Sex differences in the rodent medial prefrontal cortex - What Do and Don't we know?

The prefrontal cortex, particularly its medial subregions (mPFC), mediates critical functions such as executive control, behavioral inhibition, and memory formation, with relevance for everyday functioning and psychopathology. Despite broad characterization of the mPFC in multiple model organisms, the extent to which mPFC structure and function vary according to an individual's sex is unclear - a knowledge gap that can be attributed to a historical bias for male subjects in neuroscience research. Recent efforts to consider sex as a biological variable in basic science highlight the great need to close this gap. Here we review the knowns and unknowns about how rodents categorized as male or female compare in mPFC neuroanatomy, pharmacology, as well as in aversive, appetitive, and goal- or habit-directed behaviors that recruit the mPFC. We propose that long-standing dogmatic concepts of mPFC structure and function may not remain supported when we move beyond male-only studies, and that empirical challenges to these dogmas are warranted. Additionally, we note some common pitfalls in this work. Most preclinical studies operationalize sex as a binary categorization, and while this approach has furthered the inclusion of non-male rodents it is not as such generalizable to what we know of sex as a multidimensional, dynamic variable. Exploration of sex variability may uncover both sex differences and sex similarities, but care must be taken in their interpretation. Including females in preclinical research needs to go beyond the investigation of sex differences, improving our knowledge of how this brain region and its subregions mediate behavior and health. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models".

Rodent models of stress and dendritic plasticity - Implications for psychopathology.

Stress, as commonplace as it is, is a major environmental risk factor for psychopathology. While this association intuitively, anecdotally, and empirically makes sense, we are still very early in the process of understanding what the neurobiological manifestations of this risk truly are. Seminal work from the past few decades has established structural plasticity in the brain as a potential key mechanism. In this review we discuss evidence linking particularly chronic stress exposure in rodent models to plasticity at the dendrites, like remodeling of dendritic branches and spines, in a range of brain regions. A number of candidate mechanisms that seek to explain how stress influences neuroanatomy at this level have been proposed, utilizing in vivo, ex vivo and in vitro methods. However, a large gap still remains in our knowledge of how such dynamic structural changes ultimately relate to downstream effects such as altered affective and cognitive states relevant for psychopathology. We propose that future work expand our understanding of plasticity of specific stress-related brain circuits and cell-types. We also note that the vast majority of the work has been conducted solely on male rodents. The next big strides in our understanding of the neurobiology of psychopathology will require the inclusion of female subjects, as several studies have suggested both sex divergent and convergent features. By understanding plasticity, we can harness it. The growth of this body of knowledge will inform our efforts to improve the therapeutic options for stress-related psychopathology.

Pathophysiology of primary burning mouth syndrome with special focus on taste dysfunction: a review.

Primary burning mouth syndrome (BMS) is a chronic oral condition characterized by burning pain often accompanied with taste dysfunction and xerostomia. The most compelling evidence concerning BMS pathophysiology comes from studies on the somatosensory system using neurophysiologic or psychophysical methods such as blink reflex, thermal quantitative sensory testing, as well as functional brain imaging. They have provided convincing evidence for neuropathic involvement at several levels of the somatosensory system in BMS pain pathophysiology. The number of taste function studies trying to substantiate the subjective taste disturbances or studies on salivary factors in BMS is much more limited, and most of them suffer from definitional and methodological problems. This review aims to critically evaluate the existing literature on the pathophysiology of BMS, paying special attention to the correctness of case selection and the methodology used in published studies, and to summarize the current state of knowledge. Based on the recognition of several gaps in the current understanding of the pathophysiology of BMS especially as regards taste and pain system interactions, the review ends with future scenarios for research in this area.

The effect of dietary intervention on paraffin-stimulated saliva and dental health of children participating in a randomized controlled trial.

OBJECTIVES: The aim was to study the impact of dietary intervention on the properties of paraffin-stimulated saliva, and on dental caries. STUDY DESIGN: At 7 months of age 1062 infants (540 intervention; 522 controls) started in the prospective, randomized Special Turku Intervention Project (STRIP) aimed at restricting the child's saturated fat and cholesterol intake to prevent atherosclerosis of adult age (www.clinicaltrials.gov NCT 00223600). At 3 years of age, every fifth child was invited to an oral sub-study, and 148 (78 boys) children attended. At 6, 9, 12 and 16 years of age 135, 127, 114 and 88 children were restudied, respectively. Dietary intakes of carbohydrates, protein, saturated fat, calcium, phosphate, and fibre were regularly recorded using 4-day food records. Height and weight were regularly monitored. Paraffin-stimulated saliva samples were collected at 6, 9, 12 and 16 years of age, and analyzed for flow rate, buffer capacity, calcium, phosphate and proteins. Dental health was recorded and expressed as d3mft/D3MFT, and as time of caries onset. RESULTS: Dietary intakes of calcium, phosphate and fibre, and salivary flow rate increased with time in both groups (p<0.001, GLM for repeated measures). Fibre intake and salivary flow rate were higher in the intervention than in the control group (p=0.042 and p=0.0394, respectively, GLM for repeated measures). There were no correlations between dietary intakes and salivary concentrations of calcium or phosphate. Children who did not have caries experience (d3mft/D3MFT=0) during the entire follow-up had higher salivary calcium than those who had caries already at 3 years of age. The association between salivary calcium and caries onset was significant up to 12 years of age. Toothbrushing frequency was statistically significantly associated with caries-onset at ages 6 (gamma statistic 0.457, p=0.046) and 12 years (gamma statistic 0.473, p=0.019). CONCLUSIONS: The current long-term dietary intervention increased children's paraffin-stimulated salivary flow rate. The concentration of salivary calcium was directly correlated to dental health. Higher salivary flow rate in the intervention group is believed to be due to higher fibre intake in the intervention group.

