Unlike children, adults with epilepsy appear to have decreased levels of plasma [corrected] BDNF. Reduced plasma [corrected] BDNF levels can be used to differentiate adult patients with ES or PNES from healthy controls. Further human studies are needed to better understand the pathophysiology explaining the decreased plasma [corrected] BDNF levels found in epilepsy and in PNES.

Neurons containing the decapeptide GnRH originate in the olfactory placodes and migrate into the central nervous system during fetal development. The neurotransmitter gamma-aminobutyric acid (GABA) has been proposed as a trophic factor and may also influence neuronal migration. Immunocytochemical analyses were conducted in fetal rats, mice, and humans to identify potential developmental relationships between cells containing GABA, and GnRH neurons. Cells containing GABA were found along the nasal portion of the GnRH migration pathway in rats, mice, and humans during development. A peak number of cells containing immunoreactive GABA was observed in the nasal compartment of rats at embryonic day 15. At this time (E15), a majority of GnRH neurons were clustered in the region of the cribriform plate. By postnatal day 1, all GnRH neurons had migrated into the CNS and GABA cells were virtually absent from the nasal compartment. Double-label and confocal analyses of GABA and GnRH in mice and rats demonstrated that some olfactory GABAergic neurons coexpress GnRH. This implies that neurons that transiently express GABA originate in olfactory placodes and migrate into the forebrain. Based on the transient dual-label and adjacent relationships between GABA and GnRH containing cells in the nasal compartment, and other data showing migrational and trophic roles for GABA in development, we suggest that GABA may directly influence GnRH neuronal migration and development.

Luteinizing hormone-releasing hormone (LRH) may be synthesized as part of a larger prohormone, as are several other neuropeptides. In this study, we sought not only to define the distribution and morphological characteristics of LRH neurons within the human preoptic area and hypothalamus, but also to identify sites of initial synthesis, posttranslational conversion to the decapeptide, and storage of LRH in these neurons. Immunoreactive molecular forms were differentiated using a series of antisera with distinct specificities in the peroxidase-antiperoxidase technique. These antisera were capable of detecting the fully processed hormone as well as extended decapeptide sequences. Immunopositive LRH neurons were more abundant in the infundibular area of the hypothalamus than in the preoptic area. Numbers of immunopositive perikarya and subcellular distribution of reaction product varied with binding requirements of the antisera. After treatment with an antiserum that requires the fully processed decapeptide for binding, the reaction product was associated almost entirely with granules in perikarya and processes, while very little was associated with either rough endoplasmic reticulum (RER) or Golgi apparatus. In contrast, with an antiserum capable of detecting extended forms of the decapeptide, the RER and Golgi were labeled in addition to granules. From these data, we infer that in humans, mature decapeptide is present in granules within LRH neuronal perikarya and processes. Furthermore, the molecular forms associated with RER and Golgi may be precursors in which the decapeptide sequence is extended.

Immunocytochemistry performed on 80-microns unembedded tissue sections was used to study the localization of GnRH-containing neurons and fibers in the basal forebrain and amygdala of six adult (four male, two female) human brains. Sections from one of the female brains were subjected to computer-assisted microscopic mapping to generate a three-dimensional analysis of immunoreactive structures. In all six brains examined, cell bodies were concentrated in the preoptic area and basal hypothalamus, but were also evident in the septal region, anterior olfactory area, and cortical and medial amygdaloid nuclei. GnRH-containing fibers were observed within the hypothalamus (predominantly infundibular region and preoptic area), septum, stria terminalis, ventral pallidum, dorsomedial thalamus, olfactory stria, and anterior olfactory area. Many fibers could also be seen coursing along the base of the brain between the hypothalamus and cortical and medial amygdaloid nuclei. The localization of GnRH-containing cells and fibers in several of these areas represents new observations in the human brain and suggests a role for the amygdaloid complex in the regulation of gonadotropin secretion. The comprehensive view provided by these data may be useful in the clinical application of novel transplantation strategies.

