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The size of the intra-/infrapyramidal mossy fiber projections (IIP-MF) and their left/right asymmetry were assessed in 86 mice of either sex, including 26 animals from two mouse lines bred for strong or weak paw preference, 38 mice of a randomly bred F3 generation derived from an eight-way cross, and 22 mice with variably sized corpora callosa in which only the left hippocampus was measured. Prior to morphometry, all mice were tested for paw preference. In addition, we compared the strain means in paw preference as observed in nine inbred mouse strains with known differences in their IIP-MF distribution. Mice bred for strong paw preference had a 70% larger IIP-MF projection than weakly lateralized and dyscallosal mice; random-bred mice fell in-between the extremes. The individual scores of the strength of paw preference were positively correlated with the extent of the IIP-MF. Among the inbred strains, the extent of the IIP-MF was similarly correlated with the strength of paw preference. The acallosal mice showed a significant negative correlation between extent of the IIP-MF projection and test-retest reliability of paw use. The left-right asymmetry of the IIP-MF was significantly and positively correlated with the direction of paw preference in the entire sample. We conclude that size and asymmetry of the IIP-MF projection are some of the many factors influencing the direction of paw preference and its strength, albeit moderately. We hypothesize that mice with larger IIP-MF projections use a given paw more consistently, being perhaps more resistant to interferences, and that left-right asymmetries of the IIP-MF may bias and/or reinforce an initial choice of a paw. In addition, the data provide another example of correlations between IIP-MF variations and nonspatial behavior.

In the present study, variations of cholinergic and GABAergic markers in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) and the hippocampus of eight different inbred mouse strains were investigated. By means of immunocytochemistry against the acetylcholine-synthesizing enzyme choline acetyltransferase (ChAT), the cholinergic neurons were visualized and the number of ChAT-positive neuronal profiles in the MS/vDB was counted. Cholinergic and GABAergic septo-hippocampal projection neurons were detected with a combined retrograde tracing and immunocytochemical approach. In order to quantify the cholinergic innervation of various hippocampal sub-regions, we estimated the density of acetylcholinesterase (AChE)-containing fibers as visualized by AChE histochemistry. Additionally, the densities of muscarinic receptors (mainly the subtypes M1 and M2) in different hippocampal areas of seven inbred strains were measured by means of quantitative receptor autoradiography. We found significant strain differences for the number of ChAT-positive neurons in the MS/vDB; in the numbers of cholinergic septo-hippocampal projection neurons; in the density of cholinergic fibers in hippocampal subfields CA3c, CA1, and in the dentate gyrus; and in the density of muscarinic receptors in the hippocampus. In contrast the GABAergic component of the septo-hippocampal projection did not differ between the strains investigated. The number of ChAT-reactive neurons in the MS/vDB was not correlated with either hippocampal cholinergic markers. This might be attributed to different collateralization of cholinergic neurons or to different projections of these neurons to other brain regions. These results show a strong hereditary variability within the septo-hippocampal cholinergic system in mice. In view of the role of the cholinergic system in learning and memory processes, strain differences in cholinergic markers might be helpful in explaining behavioral variation.

We investigated the contribution of the septo-hippocampal cholinergic and GABAergic system to spatial and nonspatial aspects of learning and memory that had previously been found to correlate with the extent of the hippocampal intra- and infrapyramidal mossy fiber projection in different inbred mouse strains. The following cholinergic and GABAergic markers were measured in the septi and hippocampi of male mice: the number of cholinergic and parvalbumin-containing neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB), the number of septo-hippocampal cholinergic and GABAergic projection neurons, the density of cholinergic fibers in different hippocampal subfields, and the density of muscarinic receptors (predominantly M1 and M2) in the hippocampus. In addition, animals were behaviorally tested for spatially dependent and activity-dependent variables in a water maze and spatial and nonspatial working and reference memory in different experimental set-ups in an eight-arm radial maze. Using only those variables for which significant strain differences were obtained, we looked for covariations between behavior and neuroanatomy. The density of cholinergic fibers in the dentate gyrus was significantly correlated with activity-dependent learning in the water maze, whereas the number of septo-hippocampal cholinergic projection neurons correlated with spatial and, to a lesser extent, also with nonspatial aspects of radial maze learning. Only weak correlations were found between receptor densities and behavioral traits. From these data we conclude that variations in the septo-hippocampal cholinergic system, like variations in the mossy fiber projection, entail functional consequences for different types of maze learning in mice.