Effects of tacrolimus on an organotypic raft-culture model mimicking oral mucosa.

BACKGROUND: Tacrolimus ointment has shown efficacy in treating T-cell-mediated inflammatory oral mucosal diseases, including lichen planus. However, the safety of topical tacrolimus has been questioned, based on its possible association with malignant transformation. AIM: To evaluate the safety aspects of tacrolimus in a three-dimensional in vitro model of oral mucosa containing both multilayered epithelium and connective tissue (raft culture). METHODS: Raft cultures mimicking oral mucosa were topically exposed to tacrolimus, and the effects on cell proliferation and adhesion, epidermal growth factor receptors (EGFR, ERBB2, ERBB3, ERBB4), and apoptosis were evaluated with immunohistochemistry and terminal dUTP nick-end labelling, respectively. Results. The epithelium of the cultures was found to be slightly thinner, but no changes in cell proliferation or adhesion, apoptosis, or expression of epidermal growth factor receptors were detected. CONCLUSIONS: Our results suggest that short-term topical tacrolimus exposure of in vitro constructed oral mucosa does not induce changes in a number of factors known to be involved in malignant transformation.

Host-bacteria crosstalk at the dentogingival junction.

The dentogingival junction is of crucial importance in periodontal host defense both structurally and functionally. Oral bacteria exert a constant challenge to the host cells and tissues at the dentogingival junction. The host response is set up to eliminate the pathogens by the innate and adaptive defense mechanisms. In health, the commensal bacteria and the host defense mechanisms are in a dynamic steady state. During periodontal disease progression, the dental bacterial plaque, junctional epithelium (JE), inflammatory cells, connective tissue, and bone all go through a series of changes. The tissue homeostasis is turned into tissue destruction and progression of periodontitis. The classical study of Slots showed that in the bacterial plaque, the most remarkable change is the shift from gram-positive aerobic and facultatively anaerobic flora to a predominantly gram-negative and anaerobic flora. This has been later confirmed by several other studies. Furthermore, not only the shift of the bacterial flora to a more pathogenic one, but also bacterial growth as a biofilm on the tooth surface, allows the bacteria to communicate with each other and exert their virulence aimed at favoring their growth. This paper focuses on host-bacteria crosstalk at the dentogingival junction and the models studying it in vitro.

Bone morphogenetic protein-6 is a marker of serous acinar cell differentiation in normal and neoplastic human salivary gland.

Bone morphogenetic protein (BMP-6, also known as vegetal-pale-gene-related and decaplentaplegic-vegetal-related) is a member of the transforming growth factor-beta superfamily of multifunctional signaling molecules. BMP-6 appears to play various biological roles in developing tissues, including regulation of epithelial differentiation. To study the possible involvement of BMP-6 in normal and neoplastic human salivary glands, we compared its mRNA and protein expression in 4 fetal and 15 adult salivary glands and in 22 benign and 32 malignant salivary gland tumors. In situ hybridization and Northern blot analysis indicated that BMP-6 transcripts are expressed at low levels in acinar cells of adult submandibular glands but not in ductal or stromal cells. BMP-6 was immunolocated specifically in serous acini of parotid and submandibular glands. None was found in primitive fetal acini or any other types of cell in adult salivary glands, including mucous acini and epithelial cells of intercalated, striated, and excretory ducts. All 16 cases of acinic cell carcinoma consistently exhibited cytoplasmic BMP-6 staining in the acinar tumor cells. Other cell types in these tumors, including intercalated duct-like cells, clear, vacuolated cells, and nonspecific glandular cells, exhibited no cytoplasmic BMP-6 staining. Other benign and malignant salivary gland tumors lacked BMP-6 immunoreactivity, except in areas of squamous differentiation. The results indicate that in salivary glands, BMP-6 expression is uniquely associated with acinar cell differentiation and suggest that BMP-6 may play a role in salivary gland function. More importantly, our experience of differential diagnostic problems related to salivary gland tumors suggests that the demonstration of consistent and specific BMP-6 immunoreactivity in acinic cell carcinoma is likely to be of clinical value.

Progesterone metabolism in human saliva in vitro.

Human salivary glands are known to be able to metabolize progesterone as well as other steroid hormones. The rate of progesterone metabolism in the salivary glands is so low that it is not thought to affect salivary progesterone concentrations. On the other hand it is usually recommended that saliva should be frozen quickly after the collection to prevent any kind of metabolism in saliva. When saliva is collected at home e.g. delayed freezing or partial thawing during to transport to laboratory may create circumstances where progesterone metabolism may occur. However, it is not known to which extent progesterone metabolism continues in saliva and whether this continued metabolism of progesterone affects salivary hormone levels. Paraffin-stimulated salivary samples were collected from female (N = 6) and male (N = 6) dental students and perimenopausal women (N = 8). The salivary samples were incubated with 14C-progesterone for 2 h at 37 degrees C in a shaking water bath. Metabolites were analyzed using thin-layer chromatography and autoradiography and quantified by liquid scintillation counting. Human saliva was found to be able to metabolize progesterone, but its metabolic activity was very low, 9.3 and 6.8 pmol/ml/h in young adults and perimenopausal women, respectively. Metabolic activity was higher in whole saliva than in the corresponding activities of the supernatant or sonicated fraction of the same saliva. The supernatant fraction, which was thought to be mainly representative of glandular saliva, was metabolically least active. The polar metabolites of progesterone predominated in all incubations. The metabolic activity of saliva is probably mainly due to its cellular content and the contribution of this activity to salivary progesterone concentrations is not significant.