Autophosphorylation of αCaMKII regulates alcohol consumption by controlling sedative effects of alcohol and alcohol-induced loss of excitatory synapses.

Calcium/calmodulin-dependent kinase II (CaMKII) is a key enzyme at the glutamatergic synapses. CAMK2A gene variants have been linked with alcohol use disorder (AUD) by an unknown mechanism. Here, we looked for the link between αCaMKII autophosphorylation and the AUD aetiology. Autophosphorylation-deficient heterozygous αCaMKII mutant mice (T286A+/- ) were trained in the IntelliCages to test the role of αCaMKII activity in AUD-related behaviours. The glutamatergic synapses morphology in CeA was studied in the animals drinking alcohol using 3D electron microscopy. We found that T286A+/- mutants consumed less alcohol and were more sensitive to sedating effects of alcohol, as compared to wild-type littermates (WT). After voluntary alcohol drinking, T286A+/- mice had less excitatory synapses in the CeA, as compared to alcohol-naive animals. This change correlated with alcohol consumption was not reversed after alcohol withdrawal and not observed in WT mice. Our study suggests that αCaMKII autophosphorylation affects alcohol consumption by controlling sedative effects of alcohol and preventing synaptic loss in the individuals drinking alcohol. This finding advances our understanding of the molecular processes that regulate alcohol dependence.

Phosphorylation of PSD-95 at serine 73 in dCA1 is required for extinction of contextual fear.

The updating of contextual memories is essential for survival in a changing environment. Accumulating data indicate that the dorsal CA1 area (dCA1) contributes to this process. However, the cellular and molecular mechanisms of contextual fear memory updating remain poorly understood. Postsynaptic density protein 95 (PSD-95) regulates the structure and function of glutamatergic synapses. Here, using dCA1-targeted genetic manipulations in vivo, combined with ex vivo 3D electron microscopy and electrophysiology, we identify a novel, synaptic mechanism that is induced during attenuation of contextual fear memories and involves phosphorylation of PSD-95 at Serine 73 in dCA1. Our data provide the proof that PSD-95-dependent synaptic plasticity in dCA1 is required for updating of contextual fear memory.

Impaired synaptic transmission in dorsal dentate gyrus increases impulsive alcohol seeking.

Both human and animal studies indicate that the dentate gyrus (DG) of the hippocampus is highly exploited by drug and alcohol abuse. Yet, it is poorly understood how DG dysfunction affects addiction-related behaviors. Here, we used an animal model of alcohol use disorder (AUD) in automated IntelliCages and performed local genetic manipulation to investigate how synaptic transmission in the dorsal DG (dDG) affects alcohol-related behaviors. We show that a cue light induces potentiation-like plasticity of dDG synapses in alcohol-naive mice. This process is impaired in mice trained to drink alcohol. Acamprosate (ACA), a drug that reduces alcohol relapse, rescues the impairment of dDG synaptic transmission in alcohol mice. A molecular manipulation that reduces dDG synaptic AMPAR and NMDAR levels increases impulsive alcohol seeking during cue relapse (CR) in alcohol mice but does not affect alcohol reward, motivation or craving. These findings suggest that hindered dDG synaptic transmission specifically underlies impulsive alcohol seeking induced by alcohol cues, a core symptom of AUD.

Disrupting interaction between miR-132 and Mmp9 3'UTR improves synaptic plasticity and memory in mice.

As microRNAs have emerged to be important regulators of molecular events occurring at the synapses, the new questions about their regulatory effect on the behavior have araised. In the present study, we show for the first time that the dysregulated specific targeting of miR132 to Mmp9 mRNA in the mouse brain results in the increased level of Mmp9 protein, which affects synaptic plasticity and has an effect on memory formation. Our data points at the importance of complex and precise regulation of the Mmp9 level by miR132 in the brain.

PSD-95 in CA1 Area Regulates Spatial Choice Depending on Age.