We study the effect of noise on the behaviour of a dynamic cell population model in which cell replication and maturation take place simultaneously. We assume that the maximum proliferative potential v fluctuates uniformly about a mean value of v, and show that a decrease in v and/or the input flux uin into the population can lead to an increase in the variance in the cellular efflux uf. We draw a qualitative correspondence between this behaviour and the commonly observed increase in the variance of circulating blood cell numbers following chemotherapy and radiotherapy, both of which lead to a decrease in v and uin, and bone marrow transplant which probably corresponds to a decrease in uin.

Male mice from nine inbred mouse strains were tested at the age of 3 months in either a spatial or a non-spatial version of the radial maze. Only four out of eight arms contained food rewards, permitting simultaneous assessment of working and reference memory in both situations. Other animals from the same strains were processed histologically to estimate the strain-specific extents of the mossy fibre projections. No significant between-task correlations were obtained for either working or reference memory. However, measures of working and reference memory correlated with each other within tasks. This suggests that these concepts may perhaps not be validly used in the mouse. Large, positive correlations of the size of the intra- and infrapyramidal mossy fibre projection with both working and reference memory were obtained in the spatial radial maze task, but not in the non-spatial one. We conclude that heritable variations of the hippocampal intra- and infrapyramidal mossy fibre projection influence processes related to spatial learning capabilities in radial mazes.

Behavioral responses to novelty in an open field and spatial learning in a radial maze with four arms out of eight reinforced were tested in male and female CFY and Long-Evans rats. Subsequently, the sizes of the total hippocampi and of various hippocampal cell layers and terminal fields at the midseptotemporal level were measured in Timm-stained sections. No strain differences were found in the open field (except for defecation). In the radial maze, Long-Evans rats showed better spatial reference memory capabilities than rats of the CFY strain. The relative sizes of the intra- and infrapyramidal mossy fiber (IIP-MF) projections did not differ between the strains. Within the more variable CFY strain, a positive correlation between the size of the IIP-MF projection and radial maze performance was found. The absolute sizes of the entire hippocampi and all hippocampal layers at the midseptotemporal level were larger in the CFY strain. The size of the suprapyramidal mossy fiber projection was related to the number of granule cells and to the ratio between granule and CA3 pyramidal cells. In contrast, the size of the IIP-MF projection did not correlate with either of these variables. The results indicate that the size of the mossy fiber projection may be determined mainly by the available postsynaptic surface on the dendrites of CA3 pyramidal neurons. Furthermore, an increased number of granule cells and their larger projection to the apical dendrites of pyramidal neurons does not appear to result in physiological changes with behavioral consequences.(ABSTRACT TRUNCATED AT 250 WORDS)

To elucidate the relation of genetically induced variations in two-way active avoidance performance and the extent of the hippocampal infra/intrapyramidal mossy fiber system (IIP-Mf) in inbred mouse strains DBA/2 (high performance, small IIP-Mf) and C3H (low performance, large IIP-Mf) we investigated a backcross line containing the DBA/2-derived genetic determinants for high avoidance performance in a C3H background. In the seventh backcross generation variations in performance analogous to the original strains were observed whereas the extent of mossy fibers was nearly homogeneous. This result suggests that both variables are determined by separate genetic factors at least in these strains and that differences in mossy fiber distribution are not an essential prerequisite for different active avoidance performance.

Newborn male pups of the inbred mouse strain DBA/2J were injected with a buffered solution of L-thyroxine, known to induce a hyperplasia of the intra- and infrapyramidal mossy fiber terminal fields (iip-MF). Because previous studies have shown that the size of the iip-MF correlates positively with both reference memory and working memory in a spatial radial maze task, we expected improved performance on such a task in the treated animals. Such an improvement was in fact found for both reference and working memory. We conclude that the iip-MF are functionally involved in the regulation of spatial learning and memory in mice.

