Isolated clefts of the lip and/or palate (ICLP) are developmental craniofacial abnormalities that have consistently been linked to increased social inhibition or shyness. Two explanations have been proposed: 1) psychosocial factors related to differences in facial appearance may lead to low selfconcept and subsequent shyness, or 2) abnormal development of brain structures involved in social function, such as the ventral frontal cortex (VFC), may underlie the difference. To investigate these two possibilities this study was designed to evaluate measures of social function in relation to measures of self-concept and VFC morphology. Subjects included 30 boys (age 7-12) with ICLP and a comparison group of 43 boys without cleft in the same age category. Social function and selfconcept were assessed using questionnaires with standardized scoring filled out by subjects and one of their parents. The cortical volume and surface area of the VFC, composed of the orbitofrontal cortex (OFC) and straight gyrus (SG), were evaluated using structural magnetic resonance imaging. The ICLP subjects had significantly impaired social function relative to the comparison group. No difference in self-concept was identified. VFC morphology revealed significant differences between groups, particularly decreased volume and surface area in the left SG of the ICLP group. Moreover, abnormal VFC measures were correlated with social dysfunction but measures of self-concept were

Females have been shown in a number of studies to be more adept in social perception compared with males. In addition, studies have reported that brain regions important in interpretation of nonverbal social cues, such as the ventral frontal cortex (VFC), are morphologically different between genders. To investigate the relationship between the structure of the VFC and social cognition, gray matter volume and surface area of the VFC were measured on magnetic resonance imaging (MRI) scans from 30 men and 30 women matched for age and IQ. The VFC was subdivided into the orbitofrontal cortex (OFC) and the straight gyrus (SG). The SG, but not the OFC, was proportionately larger in women. A subset of subjects was administered the Interpersonal Perception Task (IPT), a test of social perceptiveness, and the Personal Attributes Questionnaire (PAQ), a scale of femininity and masculinity. Identification with more feminine traits on the PAQ correlated with greater SG gray matter volume and surface area. In addition, higher degrees of femininity correlated with better performance on the IPT. Taken together, these data suggest a complex relationship between femininity, social cognition, and the structure of the SG.

The neurotransmitter serotonin controls a wide range of biological systems, including its own synthesis and release. As the rate-limiting enzyme in serotonin biosynthesis, tryptophan hydroxylase (TPH) is a potential target for this autoregulation. Using the serotonergic neuron-like CA77 cell line, we have demonstrated that treatment with a 5-hydroxytryptamine autoreceptor agonist, CGS 12066A, can lower TPH mRNA levels and promoter activity. We reasoned that this repression might involve inhibition of MAP kinases, since 5-HT1 receptors can increase mitogen-activated protein (MAP) kinase phosphatase levels. To test this hypothesis, we first showed that the TPH promoter can be activated 20-fold by mitogen-activated extracellular-signal regulated kinase kinase kinase (MEKK), an activator of MAP kinases. This activation was then blocked by CGS 12066A. The maximal MAP kinase and CGS repression regulatory region was mapped to between ؊149 and ؊45 base pairs upstream of the transcription start site. The activation by MEKK appears to be cell-specific, because MEKK did not activate the TPH promoter in nonneuronal cell lines. At least part, but not all, of the MAP kinase responsiveness was mapped to an inverted CCAAT box that binds the transcription factor NF-Y. These data suggest a model for the autoregulation of serotonin biosynthesis by repression of MAP kinase stimulation of the TPH promoter. Serotonin (5-hydroxytryptamine; 5-HT)1 is a monoamine neurotransmitter involved in diverse physiological functions including regulation of mood, aggression, anxiety, sleep, satiety, and sexual activity (1). Dysfunction in serotonergic systems has been implicated in the etiology of depression, aggressive behavior, and anxiety disorders (2, 3). The pathophysiological mechanisms behind these illnesses, however, are poorly understood, and very little is known about the control of serotonin levels in neurons.Serotonin biosynthesis is restricted to serotonergic neurons in the brain raphe and gut, the pineal gland, enterochromaffin cells in the gastrointestinal tract, and rodent mast cells (4,5). This is largely due to the cell-specific expression of tryptophan hydroxylase (TPH), the first and rate-limiting step in serotonin biosynthesis, which catalyzes the conversion of tryptophan to 5-hydroxytryptophan. As the rate-limiting enzyme, TPH is a potential target for control of serotonin levels. There is extensive evidence for post-translational regulation of TPH enzyme activity through phosphorylation by Ca 2ϩ /calmodulin-dependent protein kinase, cAMP-dependent protein kinase, and a member of the 14-3-3 protein family (6 -8).Another mechanism for the control of serotonin levels is through a negative feedback loop via activation of presynaptic 5-HT1 autoreceptors, which inhibit neuronal firing and serotonin release (5, 9). Stimulation of 5-HT1 autoreceptors also decreases the conversion of tryptophan to 5-hydroxytryptophan, suggesting that extracellular serotonin can regulate TPH activity (5). No studies to date directly demonstrate that 5...

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ObjectiveTo investigate evidence of the potential role of early cortical vulnerability in the development of primary progressive aphasia (PPA).MethodA woman with a diagnosis of PPA and her 9 adult siblings, 7 with developmental language disabilities, underwent neuropsychological testing, structural MRI, and resting-state fMRI. Whole-exome sequencing was conducted for genes associated with dyslexia or with neurodegenerative dementia.ResultsThe siblings demonstrated lower verbal than nonverbal cognitive test scores in a developmental dyslexia pattern. On structural MRI, although the siblings did not differ from controls in total brain volume, the left hemisphere language area volume was significantly smaller than the right. Furthermore, cortical connectivity between the left superior temporal area, previously identified as the region of peak atrophy in the proband early in the course of illness, and adjacent language network components, including the planum temporale, was decreased in the siblings. No distinctive genetic signatures were identified.ConclusionThis report further supports the hypothesis that at least some cases of PPA may be based on a familial language network vulnerability that interferes with the acquisition of language in some members and that makes the language network a locus of least resistance to the effects of an independently late-arising neurodegenerative disease in others. This association offers a conceptual model to explain why identical neurodegenerative diseases may selectively target the language network in some individuals while targeting networks that regulate memory or behavior in others. The genetic basis for this vulnerability remains to be determined.