Cognitive processes that require spatial information rely on synaptic plasticity in the dorsal CA1 area (dCA1) of the hippocampus. Since the function of the hippocampus is impaired in aged individuals, it remains unknown how aged animals make spatial choices. Here, we used IntelliCage to study behavioral processes that support spatial choices of aged female mice living in a group. As a proxy of training-induced synaptic plasticity, we analyzed the morphology of dendritic spines and the expression of a synaptic scaffold protein, PSD-95. We observed that spatial choice training in young adult mice induced correlated shrinkage of dendritic spines and downregulation of PSD-95 in dCA1. Moreover, long-term depletion of PSD-95 by shRNA in dCA1 limited correct choices to a reward corner, while reward preference was intact. In contrast, old mice used behavioral strategies characterized by an increased tendency for perseverative visits and social interactions. This strategy resulted in a robust preference for the reward corner during the spatial choice task. Moreover, training decreased the correlation between PSD-95 expression and the size of dendritic spines. Furthermore, PSD-95 depletion did not impair place choice or reward preference in old mice. Thus, our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices, old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment.SIGNIFICANCE STATEMENT It remains poorly understood how aging affects behavioral and molecular processes that support cognitive functions. It is, however, essential to understand these processes to develop therapeutic interventions that support successful cognitive aging. Our data indicate that while young mice require PSD-95-dependent synaptic plasticity in dCA1 to make correct spatial choices (i.e., choices that require spatial information), old animals observe cage mates and stick to a preferred corner to seek the reward. This strategy is resistant to the depletion of PSD-95 in the CA1 area. Overall, our study demonstrates that aged mice combine alternative behavioral and molecular strategies to approach and consume rewards in a complex environment. Second, the contribution of PSD-95-dependent synaptic functions in spatial choice changes with age.

Long-term Memory Upscales Volume of Postsynaptic Densities in the Process that Requires Autophosphorylation of αCaMKII.

It is generally accepted that formation and storage of memory relies on alterations of the structure and function of brain circuits. However, the structural data, which show learning-induced and long-lasting remodeling of synapses, are still very sparse. Here, we reconstruct 1927 dendritic spines and their postsynaptic densities (PSDs), representing a postsynaptic part of the glutamatergic synapse, in the hippocampal area CA1 of the mice that underwent spatial training. We observe that in young adult (5 months), mice volume of PSDs, but not the volume of the spines, is increased 26 h after the training. The training-induced growth of PSDs is specific for the dendritic spines that lack smooth endoplasmic reticulum and spine apparatuses, and requires autophosphorylation of αCaMKII. Interestingly, aging alters training-induced ultrastructural remodeling of dendritic spines. In old mice, both the median volumes of dendritic spines and PSDs shift after training toward bigger values. Overall, our data support the hypothesis that formation of memory leaves long-lasting footprint on the ultrastructure of brain circuits; however, the form of circuit remodeling changes with age.

Evaluation of the health behaviors of women in multiple pregnancies - a preliminary study.

OBJECTIVES: The aim of the paper was to assess which health behavior indicators were characteristic for women with a multiple pregnancy. MATERIAL AND METHOD: The study involved 35 women in multiple pregnancies. The inclusion criteria were: the completion of the 22nd week of pregnancy (22 Hbd, i.e., 22 weeks and 1/7) and the consent of the women to participate in the study. We used an original questionnaire devised by us specifically for our study, as well as a standardized research tool, Juczynski's Health Behavior Inventory questionnaire, for the assessment of the pregnant women's health behaviors. RESULTS: The overall rate of health behaviors was high and was on average 93.9 ± 10.8 points (7 sten scores). Indicators of the health behaviors of women in multiple pregnancies were high across all categories. However, the highest rate was observed in preventive behaviors. CONCLUSIONS: The overall rate of health behaviors of women with a multiple pregnancy and all the individual behavior category indicators were high. However, the highest rate was for preventive behaviors. The indicator values of the health behaviors of the pregnant women in the study were not dependent on the variables adopted in this paper.

Generation of silent synapses in dentate gyrus correlates with development of alcohol addiction.

The brain circuits and synaptic processes that underlie alcohol addiction are currently the subject of intensive research. Here we focus on hippocampal circuitry and show that chemogenetic inhibition of dentate gyrus (DG) during presentation of alcohol-associated cues has long-lasting effects on mice behavior. DG inhibition enhances alcohol seeking and drinking, suggesting that DG regulates addiction-related behaviors. To test this hypothesis, we perform whole-cell patch-clamp recordings from the granule cells of DG and look for electrophysiological correlates of alcohol addiction. We observe that presentation of alcohol-associated cue light that induces relapse to alcohol-seeking results in generation of silent synapses, that lack functional AMPA receptors. Furthermore, using human criteria of addiction, we differentiate mice controlling their alcohol consumption from those that undergo transition to addiction to discover that the levels of silent synapses induced by alcohol cues are specifically increased in the addicted mice. As the total level of dendritic spines that harbor synapses is constant at this time point, our data indicate that synapses of perforant path to DG are weakened during cue relapse. Finally we demonstrate that, acamprosate, a drug that limits alcohol drinking and seeking in addicts, prevents generation of silent synapses in DG upon presentation of alcohol-associated cues. Altogether, our data suggest that weakening of DG synapses upon cue relapse contributes to persistent alcohol addiction-related behaviors.

