Infant avoidance training alters cellular activation patterns in prefronto-limbic circuits during adult avoidance learning: II. Cellular imaging of neurons expressing the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1).

Positive and negative feedback learning is essential to optimize behavioral performance. We used the two-way active avoidance (TWA) task as an experimental paradigm for negative feedback learning with the aim to test the hypothesis that neuronal ensembles activate the activity-regulated cytoskeletal (Arc/Arg3.1) protein during different phases of avoidance learning and during retrieval. A variety of studies in humans and other animals revealed that the ability of aversive feedback learning emerges postnatally. Our previous findings demonstrated that rats, which as infants are not capable to learn an active avoidance strategy, show improved avoidance learning as adults. Based on these findings, we further tested the hypothesis that specific neuronal ensembles are "tagged" during infant TWA training and then reactivated during adult re-exposure to the same learning task. Using cellular imaging by immunocytochemical detection of Arc/Arg3.1, we observed that, compared to the untrained control group, (1) only in the dentate gyrus the density of Arc/Arg3.1-expressing neurons was elevated during the acquisition phase of TWA learning, and (2) this increase in Arc/Arg3.1-expressing neurons was not specific for the TWA learning task. With respect to the effects of infant TWA training we found that compared to the naïve non-pretrained group (a) the infant pretraining group displayed a higher density of Arc/Arg3.1-expressing neurons in the anterior cingulate cortex during acquisition on training day 1, and (b) the infant pretraining group displayed elevated density of Arc/Arg3.1-expressing neurons in the dentate gyrus during retrieval on test day 5. Correlation analysis for the acquisition phase revealed for the ACd that the animals which showed the highest number of avoidances and the fastest escape latencies displayed the highest density of Arc/Arg3.1-expressing neurons. Taken together, we are the first to use the synaptic plasticity protein Arc/Arg3.1 to label neuronal ensembles which are involved in different phases of active avoidance learning and whose activity patterns are changing in response to previous learning experience during infancy. Our results indicate (1) that, despite the inability to learn an active avoidance response in infancy, lasting memory traces are formed encoding the subtasks that are learned in infancy (e.g., the association of the CS and UCS, escape strategy), which are encoded in the infant brain by neuronal ensembles, which alter their synaptic connectivity via activation of specific synaptic plasticity proteins such as Arc/Arg3.1 and Egr1, and (2) that during adult training these memories can be retrieved by reactivating these neuronal ensembles and their synaptic circuits and thereby accelerate learning.

Symmetric palatal swelling as the first clinical manifestation of a mantle cell non-Hodgkin's lymphoma: A case report and review of literature.

The mantle cell lymphoma (MCL) is a rare (3.7%) low-grade non-Hodgkin lymphoma originating from the B-cell precursor-subpopulation. The clinical appearance in the oral cavity is rare. Since 1980, nine cases have been reported. A 41-year-old patient showed a MCL presenting with a symmetric, painless palatal swelling without any other clinical symptoms. Histological sections revealed malignant monotonous lymphoid cells (CD20+, CD43+, Ki67+) and the typical cyclinD1 over-expression by the chromosomal translocation t(11;14)(q13;q32). The proliferating cells weekly expressed CD5, kappa-and lambda-light chains and no EMA, CD10, bcl-6, CD30, and CD23. The patient was treated according to the European MCL younger study, and the MCL is regressive. The high incidence of dento-alveolar abscesses, inflammations, or benign tumor-formations leads to associate any maxillary or palatal swelling with this clinical condition. Considering the serious consequences of a missed therapy a histological examination of any untypical "swelling" is demanded.

Knowledge of the anatomical polyp location might bias the pathological classification of histologically equivocal colorectal serrated polyps - a consensus study performed by pathology trainees.

Colorectal serrated polyps (CSPs) comprise hyperplastic polyps (HPs), traditional (TSAs) and sessile (SSAs) serrated adenomas, as well as inflammatory cloacogenic polyps (ICPs). These lesions have typical anatomical locations and share a histomorphological overlap. In this study, we assessed the so far neglected issue as to what extent the histological classification of these lesions performed by pathology trainees is biased by the pathologists' knowledge of the polyp location in dependency on the duration of their training. To reach this aim, 49 CSPs were classified by three pathology trainees blinded to clinical data. In a second round of examination, the same raters were provided with the polyp location. A third round was conducted after a consensus conference. Intra- and inter-rater analyses were performed using Kappa (K) statistics and Spearman correlations. Our data suggest that the histological classification of CSPs performed by pathology trainees might be influenced in a clinically significant fashion by knowledge of the anatomical polyp location depending on the duration of their pathology training.

Cognitive training during infancy and adolescence accelerates adult associative learning: critical impact of age, stimulus contingency and training intensity.

