A review on family history of breast cancer: screening and counseling proposals for women with familial (non-hereditary) breast cancer

In a neural model of olfactory bulb processing, we demonstrate the putative role of the modulation of two types of inhibition, inspired by electrophysiological data on the effect of acetylcholine and noradrenaline on olfactory bulb synaptic transmission. Feedback regulation of modulation based on bulbar activity serves to 'normalize' the activity of output neurons in response to different levels of input activities. This mechanism also decreases the overlap between pairs of output patterns (Mitral cell activities), enhancing the discrimination between overlapping olfactory input patterns. The effect of the modulation at the two levels of interneurons is complementary: while an increase in periglomerular inhibition decreases the number of responding output neurons, a decrease in granule cell inhibition increases the firing frequencies of these neurons.     

Prolonged exposure to halothane and associated changes in carbohydrate metabolism in rat muscles in vivo

Halothane, an anesthetic presently used in animal experimentation, is reported to stimulate glycogen breakdown in isolated preparations of rat skeletal muscles, suggesting that it may not be a suitable anesthetic for the study of glycogen metabolism in rats in vivo. The purpose of this study was to establish whether prolonged exposure to halothane in rats in vivo is associated with accelerated glycogenolysis. Exposure of rats to halothane for up to 1 h was not accompanied by either any change in the levels of glycogen or increase in activity ratios of glycogen phosphorylase in muscles, irrespective of their fiber compositions. In marked contrast, the levels of lactate, inorganic phosphate, glucose 1-phosphate, glucose 6-phosphate, fructose 1,6-bisphosphate, and fructose 2, 6-bisphosphate changed progressively during anesthesia. Accordingly, the interpretation of muscle metabolite levels must be performed with caution in experiments involving prolonged exposure to halothane. Overall, our findings indicate that the reported halothane-mediated stimulation of glycogen breakdown in vitro is likely to be an artifact and that halothane is a suitable anesthetic for experiments concerned with glycogen metabolism in rats.     

Response plasticity in hamster olfactory bulb: peripheral and central processes

It is a well-established fact that prolonged odor stimulation leads to marked sensory adaptation. This study demonstrates comparable electrophysiological phenomena occurring at the level of the olfactory receptor and at more central olfactory structures. Recordings of overall receptor response and of olfactory bulb unit responses were made during repeated odor stimulation. During the course of a single, continuous odor presentation response decrements were seen in the EOG (at the olfactory receptors) and were mirrored at the mitral cell layer of the bulb. When brief periods without stimulation were introduced between such odor presentations, receptor responsiveness rebounded to its original level, but mitral cell responses did not. On the basis of this dissociation it is suggested that the pattern of response decrement within the bulb represents a case of stimulus-specific habituation in a simple cortical subsystem and is well worth future investigation as a model of neural plasticity. Surgical disconnection of the olfactory bulb from one or more of its centrifugal inputs results in hyperactive, hyperresponsive mitral cells, which habituate more rapidly and show longer recovery times than do those in the intact bulb. In addition, the synchronization of such units to the inhalation cycle is markedly reduced as compared with normal preparations. These facts together suggest that the habituation of mitral cell activity does not depend on centrifugal inputs, although one or more of such inputs act indirectly in an inhibitory fashion to modulate and tune mitral cell response characteristics.     

Activity-dependent regulation of dopamine content in the olfactory bulbs of naris-occluded rats

Several lines of evidence strongly suggest that reduced olfactory nerve activity results in decreased bulb dopamine content. In the present study, high performance liquid chromatography with electrochemical detection was used to assess catecholamine levels in bulbs from postnatal day 60 rats that had undergone either unilateral naris cautery or a sham surgery on day 30. Thirty days of odor deprivation dramatically reduced dopamine and dihydroxyphenylacetic acid levels in functionally-deprived bulbs (ipsilateral to occluded nares) as compared to contralateral controls, while norepinephrine and dihydroxyphenylglycol levels were unchanged. The loss of dopamine was more severe in medial as compared to lateral aspects of experimental bulbs, while the loss of dihydroxyphenylacetic acid was similar on the two sides. To test directly the hypothesis that afferent activity regulates dopamine and dihydroxyphenylacetic acid content, 1 h of high frequency tetanic nerve stimulation was provided to the rostral-medial olfactory nerve layer in deprived olfactory bulbs, and catecholamine levels were assessed from 6 to 192 h later. Partial and temporary recovery of dopamine was observed in medial aspects of the bulb when rats were examined 96 h later, while consistent recovery of dihydroxyphenylacetic acid content was not apparent. These data corroborate evidence that olfactory nerve activity is a potent regulator of bulb dopamine and indicate that continued afferent input is necessary to maintain dopamine levels.     