Mapping fear memory consolidation and extinction-specific expression of JunB.

Understanding the molecular and cellular process specifically regulated during fear memory consolidation and extinction is a critical step toward development of new strategies in the treatment of human fear disorders. Here we used inhibitory component of AP-1 transcription factor, JunB, in order to map brain regions where JunB-dependent transcription is regulated during consolidation and extinction of contextual fear memory. We found that contextual fear memory consolidation induced JunB expression in the medial nucleus and intercalated cells of the amygdala while extinction training induced JunB in the CA1 and CA3 areas of the dorsal hippocampus. JunB upregulation induced by contextual fear memory extinction was absent in alphaCaMKII autophosphorylation-deficient mice which have impaired contextual fear memory extinction. Thus, our data suggest that JunB expression in the medial nucleus and intercalated cells of the amygdala is involved in fear memory consolidation while alphaCaMKII-autophosphorylation-dependent JunB expression in the areas CA1 and CA3 of the dorsal hippocampus regulates fear memory extinction.

[Epidemiological and clinical characteristics of 705 salivary glands neoplasms]. / Charakterystyka epidemiologiczno-kliniczna 705 nowotworów gruczolów slinowych.

UNLABELLED: The epidemiological data concerning the rare group of tumors derived from salivary glands recorded in the National Cancer Registry is insufficient because it records only malignant salivary glands tumors. AIMS OF THE STUDY: The epidemiological and clinical characteristics of 699 patients with salivary glands tumors (n=705). MATERIAL: The data were retrieved from ENT Department District Hospital in Kielce (01.09.1989-28.02.2001) and from Department of Otolaryngology Head and Neck Surgery Holy Cross Cancer Centre in Kielce (01.03.2001-31.12.2008). RESULTS AND CONCLUSIONS: In the analyzed group of 699 patients with 705 salivary glands tumors women predominated, consisting 54,2% of all group. The average age in group of malignant tumors was higher than in nonmalignant group. The risk of malignant neoplasms development increased with patient age. In the analyzed group of 705 salivary glands tumors the nonmalignant neoplasms dominated-78,3%. Out of all cases, 547 (77,6%) were localized in the parotid gland, 80 (11,3%) in submandibular gland and 78 (11,1%) in minor salivary glands. Nonmalignant tumors were more frequent in the parotid gland (82,8%) and submandibular gland (71,3%), whereas in minor salivary glands nonmalignant and malignant neoplasms the occurrence was nearly the same. In general-the smaller the salivary gland, the risk of development malignant tumors was higher. In group of nonmalignant salivary gland tumors two histopathological types dominated - pleomorphic adenoma and Warthin's tumor, which comprised 91,8% of the whole group. In the group of 153 malignant salivary gland tumors the most common histopathology were - adenoid cystic carcinoma, mucoepidermoid carcinoma and adenocarcinoma. In the analyzed period of 20 years' time, the incidence of salivary glands tumors increased with high siginificance, both for nonmalignant, as well malignant tumors.

[Epidemiology and clinical characteristics of the sinonasal malignancies]. / Nowotwory zlosliwe jam nosa i zatok przynosowych w materiale wlasnym--charakterystyka epidemiologiczna i kliniczna.

