Research activities    

  Articlel Wall Street Journal      /   curious?

 Early life emotional experience alters limbic brain circuits and emotional and cognitive behavior

Whereas the basic wiring diagram of the brain is genetically preprogrammed, its fine tuning throughout different phases of infancy, childhood, and adulthood are highly experience dependent. Normal brain development requires the precise interactions of environmental signals with genes and molecules that drive cellular differentiation and circuit formation. A critical regulator of these events is the dyadic interaction between the newborn and its parents, which controls the sensory and the socio-emotional environment of the developing individual and thereby interferes with brain development. The dyadic interaction between the newborn and its parents, carried by the reciprocal exhibition of parental/maternal behavior and newborn signaling, promotes physiological and immunological resilience, physical maturation and species-typical social and emotional development in the young individual. Such continued, adequate and well balanced stimulation contributes to the formation of a normally functioning limbic system. In contrast, disturbances or the interruption of the parent/mother-infant interactions may result in the formation of defective synaptic circuits, being responsible for the retarded or disturbed behavioral outcome which is observed in deprived individuals. Although on the behavioral level there is considerable evidence for rodents and primates including man that parental/maternal deprivation impairs the development of mental capacities and socio-emotional competence, systematic and multidisciplinary investigations are lacking to clarify causal relationships between behavioral pathology and abnormal brain cytoarchitecture and function. Thus, the aim of our research is to identify and characterize the cellular principles, the endocrine/hormonal, neurochemical and molecular mechanisms which underlie learning-and experience-induced brain maturation and to evaluate the behavioral effects of socio-emotional deprivation and early life stress.

Our experiments in different animal models   

unveiled the remarkable influence of the parent-infant contact on brain development and are in line with our working hypothesis that juvenile learning events and emotional experience have a strong impact on the functional maturation of the limbic pathway. The detailed knowledge of the neurobiology of such self-organizing plastic systems may begin to change our conceptual approaches to psychopathology and open new avenues of therapeutics for the major psychiatric illnesses that are critically dependent on such learning and memory mechanisms. Furthermore, the knowledge of the basic principles of learning- and memory-related neuronal plasticity may in the future be applied for innovative neuropaedagogic concepts for the preschool/elementary school levels.

 Changing the wiring: Cellular mechanisms of experience-induced synaptic plasticity

C. Helmeke J. Bock, W. Ovtscharoff jr, A. Abraham, R. Schnabel, U. Kreher, S. Becker, R. Antemano

Our studies in rodents (Octodon degus, Rattus rattus norwegicus) revealed that early traumatic emotional experience, such as stress during pregnancy, parental separation and chronic social isolation and early weaning, modifies the excitatory as well as monoaminergic modulatory synaptic input in the cortical and subcortical limbic areas in a time-dependent manner.These results confirm that early socio-emotional environment interferes with synaptic development in the prefrontal cortex and other limbic areas. Since the limbic system is critical for a variety of emotional behaviors and associative aspects of learning, such experience-induced morphological changes may lead to altered behavioral and cognitive capacities in later life.

In order to identify changes of ultrastructural parameters in relation to early experience we developed techniques for the three dimensional reconstruction of dendrites and spines from confocal laserscan image stacks and from ultrathin sections, in which synaptic parameters such as  the surface, volume, curvatures, shape of the PSD etc can be measured.

Analysis of fine morphological parameters of dendritic spines are analysed on Dyl-injected or GFP-transfected cortical, hippocampel and amygdalar neurons to study effects of stress, deprivation, learning and memory formatin.The 3D-measurements of spines are performed in image stacks produced by a confocal laser scanning microscope or serial ultrathin sections from electron microscopy applying newly developed image analysis softwares.

3-dimensional reconstruction of dendrite segment  with spine (yellow) and presynaptic bouton (red). Dendritic segment was imported into "3D Studio Max" to produce a final image.	3D-Rendering	Measure of volume  and surface area     1. picture: 2D 2. picture: 3D-skeletal 3. picture: 3D
3-dimensional reconstruction	Cells surfaced by PC from  2D traced profiles into 3D reconstructed volume.	Electron micrograph from cultivated hippocampal neuron illustrates different  synaptic populations (spine and shaft) . Calibration bar 0.25 µm.