Olfactory bulb habituation to odor stimuli.

Habituation is a simple form of memory, yet its neurobiological mechanisms are only beginning to be understood in mammals. In the olfactory system, the neural correlates of habituation at a fast experimental timescale involving very short intertrial intervals (tens of seconds) have been shown to depend on synaptic adaptation in olfactory cortex. In contrast, behavioral habituation to odorants on a longer timescale with intertrial intervals of several minutes depends on processes in the olfactory bulb, as demonstrated by pharmacological studies. We here show that behavioral habituation to odorants on this longer timescale has a neuronal activity correlate in the olfactory bulb. Spiking responses of mitral cells in the rat olfactory bulb adapt to, and recover from, repeated odorant stimulation with 5-min intertrial intervals with a time course similar to that of behavioral habituation. Moreover, both the behavioral and neuronal effects of odor habituation require functioning N-methyl-d-aspartic acid receptors in the olfactory bulb. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Investigation of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone for in vivo and iIn vitro murine embryopathy and embryonic ras mutations

The evoked potential recorded in the rat piriform cortex in response to electrical stimulation of the olfactory bulb is composed of an early component occasionally followed by a late component (60-70 ms). We previously showed that the late component occurrence was enhanced following an olfactory learning. In the present study carried out in naive rats, we investigated the precise conditions of induction of this late component, and its spatiotemporal distribution along the olfactory pathways. In the anaesthetized rat, a stimulating electrode was implanted in the olfactory bulb. Four recording electrodes were positioned, respectively, in the olfactory bulb, the anterior and posterior parts of the piriform cortex, and the entorhinal cortex. Simultaneous recording of signals evoked in the four sampled structures in response to stimulation of the olfactory bulb revealed that the late component was detected in anterior and posterior piriform cortex as well as in entorhinal cortex, but not in the olfactory bulb. The late component occurred reliably for a narrow range of low intensities of stimulation delivered at frequencies not exceeding 1 Hz. Comparison of late component amplitude and latency across the different recorded sites showed that this component appeared first and with the greatest amplitude in the posterior piriform cortex. In addition to showing a functional dissociation between anterior and posterior parts of the piriform cortex, these data suggest that the posterior piriform cortex could be the locus of generation of this late high amplitude synchronized activity, which would then propagate to the neighbouring regions.     

Beta-frequency (15-35 Hz) electroencephalogram activities elicited by toluene and electrical stimulation in the behaving rat

Bursts of beta-frequency (15-35 Hz) electroencephalogram activity occur in the olfactory system during odour sampling, but their mode of propagation within the olfactory system and potential contribution to the mechanisms of learning and memory are unclear. We have elicited large-amplitude beta activity in the rat olfactory system by applying noxious olfactory stimuli (toluene), and have monitored the bursts via chronically-implanted electrodes. Following exposure to toluene, coherent bursts with a peak frequency of 19.8 +/- 0.9 Hz were observed in the olfactory bulb, piriform cortex, entorhinal cortex and dentate gyrus. The timing of the bursts and the phases of electroencephalogram cross-spectra indicate that beta bursts propagate in a caudal direction from the olfactory bulb to the entorhinal cortex. The time delays between peaks of bursts in these structures were similar to latency differences for field potentials evoked by olfactory bulb or piriform cortex test-pulses. Peaks of burst cycles in the dentate region, however, were observed just prior to those in the entorhinal cortex. Surprisingly, power in toluene-induced beta-frequency oscillations was not increased following long-term potentiation induced by tetanic stimulation of the olfactory bulb, piriform cortex and entorhinal cortex. The activity of local inhibitory mechanisms may therefore counteract the effects of synaptic enhancements in afferent pathways during beta bursts. Low-frequency electrical stimulation of the piriform cortex was most effective in inducing coherent oscillatory responses in the entorhinal cortex and dentate gyrus at stimulation frequencies between 12 and 16 Hz. The results show that repetitive polysynaptic volleys at frequencies in the beta band induced by either toluene or electrical stimulation are transmitted readily within the olfactory system. The propagation of neural activity within this frequency range may therefore contribute to the transmission of olfactory signals to the hippocampal formation, particularly for those odours which induce high-amplitude bursts of beta activity.     