Meningiomas arise from the arachnoidal cells surrounding the brain and are one of the most common tumors of the central nervous system. These tumors are known to be hormonally modulated and may occur in association with breast carcinoma. Overexpression of the erbB-2 oncogene product and mutation of the tumor suppressor p53 gene are considered causal driving forces in the pathogenesis of adenocarcinomas of the breast. To determine whether abnormal expression of these genes also plays a role in the pathogenesis of meningiomas, we analyzed the expression of the erbB-2 and p53 proteins in 17 atypical and 35 typical meningioma tissue specimens by immunohistochemistry. The staining intensity was assigned a relative value of 0 to 5+, where 5+ denoted confluent immunoreactivity, 4+ to 1+ denoted varying degrees of focal positivity, and 0 denoted no evidence of staining. Levels of p53 and erbB-2 immunohistochemical staining were then correlated with tumor histology. For p53 immunoreactivity, typical meningiomas had a median staining score of 1.0, compared to 4.0 for atypical meningiomas (P < 0.0001, Mann-Whitney U test). For erbB-2 immunoreactivity, typical meningiomas had a median staining score of 5.0 compared to 1.0 for atypical meningiomas (P < 0.0001, Mann-Whitney U test). The inverse relationship between levels of erbB-2 and p53 immunoreactivity was found to be statistically significant (P < 0.0001, ANOVA). Expression of the erbB-2 protein was not associated with gene amplification or the presence of activating mutation in the transmembrane region of the protein. These findings may improve our understanding of the molecular events that occur in the neoplastic transformation of meningothelial cells. The patterns of erB-2 and p53 immunoreactivity may prove to be useful markers with which to identify potentially more malignant meningiomas.

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The inhibin/activin family of proteins is known to have a broad distribution of synthesis and expression in many species, as well as a variety of functions in reproductive and other physiological systems. Yet, our knowledge regarding the production and function of inhibin and activin in the central nervous system is relatively limited, especially in humans. The present study aimed to explore the distribution of inhibin/activin protein subunits and receptors in the adult human brain. The human hypothalamus and surrounding basal forebrain was examined using post-mortem tissues from 29 adults. Immunocytochemical studies were conducted with antibodies directed against the inhibin/activin α, βA, and βB subunits, betaglycan and the activin type IIA and IIB receptors. An immunoassay was also utilised to measure dimeric inhibin A and B levels in tissue homogenates of the infundibulum of the hypothalamus. Robust βA subunit immunoreactivity was present in the paraventricular, supraoptic, lateral hypothalamic, infundibular, dorsomedial and suprachiasmatic nuclei of the hypothalamus, in the basal ganglia, and in the nucleus basalis of Meynert. A similar staining distribution was noted for the βB subunit, betaglycan and the type II receptor antibodies, whereas α subunit staining was not detected in any of the major anatomical regions of the human brain. Inhibin B immunoreactivity was present in all tissues, whereas inhibin A levels were below detectable limits. These studies show for the first time that the inhibin/activin protein subunits and receptors can be co-localised in the human brain, implicating potential, diverse neural functions.

We recently demonstrated that three arcuate nucleus-derived peptides, neuropeptide Y (NPY), agouti-related protein (AGRP), and alphaMSH, are contained in axon terminals that heavily innervate hypophysiotropic TRH neurons in the rat brain and may contribute to the altered set-point of the hypothalamo-pituitary-thyroid axis during fasting. To determine whether a similar regulatory system exists in human brain, we performed a series of immunohistochemical studies using antisera against NPY, AGRP, alphaMSH, and TRH in adult hypothalami obtained within 15 h of death. Numerous small to medium-sized, fusiform and multipolar NPY-, AGRP-, and alphaMSH-immunoreactive (-IR) cells were widely distributed throughout the rostro-caudal extent of the infundibular (arcuate) nucleus. A similar distribution pattern was found for NPY- and AGRP-IR neurons in the arcuate nucleus, whereas alphaMSH-IR cells appeared to form a separate cell population. By double labeling fluorescent immunohistochemistry, 82% of NPY neurons cocontained AGRP, and 87% of AGRP neurons coexpressed NPY. No colocalization was found between alphaMSH- and AGRP-IR neurons. NPY-, AGRP-, and alphaMSH-containing axons densely innervated the hypothalamic paraventricular nucleus and were found in close juxtaposition to TRH-synthesizing cell bodies and dendrites. These studies demonstrate that in man, the NPY-, AGRP-, and alphaMSH-IR neuronal systems in the infundibular and paraventricular nuclei are highly reminiscent of that observed in the rat and may similarly be involved in regulating the hypothalamo-pituitary-thyroid axis in the human brain.