and (iv) the blockade of dopaminergic neurotransmission on adult two-way active avoidance learning in rats. We found that preweaning, i.e. three week old, rats were less capable of avoidance learning compared to adults. Our main findings revealed that preweaning avoidance training alone improved avoidance learning in adulthood. Furthermore, maternal separation alone also improved avoidance learning in preweaning and in adult rats, but this effect of maternal separation did not add up to the beneficial effect of preweaning avoidance training on adult learning. In addition, the pharmacological blockade of dopamine receptors during preweaning avoidance training via systemic application of haloperidol impaired preweaning avoidance performance in a dose-dependent manner. Testing the haloperidol-treated preweaning presumed "non-learners" as adults revealed that they still showed improved learning as adults. Taken together, our results strongly support the hypothesis that emotional as well as cognitive experience at preweaning age leaves an enduring "memory trace," which can facilitate learning in adulthood. Our pharmaco-behavioral studies suggest that unlike the adult brain, preweaning learning and memory formation is less dependent on dopaminergic mechanisms, which raises the intriguing question of possible alternative pathways.

Methylphenidate (MP) is widely used to treat attention deficit/hyperactivity disorder in children. However, basic research has been mainly focused on MP treatment in adult, behaviorally normal rodents. Here we analyzed MP-evoked changes of dopamine (DA) release in the limbic system of juvenile rodents with hyperactive and attention deficit-like symptoms. Using dual probe in vivo microdialysis, DA levels were quantified in the medial prefrontal cortex and nucleus accumbens of juvenile and adolescent degus (Octodon degus). Acute stress- and acute MP-evoked dopaminergic responses in normal juvenile and adolescent animals were compared with (i) animals showing symptoms of hyperactivity and attention deficits induced by early life stress, i.e. repeated parental separation during the first 3 weeks of life, and (ii) animals chronically treated with MP during pre-adolescence. Our main results revealed that (i) early life stress and (ii) chronic MP treatment during pre-adolescence cross-sensitize limbic dopaminergic functions in adolescent animals. Furthermore, we demonstrated a unique pattern of acute MP-evoked DA release in the juvenile compared with the adolescent medial prefrontal cortex and nucleus accumbens. Our findings that the functional maturation of dopaminergic limbic function is significantly altered by early life experience, i.e. repeated parental separation and chronic MP treatment, allow novel insights into the etiology of attention deficit/hyperactivity disorder and into the long-term consequences of MP treatment on brain development.

Exposing pups of the rodent species Octodon degus to periodic separation stress during the first three postnatal weeks leads to behavioral alterations, which include reduced attention towards an emotional stimulus and motoric hyperactivity. These behavioral changes, which are reminiscent of symptoms of attention deficit hyperactivity disorder (ADHD), are paralleled by synaptic changes in the dorsal anterior cingulate cortex (ACd), a limbic cortex region, which plays a key role in the modulation of attentional and executive functions. ADHD is typically treated with methylphenidate (MP), a drug acting on the dopaminergic system. However, the effect of chronic MP-treatment on neuronal and synaptic maturation in the developing brain is unknown. Applying the Golgi-Cox stainining technique, we tested in which way chronic MP-treatment interferes with dendritic and synaptic development in the ACd and whether this treatment can restore the stress-induced changes of neuronal connectivity. We found that chronic treatment with 1 mg/kg MP recovers stress-induced changes of spine densities in the ACd. Furthermore, MP-treatment resulted in increased dendritic length and complexity in both, stressed as well as unstressed control animals. These results indicate that synaptic reorganization as well as dendritic growth in the prefrontal cortex continue into prepuberty and are modulated by MP-treatment.

Decades of research in the area of developmental psychobiology have shown that early life experience alters behavioral and brain development, which canalizes development to suit different environments. Recent methodological advances have begun to identify the mechanisms by which early life experiences cause these diverse adult outcomes. Here we present four different research programs that demonstrate the intricacies of early environmental influences on behavioral and brain development in both pathological and normal development. First, an animal model of schizophrenia is presented that suggests prenatal immune stimulation influences the postpubertal emergence of psychosis-related behavior in mice. Second, we describe a research program on infant rats that demonstrates how early odor learning has unique characteristics due to the unique functioning of the infant limbic system. Third, we present work on the rodent Octodon degus, which shows that early paternal and/or maternal deprivation alters development of limbic system synaptic density that corresponds to heightened emotionality. Fourth, a juvenile model of stress is presented that suggests this developmental period is important in determining adulthood emotional well being. The approach of each research program is strikingly different, yet all succeed in delineating a specific aspect of early development and its effects on infant and adult outcome that expands our understanding of the developmental impact of infant experiences on emotional and limbic system development. Together, these research programs suggest that the developing organism's developmental trajectory is influenced by environmental factors beginning in the fetus and extending through adolescence, although the specific timing and nature of the environmental influence has unique impact on adult mental health.

Zusammenfassung Frühkindliche emotional gesteuerte Lernprozesse, wie die Entstehung der Kind-Eltern Beziehung, sind von grundlegender Bedeutung für die Ausbildung normaler sozioemotionaler und intellektueller Fähigkeiten. Tierexperimentelle Untersuchungen haben gezeigt, dass Störungen dieser emotionalen Bindung zu Veränderungen der Gehirnorganisation und zu Defiziten nicht nur im emotionalen, sondern auch im kognitiven Bereich führen. Das Ziel unserer Forschungsarbeiten ist es, die zellulären und molekularen Mechanismen zu untersuchen, die der erfahrungsabhängigen Gehirnreifung zu Grunde liegen, und herauszufinden, in welcher Weise frühkindliche emotionale Erfahrungen diese Prozesse beeinflussen. In unseren Untersuchungen am Modell der Filialprägung des Haushuhnkükens und der Elterndeprivation bei der Strauchratte (Octodon degus) konnten wir zeigen, dass die Unterbrechung des Kind-Eltern Kontaktes (Elternseparation) zu langfristigen spezifischen synaptischen Veränderungen in limbischen kortikalen Regionen führt, die bei emotionalem Verhalten, Lernen und Gedächtnisbildung eine grundlegende Rolle spielen. Zudem stellte sich heraus, dass es im Verlauf von frühkindlichen Erfahrungen zu erheblichen Veränderungen des Gehirnstoffwechsels kommt, die möglicherweise einen Ausgangspunkt für die später auftretenden synaptischen Veränderungen bilden. Weiterführende, interdisziplinäre Untersuchungen sollen zeigen, inwieweit die aus solchen tierexperimentellen Ansätzen gewonnenen Erkenntnisse einerseits in die Entwicklung neuer pädagogischer Konzepte im Vorschulbereich einfließen können, und ob sie andererseits auch dazu beitragen könnten, die Entstehung von entwicklungs- und umweltinduzierten Verhaltens- und Lernstörungen besser zu verstehen.