Neuropeptide-Y and Y-receptors in the autocrine-paracrine regulation of adrenal gland under physiological and pathophysiological conditions (Review)

Neuropeptide-Y (NPY) is a 36-amino acid peptide, which belongs, along with peptide YY (PYY), to the pancreatic polypeptide (PP) family. The members of this family of peptides act via G protein-coupled receptors (Rs), six subtypes of which (from Y1- to Y6-R) have been identified. NPY and PYY preferentially bind the Y1-R, Y2-R and Y5-R, while PP mainly acts via the Y4-R. Evidence has been provided that the Y3-R is selective for NPY. NPY and Y-Rs are expressed in the adrenal gland (preferentially adrenal medulla) and pheochromocytomas, where they exert various autocrine-paracrine regulatory functions. Findings indicate that NPY is co-released with catecholamines under a variety of stimuli, including splanchnic nerve and cholinergic- and nicotinic-receptor activation. NPY, mainly acting via the Y1-R, Y2-R and Y3-R, either inhibits catecholamine secretion from bovine adrenal chromaffin cells or stimulates catecholamine secretion from adrenomedullary cells of humans and rats. NPY inhibits aldosterone secretion from dispersed zona glomerulosa (ZG) cells, but this effect has probably to be considered non-specific and toxic in nature, since it is obtained only using micromolar concentrations of the peptide. In contrast, NPY appears to modulate the secretory response of dispersed rat ZG cells to their main agonists (ACTH, angiotensin-II and potassium). However, there is indication that the main effect of NPY on the ZG in rats is indirect and involves the local release of catecholamines, which in turn, acting via beta-adrenoceptors, enhance the secretion of aldosterone. The prolonged treatment with NPY is also able to enhance the growth of the rat ZG. In contrast, the effects of NPY on glucocorticoid secretion from zona fasciculata-reticularis cells are negligible and doutbful. The physiological relevance of the effects of NPY on adrenal medulla and ZG remains to be addressed by future experimental studies employing more selective and potent Y-R antagonists. In contrast, indirect evidence is available that endogenous NPY system may play an important role in the modulation of adrenal functions under paraphysiological conditions (e.g. it seems to dampen exceedingly high responses to stresses). Moreover, it has been also suggested that endogenous NPY may be involved in the regulation of blood pressure and in the pathophysiology of pheochromocytomas.     

Common and differential neural mechanisms supporting imitation of meaningful and meaningless actions

Neuropsychological studies indicate that, after brain damage, the ability to imitate meaningful or meaningless actions can be selectively impaired. However, the neural bases supporting the imitation of these two types of action are still poorly understood. Using PET, we investigated in 10 healthy individuals the neural mechanisms of imitating novel, meaningless actions and familiar, meaningful actions. Data were analyzed using SPM99. During imitation, a significant positive correlation (p < .05, corrected) of regional cerebral blood flow with the amount of meaningful actions was observed in the left inferior temporal gyrus only. In contrast, a significant positive correlation (p < .05, corrected) with the amount of meaningless movements was observed in the right parieto-occipital junction. The direct categorical comparison of imitating meaningful (100%) relative to meaningless (100%) actions showed differential increases in neural activity (p < .001, uncorrected) in the left inferior temporal gyrus, the left parahippocampal gyrus, and the left angular gyrus. The reverse categorical comparison of imitating meaningless (100%) relative to meaningful (100%) actions revealed differential increases in neural activity (p < .001, uncorrected) in the superior parietal cortex bilaterally, in the right parieto-occipital junction, in the right occipital-temporal junction (MT, V5), and in the left superior temporal gyrus. Increased neural activity common to imitation of meaningless and meaningful actions compared to action observation was observed in a network of areas known to be involved in imitation of actions including the primary sensorimotor cortex, the supplementary motor area, and the ventral premotor cortex. These results are compatible with the two-route model of action imitation which suggests that there are at least two mechanisms involved in imitation of actions: a direct mechanism transforming a novel action into a motor output, and a semantic mechanism, on the basis of stored memories, that allows reproductions of known actions. Our results indicate that, in addition to shared neural processes, the direct and the semantic mechanisms that underlie action imitation also draw upon differential neural mechanisms. The direct mechanism underlying imitation of meaningless actions differentially involves visuospatial transformation processes as evidenced by activation of areas belonging to the dorsal stream. In contrast, imitation of meaningful actions differentially involves semantic processing as evidenced by activation of areas belonging to the ventral stream.     