We investigated hippocampal anatomy in artificially-produced chimeras derived by the aggregation of embryos from two widely-studied inbred mouse strains, C57BL/6J and BALB/cJ. Contrary to expectations, the chimeras were not always intermediate between the parental strains. For a number of characters, the chimeras exceeded qualitatively as well as quantitatively the phenotypical range displayed by both inbred parental strains. These findings imply that if only one parent is available for comparison, for instance, in studies involving a normally inviable genotype, separating effects of this genotype from idiosyncratic effects inherent to the chimeric model will be very difficult, if not impossible.

The combined Golgi/electron microscope (EM) technique and immunocytochemistry for glutamate decarboxylase (GAD) were used to study the differentiation of pyramidal neurons and GABAergic inhibitory non-pyramidal cells in slice cultures of rat and mouse hippocampus. Golgi-impregnated and gold-toned cultures showed the characteristic curved structure of the Ammon's horn. Hippocampal regions CA1, CA3 and fascia dentata could easily be recognized. Pyramidal neurons in CA1 displayed all characteristics of this cell type known from Golgi studies in situ. A triangular cell body gives rise to a main apical dendritic shaft which gives off several side branches. Basal dendrites and the axon originate at the basal pole of the cell body. Apical and basal dendrites are densely covered with spines. As a characteristic feature of the cultured pyramidal cells, numerous spines were observed on the cell body. Most likely due to flattening of the slice during incubation, the pyramidal neurons in CA1 are no longer arranged in a densely packed layer. This results in more space between cell bodies which is filled in by numerous horizontal and basal dendrites originating from the pyramidal cell perikaryon. CA1 pyramidal neurons in slice cultures of the rat or mouse thus resemble the pyramidal neurons in the CA1 region of the primate hippocampus where a similar loose distribution of cell bodies is found. In the electron microscope, cell bodies and dendritic shafts of the gold-toned pyramidal cells formed symmetric synaptic contacts with presynaptic terminals. Numerous boutons were observed that established asymmetric synaptic contacts on gold-toned spines of peripheral pyramidal cell dendrites. This suggests that considerable synaptic reorganization takes place because in situ spines on peripheral dendritic segments are contacted mainly by extrinsic afferents. Like in situ, at least some of the terminals that establish symmetric synaptic contacts are GABAergic. In our immunocytochemical study we observed numerous GAD-positive terminals that formed a dense pericellular plexus around immunonegative cell bodies of pyramidal neurons. In the electron microscope these structures were identified as presynaptic boutons which formed symmetric synaptic contacts on cell bodies and dendritic shafts. They most likely originated from the GAD-positive neurons scattered in all layers of the slice culture. Our results have shown that the main cell types in the hippocampus, pyramidal neurons and GABAergic inhibitory non-pyramidal cells, survive and differentiate under the present culture conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Large differences in hippocampal lamination have been found between several inbred strains of mice. These variations are thought to be caused by differences in developmental processes. We produced aggregation chimaeras between the inbred strains BALB/c and C57BL/6 and studied the lamination patterns in these animals. Next to some intermediate patterns, several patterns not occurring in the donor strains were obtained. These patterns differed also from those found in F1 hybrids. Thus, although the genetic information from both parental strains is present in both F1 and chimaeric mice, different processes occur during development.

Twenty-four male mice, belonging to 8 different inbred strains, were tested in an 8-arm radial maze. Clear strain differences were found for performance on the third day of training, which correlated very strongly with the size of the hippocampal intra- and infrapy ramidal mossy fibre (iip-MF) terminal fields. These results, combined with those from earlier experiments, indicate that genetic variations of the iip-MF projection influence processes that determine behavioural abilities of mice.

We present a simple mathematical model for the self-controlled growth of a tissue giving rise to an oscillating tissue size under certain conditions. The control is brought about by two substances (two inhibitors or one inhibitor and one nutrient) which influence the cell kinetics locally. The inhibitors are produced by the tissue itself (whereas the nutrient comes from outside but is consumed by the tissue which produces the same effect). Both diffuse freely throughout the tissue, and thus realize a communication between different parts of the tissue. In any case the tissue approaches a self-maintaining space-time structure with properties depending on the parameters of proliferation, death and inhibiting control. We discuss the conditions for this structure not to be time-independent but oscillating.