INTRODUCTION: Sinonasal malignances (SNM) usually present as a difficult diagnostic and therapeutic problem. In the paper presented, the epidemiological and clinical characteristics of SNM, diagnosed in Holy Cross Cancer Center in Kielce (Dept. of Otolaryngology, Head and Neck Surgery), from 2001 to 2007, as well as a calculated survival rates are discussed. MATERIAL AND METHODS: From the hospital data and current clinical observations of 87 patients with SNM the age, sex, localization, stage of the disease, pathology and treatment applied, was taken for analysis. In cases with at least 3 year observation, the Kaplan-Meier survival curves were calculated. Results. In the analyzed group of 87 cases, ranging from 8 to 82 years of age (average 62.3 years), there was 48 male, and 39 female patients (M:F = 1.2:1). 59.8% of all group was in the age above 60 years, with the most common age group 71-80 years (33.3%). The most common defined localization was a maxillary sinus (33.3%), but due to very advanced stage at time of diagnosis in 37.9% of cases, the precise localization within the region was not possible to define. The primary epithelial tumors were diagnosed in 52.9% (n=46), of all SNM, the non epithelial malignant tumors in 42.5% (n=37), and metastatic tumors to the nose and paranasal sinuses in 4.6% (n=4). In the group of epithelial SNM the Squamous cell carcinoma dominated (26/46-56.5%), and in the non epithelial SNM the most common group was a malignant lymphoma (10/37-27.0%). At time of diagnosis the majority of patients with epithelial SNM (80.4%) presented with advanced local stage of the disease (T3+T4a+T4b). The combined modality treatment was applied in the most of patients in the analyzed group (79.3%). The probability of 3 years disease free survival, calculated with Kaplan-Meier method was 64.0%, and 5-years survival--45.0%. CONCLUSIONS: (1) The SNM present as a very heterogeneous group of tumors. (2) The most common SNM are a Squamous cell carcinoma, and malignant lymphoma. (3) The majority of SNM are diagnosed at then advanced stage of local disease. (4) The calculated probability of 3-years survival was 64.0%, and 5-years survival 45.0%. (5) The diagnostic, as well as therapeutic approach to SNM requires a multidisciplinary cooperation.

[The epidemiology and clinical characteristics of malignant melanoma localized in nasal cavity and paranasal sinuses--analysis of 6 cases]. / Obraz epidemiologiczny i kliniczny czerniaka zlosliwego jam nosa i zatok przynosowych--analiza 6 przypadków.

INTRODUCTION: The mucosal malignant melanoma (MM), represent a rare group of tumors (0.2%--8% of all MM), with predominant localization on the mucosal surface of head and neck region, where the localization on the mucosa of nasal cavity, paranasal sinuses and oral cavity are the most common. The mucosal MM within the nose and paranasal sinuses represent approximately 4% of all malignant tumors in these localizations, affecting predominantly the age group over 60-es, equally in both sexes. The treatment of choice in mucosal MM is surgery followed by Rtg-therapy in cases of small or doubtful margins of resection. The prognosis of mucosal MM is poor with 8% to 30% of 5-years survival. MATERIALS AND METHODS: 6 cases of mucosal MM, selected from 72 of all MM in the head and neck region, diagnosed and treated from 2001 to 2007 in Dept. of ORL H&N Surgery, Holy Cross Cancer Center in Kielce. RESULTS: In group of mucosal MM which was taken to analysis there was 5 female and 1 male patient, with range of age from 55 to 80 (mean--69.4) with following localization: nasal septum--2 cases; lateral wall of nasal cavity--2; and paranasal sinuses--2. In 1 case an extremely rare pathologic form of amelanotic MM was diagnosed. The surgical resection of tumor followed by Rtg-therapy was performer in 4 cases. In 1 case, the radical surgery was the only method of treatment, and in 1 case the palliative Rtg-therapy was only applied. Within the observation period (4-96 months) 3 patients died, all due to the fatal progression of the MM. CONCLUSIONS: (1) Mucosal MM localized in the nasal cavity and paranasal sinuses, present a very rare, but highly diversified group of malignant tumors. (2) The surgery, followed by Rtg-therapy is still the treatment method of choice. (3) The prognosis of mucosal MM in the nose and paranasal sinuses is bad.

[Salivary duct carcinoma--a clinicopathological analysis of five cases]. / Rak przewodowy gruczolów slinowych (salivary duct carcinoma) - charakterystyka kliniczna i patologiczna 5 przypadków.

The 5 cases of salivary duct carcinoma (SDC); very rare, but distinct group of highly malignant salivary gland tumor are presented, and difficulties with pathological and clinical diagnosis is discussed. The SDC developed in single cases in parotid salivary gland, submandibular salivary and in mucosa of maxillary sinus, pyriform fossa and oral cavity (check). In 3 cases the second malignant tumor was present--synchronously (SDC + pleomorphic adenoma in parotid gland; SDC + squamous cell carcinoma in hypopharynx) or metachroneously (squamous cell carcinoma of upper lip followed by SDC). In one case the high levels of PSA suggesting of metastases from unknown primary within the prostate gland, or PSA expression related to SDC was observed. The four patients received radical treatment - surgical resection followed by radiotherapy; in one case only palliative treatment was applied, due to patient's poor general condition and high advancement of the primary disease. The observation ranged from 10 to 77 months (average time--31 months). The one patient died 13 months after diagnosis and palliative treatment. The three patients are alive with distant metastases to the lung and bones (77, 38 and 18 months after primary treatment was completed). Only one patient with 10 months observation after treatment is living without symptoms of recurrence or metastases.