Jörg Bock

Changes of spine density and dendritic complexity in the prefrontal cortex in offspring of mothers exposed to stress during pregnancy

Both chronic stress in adulthood and episodes of stress in the early postnatal period have been shown to interfere with neuronal development in limbic prefrontal cortical regions. The present study in rats showed for the first time that the development of layer II/III pyramidal neurons in the dorsal anterior cingulate (ACd) and orbitofrontal cortex (OFC) is significantly affected in offspring of mothers exposed to stress during pregnancy. In prenatally stressed (PS) male rat pups the ACd and OFC showed significantly lower spine densities on the apical dendrite (ACd, −20%; OFC, −25%), on basal dendrites reduced spine densities where found only in the OFC (−20% in PS males). Moreover, in both cortical areas a significant reduction of dendritic length was observed in PS males compared to control offspring, which was confined to the apical dendrites (ACd, −30%, OFC, −26%). Sholl analysis revealed that these alterations were accompanied by a significantly reduced complexity of the dendritic trees in both cortical regions. PS females displayed reductions of dendritic spine densities in the ACd and OFC on both the basal (ACd, −21%; OFC, −20%) and apical dendrites (ACd, −21%; OFC, −21%), however, in contrast to the findings in PS males, no dendritic atrophy was detected in the PS females. These findings demonstrate that gestational stress leads to significant alterations of prefrontal neuronal structure in the offspring of the stressed mothers in a sex‐specific manner.

Weaning age, social isolation, and gender, interact to determine adult explorative and social behavior, and dendritic and spine morphology in prefrontal cortex of rats.

We tested the effect of weaning at 21 or 30 days, followed by individual or group housing, on explorative and social behavior in adult male and female rats, and in males, on dendritic length and spine density in prefrontal cortex. In the open field, rats weaned early were the most active, while those weaned late and group housed were the most explorative. In the social interaction test, behavior in adult females was relatively impervious to weaning age or rearing condition. Isolated males sought out social interaction, whereas, group-reared males tended to avoid it. Social behaviors in males weaned early or group-reared correlated with decreased dendrite length and spine density, whereas, non-social behaviors correlated with increased dendritic length. Such changes are consistent with neural pruning in the development of social behavior. Although our experimental manipulations were mild, and serve as standard rearing conditions in many laboratories, their effects on brain and behavior were marked, and differed by gender. Early rearing conditions may have few appreciable effects when studied in isolation, but their interactive effects on adult social behavior are significant and varied.

Perinatal programming of emotional brain circuits: an integrative view from systems to molecules.

Environmental influences such as perinatal stress have been shown to program the developing organism to adapt brain and behavioral functions to cope with daily life challenges. Evidence is now accumulating that the specific and individual effects of early life adversity on the functional development of brain and behavior emerge as a function of the type, intensity, timing and the duration of the adverse environment, and that early life stress (ELS) is a major risk factor for developing behavioral dysfunctions and mental disorders. Results from clinical as well as experimental studies in animal models support the hypothesis that ELS can induce functional “scars” in prefrontal and limbic brain areas, regions that are essential for emotional control, learning and memory functions. On the other hand, the concept of “stress inoculation” is emerging from more recent research, which revealed positive functional adaptations in response to ELS resulting in resilience against stress and other adversities later in life. Moreover, recent studies indicate that early life experiences and the resulting behavioral consequences can be transmitted to the next generation, leading to a transgenerational cycle of adverse or positive adaptations of brain function and behavior. In this review we propose a unifying view of stress vulnerability and resilience by connecting genetic predisposition and programming sensitivity to the context of experience-expectancy and transgenerational epigenetic traits. The adaptive maturation of stress responsive neural and endocrine systems requires environmental challenges to optimize their functions. Repeated environmental challenges can be viewed within the framework of the match/mismatch hypothesis, the outcome, psychopathology or resilience, depends on the respective predisposition and on the context later in life.