A classical cross-breeding study involving the inbred mouse strains DBA/2 and C3H/HeJ revealed a rather complex mode of inheritance for the following hippocampal variables: size of stratum pyramidale, number of supra-, intra- and infrapyramidal mossy fiber synapses, and the size of terminal fields receiving entorhinal input. A polygenic mode of inheritance was inferred for these phenotypes. For the size of the regio inferior a model containing additive genetic effects only was sufficient to explain the variation between generations. The strain difference may be caused by one genetic factor only. In agreement with previous experiments a strong negative correlation between the number of intra- and infrapyramidal mossy fiber synapses and shuttle-box avoidance performance was found in the genetically heterogeneous F2 population.

The distribution of hippocampal mossy fiber terminals, visualized by means of Timm's silver sulfide stain, was determined morphometrically in a selected hippocampal region. Five inbred mouse strains and two rat strains were used, all of them characterized by genetically controlled differences in performing a two-way avoidance task (shuttle-box). Those rat and mouse strains known for low avoidance scores had significantly more mossy fiber terminals synapsing within or below the layer hippocampal pyramidal neurons.

Acute and chronic treatment of Chinese hamsters and mice with 5, 25 and 125 mg/kg isoniazid (INH) given by oral intubation did not enhance the chromosomal aberration frequencies in spermatogonia. The structural and numerical aberration rates remained in the range of spontaneous events even after the chronic treatment over 12 weeks with 3 x 125 mg/kg INH per week. This dose is much higher than normally used for prevention and therapy in man (3--16 mg/kg).

Mice systematically bred for randomization of their genotype show large individual differences when performing a two-way avoidance task (shuttle-box learning). Their behavioral scores correlate strongly (r = -0.80, P less than .01) with the number of mossy fibers synapsing on basal dendrites of hippocampal pyramidal neurons, poor avoiders having relatively more such terminals. This confirms previous findings showing that rat and mouse strains known for genetically dependent poor avoidance learning have extended intra- and infrapyramidal mossy fiber projections.

Employees of plants where alkylene oxide is manufactured or processed were subjected to mutagenicity studies carried out on lymphocyte cultures in accordance with the methods of Moorhead at al, de Jong and Anders. The employees were divided into four groups, according to their periods of exposure: (1) Long-term exposure for more than 20 years; (2) exposure for less than 20 years; (3) long-term exposure and accident (ethylene oxide inhalation or skin contact); and (4) accident, i.e., brief high exposure to ethylene oxide. Measurement of the concentrations in various sections of the plant yielded values of up to 3 ppm under conditions of normal operation. However, this figure rose briefly to 1900 ppm under plant breakdown hat workers were subjected to higher exposure in the past. One hundred metaphases per person were analyzed for chromosome aberrations. The results are given in Tables 1 through 4. A significant increase in the aberration rate was found only in employees in Group 1. This was confirmed by a control examination carried out one year later. The employees of groups 2, 3 and 4 displayed no significant increases. However, in evaluating these findings, it should be noted that the employees had been in contact with a wide range of substances and products in the course of their occupation, which means that the increased aberrations rate found cannot be attributed unequivocally to exposure to a particular substance.

In one short-term-experiment and one long-term-experiment spermatogonia of mice and Chinese hamsters were compared for their sensitivity of X-ray induced chromosome aberrations. Short-term-experiment: Six hours after varying doses of X-rays the spermatogonia of both species were analysed and the number of induced chromatid breaks determined. At the dose range from 25-125 R the number of induced chromatid breaks per cell per roentgen is 0.01 in mice. In Chinese hamsters this value is 0.0072. The frequencies of chromatid breaks were studied in both species after a single dose of 100 R until 48 h p.i. The frequency in mice decreased more slowly than in hamster spermatogonia. After 12 h p.i. the ratio breaks in mice cells: breaks in hamster cells was 3.5:1, after 24 h this ratio was 5.2:1 after 48 h both frequencies were on the same level. Long-term-experiment: Analysis of spermatogonia and primary spermatocytes has been done 5 weeks after irradiation of the mice and 2, and 4 months after irradiation of the Chinese hamsters. The number of observed reciprocal translocations turned out to be higher in spermatogonial mitoses than in diakinesis-metaphases I in each animal. The conclusion is drawn for mice that a selection against abnormal cells is taking place already during pre-meiosis. In hamster pre-meiosis, the results are only indicative for a similar effect.