Visuomotor links in awareness: evidence from extinction

In patients with extinction, ipsilesional stimuli may abolish awareness of contralesional stimuli. Explanations of extinction often assume a serial model of processing in which sensory competition and identification precedes the selection of responses. We tested the adequacy of this assumption by examining the effects of response variables on visual awareness in six patients using signal detection analysis. Ipsilesional stimuli modulated patients' response criteria in deciding whether a contralesional stimulus was a target, and response modality (verbal or motor) modulated patients' abilities to discriminate between contralesional targets and distractors. This pattern of input variables modulating response criteria and output variables modulating discriminability indicates the extent to which attentional and intentional systems are tightly intertwined, with bi-directional effects in producing visual awareness.     

Existence and theoretical aspects of homomeric and heteromeric dopamine receptor complexes and their relevance for neurological diseases

Dopamine (DA) and other receptors physically interact in the plasma membrane of basal ganglia neurons forming receptor mosaics (RMs). Two types of RMs are discussed, homomers formed only by DA-receptor (DA-R) subtypes and heteromers formed by DA-R associated with other receptors, such as A2A, A1, mGluR5, N-methyl-d-aspartate (NMDA), γ-aminobutryic acid (GABA)-A, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. By being part of horizontal molecular networks, RMs tune multiple effector systems already at membrane level, such as G protein regulated inward rectifying potassium channels and dopamine transporter activity. Also, ligand-gated ion channels such as GABA-A and NMDA receptors are modulated by DA-R, e.g., in the striatal GABA output neurons through the formation of heteromeric complexes with these receptors. Thus, intramembrane DA-R-receptor interactions play an important role in the information handling in the basal ganglia. On this basis, functional implications of DA RM in physiological and pathological conditions are discussed. The effects of temperature on RM are discussed not only because receptor-decoding mechanisms are temperature sensitive, but also in view of the suggestion that possible ordering effects (i.e., changes in the entropy of a receptor complex) induced by a ligand are as a result of alterations in the receptor oligomerization (i.e., are related to rearrangements of the RM). Hence, brain temperature may have profound effects on brain integrative functions not only because its effects on the kinetics of biochemical reactions, but also for its effects on receptor geometry, building up of RM, and alterations in protein expression, as is the case of H-channels following febrile seizures. Note: This article is dedicated to Tullio Giacomini for his 70th birthday.     

Absence of mutations in the highest mutability region of the p-53 gene in tumour-derived CHEF18 Chinese hamster cells

A series of independent tumour–derived Chinese hamsterCHEF18 cell lines was analyzed for the presence of mutationsin the cDNA region (exons 5–9) of the p53 gene, wherethe great majority of p53 mutations of human tumours accumulate.Since the gene is highly conserved among species, we used twoprimers designed on the basis of the human cDNA sequence toisolate the cDNA region from total RNA of Chinese hamster cells.The amplified fragments of 614 bp were digested with cleavaseI endonuclease and fragment length polymorphism analysis showedthat the restriction pattern of the p53 exons 5–9 regionof tumour–derived cell lines was identical to that ofdiploid Chinese hamster CHL fibroblasts. Sequencing of the amplifiedfragments showed 100% homology between sequences, which demonstratedthe absence of p53 mutations in the exons 5–9 cDNA regionexpected to have the highest mutability. Neverthless, the antibodyDO–7 recognized the presence of a stabilized p53 proteinonly in tumour–derived cell lines, which indicated thatp53 expression correlated with transformed status. ³To whom correspondence should be addressed. Tel: +00 39 50 577834; Fax: +00 39 50 576661; Email: g.rainaldi{at}imd.pi.cnr.it     