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.

Cellular blue nevus (CBN) lymph node metastases of the neck with no primary skin lesion: a case report and review of literature.

A case of cervical lymph node infiltration by a benign cellular blue nevus (CBN) and a 27-year disease history is presented. Dermal dendritic melanocytes and pigmented spindle cells presented no histological evidence of malignancy (CD34-, desmin-, PanCy-, HMB-45+, anti-S-100+, Bcl-2+, MART-1+, focally expression of melan A, 1% Ki-67+ of the tumour cell nucleoli). The differentiation of the benign blue nevus (BN) from a malignant blue nevus (MBN) and a malignant melanoma (MM) is still a challenge. Because of the malignant transformation potential of 5.2-6.3% a histological examination and a conservative surgical approach with close follow up are mandatory.

Overexpression of CD97 in intestinal epithelial cells of transgenic mice attenuates colitis by strengthening adherens junctions.

The adhesion G-protein-coupled receptor CD97 is present in normal colonic enterocytes but overexpressed in colorectal carcinoma. To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis. Unexpectedly, we found a CD97 cDNA copy number-dependent reduction of DSS-induced colitis in Tg compared to wild-type (WT) mice that was confirmed by applying a simple DSS protocol. Ultrastructural analysis revealed that overexpression of CD97 strengthened lateral cell-cell contacts between enterocytes, which, in contrast, were weakened in CD97 knockout (Ko) mice. Transepithelial resistance was not altered in Tg and Ko mice, indicating that tight junctions were not affected. In Tg murine and normal human colonic enterocytes as well as in colorectal cell lines CD97 was localized preferentially in E-cadherin-based adherens junctions. CD97 overexpression upregulated membrane-bound but not cytoplasmic or nuclear beta-catenin and reduced phospho-beta-catenin, labeled for degradation. This was associated with inactivation of glycogen synthase kinase-3beta (GSK-3beta) and activation of Akt. In summary, CD97 increases the structural integrity of enterocytic adherens junctions by increasing and stabilizing junctional beta-catenin, thereby regulating intestinal epithelial strength and attenuating experimental colitis.

Analysis of CD97 expression and manipulation: antibody treatment but not gene targeting curtails granulocyte migration.

The heptahelical receptor CD97 is a defining member of the EGF-TM7 family of adhesion class receptors. In both humans and mice, CD97 isoforms are expressed with variable numbers of tandemly arranged N-terminal epidermal growth factor-like domains that facilitate interactions with distinct cellular ligands. Results from treatment of mice with mAbs in various disease models have suggested a role for CD97 in leukocyte trafficking. Here, we aimed to thoroughly characterize the expression profile of CD97, and delineate its biological function. To this end, we applied a novel polyclonal Ab, which is the first antiserum suitable for immunohistochemistry, and combined this analysis with the study of Cd97-lacZ knock-in mice. We show that similar to the situation in humans, hematopoietic, epithelial, endothelial, muscle, and fat cells expressed CD97. Despite this broad expression pattern, the Cd97(-/-) mouse that we created had no overt phenotype, except for a mild granulocytosis. Furthermore, granulocyte accumulation at sites of inflammation was normal in the absence of CD97. Interestingly, application of CD97 mAbs blocked granulocyte trafficking after thioglycollate-induced peritonitis in wild-type but not in knock-out mice. Hence, we conclude that CD97 mAbs actively induce an inhibitory effect that disturbs normal granulocyte trafficking, which is not perturbed by the absence of the molecule.

Experience-induced changes of dendritic spine densities in the prefrontal and sensory cortex: correlation with developmental time windows.

The present study provides evidence for the hypothesis that the extent and the direction of experience-induced synaptic changes in cortical areas correlates with time windows of neuronal as well as endocrine development. Repeated brief exposure to maternal separation prior to the stress hyporesponsive period (SHRP) of the hypothalamic-pituitary-adrenal (HPA) axis induced significantly reduced dendritic spine density (-16%) in layer II/III pyramidal neurons of the anterior cingulate cortex (ACd) of 21-day-old rats, whereas separation after termination of the SHRP resulted in increased spine densities (+16%) in this neuron type. In addition, rats of both groups displayed elevated basal plasma levels of corticosterone at this age. Separation during the SHRP (postnatal days 5-7) did not influence spine density in the ACd, and basal corticosterone levels remained unchanged. In contrast, pyramidal neurons in the somatosensory cortex (SSC) displayed significantly enhanced spine densities (up to 52% increase) independent from the time of separation. These results indicate that alterations in the synaptic balance in limbic and sensory cortical regions in response to early emotional experience are region-specific and related to the maturational stage of endocrine and neuronal systems.