The concepts of self-generation, autonomous boundary and self-maintenance are explained briefly. The "protocell" is presented as a model of self-maintenance which is based on simple physical mechanisms of diffusion and reaction. The time evolution of the surface of the protocell is taken into account explicitly in the form of a Stefan condition giving rise to a non-linear feedback of the surface motion to the reaction and diffusion processes inside the protocell. The spatio-temporal dynamics are investigated, particularly in the neighbourhood of the stationary states, showing a self-maintaining behaviour under a certain range of nutritional conditions. Under another set of conditions we find an instability leading to a division process so that the population of protocells becomes self-maintaining instead of the single individual. The presented formulation of the protocell model is crucially improved compared with a previous version which required boundary conditions at infinity. The previous version was not strictly self-maintaining since dynamics outside the cell were essential for its behaviour.

Living systems are characterized as self-generating and self-maintaining systems. This type of characterization allows integration of a wide variety of detailed knowledge in biology. The paper clarifies general notions such as processes, systems, and interactions. Basic properties of self-generating systems, i.e. systems which produce their own parts and hence themselves, are discussed and exemplified. This makes possible a clear distinction between living beings and ordinary machines. Stronger conditions are summarized under the concept of self-maintenance as an almost unique character of living systems. Finally, we discuss the far-reaching consequences that the principles of self-generation and self-maintenance have for the organization, structure, function, and evolution of single- and multi-cellular organisms.

Behavioral phenotypes that are studied in mammals are seldom specific for the understanding of the biologic basis of human behavior. Phenomenologic comparisons primarily demonstrate the existence of genetically determined variabilities and do not allow for any further interpretations. A satisfactory state--using systems of lower complexity--will be reached when neuromorphologic or neurochemical variations can be traced back to phenomenologic differences with single-gene modes of inheritance. In a new study extensive data prove the single-gene inheritance of active avoidance learning. A correlated study carried out in a behavioral genetics and neuroanatomical laboratory showed that, owing to strain differences in mice, there is some probability of a multiple allelic system correlating with the hippocampal mossy fiber distribution.

Genetically-defined rodent strains permit the identification of hippocampal traits which are of functional relevance for the performance of two-way avoidance behavior. This is exemplified here by analyzing the relationship between infrapyramidal mossy fibers (a tiny projection terminating upon the basal dendrites of hippocampal pyramidal neurons) and two-way avoidance learning in about 800 animals. The necessary steps include 1) identification of structural traits sensitive to selective breeding for extremes in two-way avoidance, 2) testing the robustness of the associations found by studying individual and genetical correlations between hippocampal traits and behavior, 3) establishing causal relationships by Mendelian crossing of strains with extreme structural traits and studying the behavioral consequences of such structural 'randomization', 4) confirming causal relationships by manipulating the structural variable in inbred (isogenic) strains, thereby eliminating the possibility of genetic linkage, and 5) ruling out the possibility of spurious associations by studying the correlations between the hippocampal trait and other behaviors known to depend on hippocampal functioning. In comparison with the classical lesion approach for identifying relationships between brain and behavior, the present procedure appears to be superior in two aspects: it is non-invasive, and it focuses automatically on those brain traits which are used by natural selection to shape behaviorally-defined animal populations, i.e., it reveals the natural regulators of behavior.

A physico-chemical model of a self-maintaining unity or protocell is constructed on the basis of reaction and diffusion processes. The surface motion of the protocell is taken into account explicitly by a so-called Stefan condition, which leads to a nonlinear feedback to the reaction and diffusion processes. The spatio-temporal dynamics in the neighbourhood of the steady states is investigated in the framework of linear stability analysis with the use of an expansion in terms of spherical harmonics Ylm. It is shown that modes with l greater than or equal to 2 become successively unstable with increasing nutrient supply. The leading instability with l = 2 initiates a process of the nonlinear dynamics which is interpreted as the onset of division. A stabilizing effect of surface tension is also discussed.