Early life stress-induced histone acetylations correlate with activation of the synaptic plasticity genes Arc and Egr1 in the mouse hippocampus

Early life stress (ELS) programs the developing organism and influences the development of brain and behavior. We tested the hypothesis that ELS‐induced histone acetylations might alter the expression of synaptic plasticity genes that are critically involved in the establishment of limbic brain circuits. Maternal separation (MS) from postnatal day 14–16 was applied as ELS and two immediate early genes underlying experience‐induced synaptic plasticity, Arc and early growth response 1 (Egr1) were analyzed. We show here that repeated ELS induces a rapid increase of Arc and Egr1 in the mouse hippocampus. Furthermore, immunoblotting revealed that these changes are paralleled by histone modifications, reflected by increased acetylation levels of H3 and H4. Most importantly, using native Chromatin immunoprecipitation quantitative PCR (nChIP‐qPCR), we show for the first time a correlation between elevated histone acetylation and increased Arc and Egr1 expression in response to ELS. These rapid epigenetic changes are paralleled by increases of dendritic complexity and spine number of hippocampal CA3 pyramidal neurons in ELS animals at weaning age. Our results are in line with our working hypothesis that ELS induces activation of synaptic plasticity genes, mediated by epigenetic mechanisms. These events are assumed to represent early steps in the adaption of neuronal networks to a stressful environment.

Influence of theN-Methyl-D-aspartate Receptor AntagonistDL-2-Amino-5-phosphonovaleric Acid on Auditory Filial Imprinting in the Domestic Chick

Newly hatched domestic chicks were injected uni- or bilaterally into the imprinting relevant forebrain region mediostral neostriatum/ hyperstriatum ventrale (MNH) with different concentrations (1, 3, 12.5, 50 nmol) of the competitive NMDA antagonist DL-5-amino-5- phosphonovaleric acid (APV) prior to exposure to the imprinting stimulus (400-Hz tone pulses). In both APV-injected experimental groups there was a dose-dependent decrease of imprinting rates compared to that seen in controls, suggesting an APV-induced blockade of the learning process. In order to find out how the injected APV interferes with the stimulus-evoked enhanced metabolic activity in imprinting-relevant brain regions and to gain information about the spatial extent of its physiological effect, 2-fluorodeoxyglucose (2-FDG) experiments were performed. Chronically APV-treated chicks which failed in the imprinting tests showed similarly low 2-FDG uptake in imprinting relevant areas as naive untreated controls, further suggesting that no learning process has occurred in these animals. In imprinted chicks acute APV injections into the MNH led to a suppression of the stimulus-evoked 2-FDG uptake in this region. This pharmacologically induced reduction extended beyond the MNH region to adjacent regions. Furthermore, unilateral injections into the MNH always resulted in a bilateral reduction of 2-FDG uptake in this area. The results suggest that NMDA-mediated mechanisms in restricted telecephalic areas such as the MNH play a crucial role in the process of auditory filial imprinting.

Differential Emotional Experience Leads to Pruning of Dendritic Spines in the Forebrain of Domestic Chicks

Auditory filial imprinting induces quantitative changes of synaptic density in the forebrain area mediorostral neostriatum/hyperstriatum ventrale of the domestic chick. The aim of the present study was to examine the time window and the extent and quality of experience that is required for the induction of these synaptic changes. We found that a brief (30 min) experience with the imprinting situation (tone stimulus + mother surrogate) is sufficient to induce spine elimination, which is detectable on postnatal day 7, but not 80 min after the presentation of the imprinting stimuli. This synaptic reorganization requires the association of the acoustic imprinting tone with an emotional reward (mother surrogate); acoustic stimulation alone does not lead to detectable synaptic changes. The results of the present study provide further evidence that juvenile emotional learning events, such as filial imprinting, lead to a selective synaptic reorganization.

Early neonatal and postweaning social emotional deprivation interferes with the maturation of serotonergic and tyrosine hydroxylase-immunoreactive afferent fiber systems in the rodent nucleus accumbens, hippocampus and amygdala.