We obtained first evidence that early life stress results in lasting changes of distinct shape parameters of presumed excitatory spine synapses, which most likely reflect a experience-related fine-tuning of synaptic strength within limbic cortical circuits.

 Molecular mechanisms of spine plasticity: studies in vitro

K. Braun, U. Kreher, C. Helmeke, W. Ovtscharoff jr.

To study the mechanisms underlying the formation of dendritic spines, their morphology and function under controlled conditions, we used a model system for an inherited mental disorder, the fragile X mental retardation syndrome. Fragile-X, the main cause of inherited human mental retardation, is associated with the absence of a recently identified Fragile-X mental retardation protein (FMRP). Mice in which this protein is lacking due to a knockout (FMR1-/-) mutation, express altered levels of amino acid neurotransmitters, monoamines and their metabolites (Gruss and Braun, in press). Furthermore, they display elevated densities of dendritic spines on their cortical neurons, compared to wild type (WT) controls.  

Is FMRP involved in activity-induced plasticity of dendritic spines? Pharmacological stimulation of electrical activity, induced by bicuculline, caused a reduction in dendritic spine density, which was significant for the FMR1-/- cell but not for the WT cells. In both groups, bicuculline induced a significant shrinkage of spines which were occupied by one or more synaptophysin-immunoreactive presynaptic terminals FMRP expression was not affected in the wild-type cultures by bicuculline stimulation.

Early life stress-induced changes of metabolism and transmitter receptors: autoradiographic studies

J. Bock, K. Braun

In order to identify the brain regions, whose functional development may be affected by juvenile traumatic experience, we applied the 14C-2-fluorodesoxyglucose (2-FDG) technique in 8-day old Octodon degus pups in order to measure acute metabolic effects of the very fist experience of parental deprivation. 

We found that early stressful situations lead to alterations of metabolic activity in distinct cortical and subcortical limbic areas, and that this reduced metabolic activation can be ameliorated by the presence of the siblings and by presentation of the mother´s call.

To gain more insight into the molecular synaptic changes in response to early traumatic life events we analyzed alterations of transmitter receptor densities in parentally deprived Octodon degus. Furthermore, we analyzed if the mother´s voice can protect from the expected separation-induced changes of brain function (Ziabreva et al., 2001). 

An upregulation of D1 receptor density   

was measured in different subregions of the medial prefrontal cortex, hippocampus and amygdala, but not in the CA3 region of the hippocampus of parentally separated animals. At the behavioral level, the acoustic presence of the mother reduced the exploratory activity during open field tests, and the mother´s voice significantly suppressed D1 receptor upregulation in the medial prefrontal cortex, but not in the other brain areas.

These results indicate that vocal communication, which is an essential part for the establishment and maintenance of the infant-parent attachment is used to provide the newborn with emotional input that reduces stress during exposure to an unfamiliar environment. The mother's call can "protect" the brain from deprivation/stress-induced neurodevelopmental alterations.

Collaborations:

Prof. Dr. Gerd Poeggel, Zoologisches Institut, University of Leipzig

Prof. Micah, Leshem, Dept. Psychology, Haifa University,

Prof. Marta Weinstock, Dept. Pharmacology, Hebrew University Medical Center, Jerusalem

Prof. M. Segal, The Weizman Institute, Rehovot, Israel;

Prof. Dr. B. Michaelis, Institute for Electronics, Signal Processing and Communication, Otto-von-Guericke University Magdeburg

A. Herzog

Prof. T. Voigt, Institute of Physiology (Developmental Physiology), Medical Faculty, Otto-von-Guericke University Magdeburg

Prof. Dr. G. Richter-Levin and Prof. Micah Leshem, Haifa, Israel

Prof. Dr. B. Bogerts, Klinik für Psychiatrie, Psychotherapie und Psychosomatische Medizin, Medical Faculty, Otto-von-Guericke University Magdeburg

Prof. Dr. Alois Krost, Institut für Experimentelle Physik, Department of Semiconductor Epitaxy, Otto-von-Guericke University Magdeburg

[back to Research]