Praxic and executive components in tool use learning: the role of imitation

Recent research in comparative psychology suggests that similarities between the behaviour of two individuals may not be the consequence of imitation only, but also of nonimitative social-learning processes. In the present study we aimed to investigate whether these alternative learning processes can take place in human adults, specifically in patients whose ability to imitate has been reduced by brain damage. Left (LBD) and right (RBD) brain-damaged patients were asked to perform four tool use tasks in three experimental conditions: exposure to the apparatus (N); demonstration of the correct solution (C); and demonstration of a failed attempt followed by the correct solution to the problem (I + C). Results suggest that the left hemisphere is indeed critical for action and that selective neuropsychological deficits can affect action imitation and selection of goal-directed movements, independently from each other. Findings also indicate that when the ability to imitate actions is lowered emulation may become available.     

Delayed homicides due to infant head injury initially reported as natural (cerebral palsy) deaths.

A spectrum of neuropathology occurs in infants who sustain traumatic brain injury. Because of a prolonged survival interval, there is a risk that these deaths may not be recognized as a sequel of trauma. We reviewed the records in New York City of 5 delayed fatalities due to nonaccidental infant head injury that had survival intervals from 2.5 to 17 years. The head injuries occurred at 2 to 3 months of age, and death occurred at 2.5 to 17 years of age. Initially, they were reported as natural deaths by treating physicians, families, and/or police. All 5 infants had unexplained or poorly explained remote traumatic head injury that included subdural hematomas. At autopsy, the neuropathologic exam demonstrated remote subdural hemorrhages and lesions related to chronic hypoxic-ischemic injury including atrophy, arterial infarcts, border-zone infarcts, and cystic encephalomalacia. Each child survived the initial injury but later succumbed to the delayed effects of secondary hypoxic-ischemic encephalopathy. These 5 deaths highlight the need to investigate independently the medical history of any child (or adult) who dies with a clinical diagnosis of "cerebral palsy." The term cerebral palsy often is used as a catchall for any patient who has had neurologic impairment since infancy or childhood. If there is a direct link between the initial injury and the death, even if the injury occurred many years before death, then the injury is the proximate cause of death and dictates the manner of death. All 5 deaths were certified as homicides.     

Role of bone marrow stromal cells in the generation of human CD8+ regulatory T cells

Fibroblast-like stromal cells exert a strong inhibitory effect on lymphocyte proliferation, both directly by interacting with responding lymphocytes and indirectly by inducing the generation of regulatory T cells. Indeed, upon triggering via the CD3/TCR complex, highly effective CD8(+)regulatory cells (CD8(+)Reg(c)) are generated from cocultures of peripheral blood CD8(+)T cells and bone-marrow-derived stromal cells. When cell-to-cell interactions occur, CD8(+)Reg(c) strongly inhibit lymphocyte proliferation at a ratio of 1:1 to 1:100 between CD8(+)Reg(c) and responding lymphocytes. Phenotypic analysis indicated that CD8(+)Reg(c) are CD25(+)CD28(+) and express low levels of mRNA for Foxp3 but they do not bear CTLA4 and glucocorticoid-induced tumor necrosis factor receptor antigens. Soluble mediators such as interleukin-10, transforming growth factor-beta, and prostaglandin E(2) are not involved in the generation of CD8(+)Reg(c) from CD8(+) precursors or in the immunosuppressive mechanism mediated by CD8(+)Reg(c) on lymphocyte proliferation. Cyclosporin A (CSA) slightly downregulated generation of CD8(+)Reg(c) indicating that only a small fraction of precursors of CD8(+)Reg(c) are sensitive to this immune-suppressive drug. Along this line, treatment of effector CD8(+)Reg(c)with CSA does not affect their immunosuppressive effect, indicating that the molecular mechanism of CD8(+)Reg(c)-mediated regulation is independent of the function of CSA biochemical target molecules.