The impact of early emotional experience on the development of serotonergic and dopaminergic fiber innervation of the nucleus accumbens, hippocampal formation and the amygdala was quantitatively investigated in the precocious rodent Octodon degus. Two animal groups were compared: 1) degus which were repeatedly separated from their parents during the first three postnatal weeks, after weaning they were individually reared in chronic social isolation and 2) controls which were reared undisturbed with their families. In the deprived animals 5-hydroxytryptamine-immunoreactive fiber densities were increased in the core region of the nucleus accumbens (up to 126%), in the central nucleus of the amygdala (up to 112%) and in the outer subregion of the dentate gyrus stratum moleculare (up to 149%), whereas decreased fiber densities were detected in the dentate subgranular layer (down to 86%) and in the stratum lacunosum of the hippocampal cornu ammonis region 1 (down to 86%). Tyrosine hydroxylase-immunoreactive fiber densities were increased in the core (up to 115%) and shell region (up to 113%) of the nucleus accumbens of deprived animals, whereas decreased fiber densities (down to 84%) were observed in the hilus of the dentate gyrus. In the stratum granulosum and subgranular layer the fiber densities increased up to 168% and 127% respectively. In summary, these results indicate that the postnatal establishment of the monoaminergic innervation of limbic areas is modulated in response to early emotional experience, and that this environmental morphological adaptation is highly region specific.

Tumor suppressor down-regulated in renal cell carcinoma 1 (DRR1) is a stress-induced actin bundling factor that modulates synaptic efficacy and cognition

Stress has been identified as a major causal factor for many mental disorders. However, our knowledge about the chain of molecular and cellular events translating stress experience into altered behavior is still rather scant. Here, we have characterized a murine ortholog of the putative tumor suppressor gene DRR1 as a unique stress-induced protein in brain. It binds to actin, promotes bundling and stabilization of actin filaments, and impacts on actin-dependent neurite outgrowth. Endogenous DRR1 localizes to some, but not all, synapses, with preference for the presynaptic region. Hippocampal virus-mediated enhancement of DRR1 expression reduced spine density, diminished the probability of synaptic glutamate release, and altered cognitive performance. DRR1 emerges as a protein to link stress with actin dynamics, which in addition is able to act on synaptic function and cognition.

The experience-dependent maturation of prefronto-limbic circuits and the origin of developmental psychopathology: implications for the pathogenesis and therapy of behavioural disorders

The maturation of prefronto‐limbic neuronal pathways that mediate essential affective and social regulatory functions is experience dependent. Immediately after birth the infant’s affective experiences, especially those embedded in the relationship with the primary caregiver, trigger the reorganization and adaptive fine‐tuning of synaptic circuits. Research in humans and in animal models supports the hypothesis that socio‐emotional deprivation and emotional trauma during early childhood may leave ‘scars’ in prefronto‐limbic function, brain regions that are essential for emotional behaviour, learning, and memory. The focus of this review is to point out that mechanisms involved in structuring and optimizing neural circuits during brain development might also be used in moulding personality and behaviour during psychotherapy in the adult brain.

Refinement of dendritic and synaptic networks in the rodent anterior cingulate and orbitofrontal cortex: Critical impact of early and late social experience

The process of weaning programs the neurobehavioral development and therefore provides a critical formative period for adult behavior. However, the neural substrates underlying these behavioral changes are largely unknown. To test the hypothesis that during childhood neuronal networks in the prefrontal cortex are reorganized in response to the timing and extent of social interactions, we analyzed the length, ramification, and spine density of apical and basal dendrites of layer II/III pyramidal neurons in four groups of male rats. (1) Early weaning at postnatal day (PND) 21 + postweaning social rearing (EWS), (2) late weaning at PND 30 + postweaning social rearing (LWS), (3) early weaning + postweaning social isolation (EWI), (4) late weaning + postweaning social isolation (LWI). Compared with late weaned animals, the early weaned animals displayed elevated spine densities on apical and basal dendrites only in the anterior cingulate (ACd), but not in the orbitofrontal cortex (OFC), irrespective of the postweaning housing conditions. For dendritic length and complexity an interaction between the factors weaning and postweaning rearing conditions was observed. In the ACd the EWI animals had longer and more complex apical dendrites compared with all other groups, whereas in the OFC the EWI animals displayed a significant reduction of apical dendritic length and complexity compared with the EWS group. Taken together, our findings show that the timing as well as the amount of social contact with family members significantly affects the refinement of prefrontal cortical synaptic networks, which are essential for emotional and cognitive behavior.