Neuropeptide FF receptors of mouse olfactory bulb: binding properties and stimulation of adenylate cyclase activity

Neuropeptide FF (NPFF) receptors have been characterized in mouse olfactory bulb membranes by using [125I][1DMe]Y8Fa. The specific binding of this NPFF analogue was time and concentration dependent, reversible, saturable, and of high affinity (Kd = 0.022 nM, Bmax = 56.4 fmol/mg protein). In olfactory bulb membranes, NaCl increased the affinity of [125I][1DMe]Y8Fa by decreasing the dissociation rate constant (k-1). In contrast, the nonhydrolyzable analogue of GTP, Gpp[NH]p, decreased the maximal number of binding sites suggesting a coupling of NPFF receptors to a G-protein. In mouse olfactory bulb and spinal cord membranes, NPFF analogues stimulated adenylate cyclase activity in a time- and dose-dependent manner, whereas in the cerebellum, which does not possess NPFF receptors, low cAMP production was stimulated by NPFF. Our data are consistent with guanine nucleotide binding protein regulation of NPFF receptors positively coupled to adenylate cyclase.     

Activation of beta-adrenergic receptor kinase during myocardial ischemia

During myocardial ischemia, a local release of noradrenaline coincides with an increased density of beta-adrenergic receptors. The functional activity of these receptors, however, is mainly determined by their state of phosphorylation. The beta-adrenergic receptor kinase (beta ARK) specifically phosphorylates and thereby inactivates beta-adrenergic receptors after stimulation by receptor agonists, facilitating the binding of the inhibitor protein beta-arrestin to the receptors. beta ARK activation involves a translocation of the enzyme to the membrane. In the present study, we investigated the density and the functional activity of beta-adrenergic receptors, the enzymatic activity of beta ARK in membranes and cytosol, the mRNA levels of beta ARK-1, and the expression of beta-arrestin during stop-flow and low-flow ischemia in the isolated perfused rat heart. After 60 minutes of stop-flow ischemia, beta-adrenergic receptor density was upregulated, but beta-agonist-mediated adenylate cyclase activity was blunted. Simultaneously, beta ARK activity in the particulate fraction was significantly induced. The increase in beta ARK activity was reversible after inhibition of ischemia-evoked noradrenaline release by desipramine. Also, exposure to externally given noradrenaline increased beta ARK activity in the particulate fraction. Cytosolic beta ARK activity remained largely unchanged during stop-flow or low-flow ischemia. The steady state concentration of beta ARK-1 mRNA increased after 20 minutes of stop-flow ischemia and then returned to baseline values after another 20 minutes. Cardiac ischemia did not alter beta-arrestin levels. During myocardial ischemia, an increase in the number of beta-adrenergic receptors is paralleled by increased membrane activity of the receptor kinase beta ARK. This increased membrane activity may contribute to enhanced receptor phosphorylation and inactivation.     

Spatial organization and plasticity of the primary and secondary olfactory projections in goldfish

Crystals of the lipophilic tracer DiI were applied to discrete regions of the olfactory epithelium of goldfish to trace the primary sensory projection to the olfactory bulb. Receptors from the anterior half of the sensory sheet project primarily to glomeruli in the medial half of the bulb and receptors in the posterior half terminate mainly within the lateral half of the bulb. This pattern disappeared following ablation of selected, discrete epithelial regions. In order to investigate reorganization of secondary olfactory projections, unoperated control and unilaterally bulbectomized animals received injections of [3H]proline into the right olfactory bulb. Densities of silver grains per unit area were determined within six different forebrain nuclei in both the right and left hemispheres of each animal. Of the six areas examined, three demonstrated a significantly greater density of afferent innervation from the ipsilateral versus contralateral bulb; a difference which disappeared in two of these three regions after bulbectomy. Thus, for at least two forebrain nuclei, bulb removal caused a change in the afferent input from the spared olfactory bulb to those regions. We conclude that both primary and secondary olfactory projections in goldfish are capable of some degree of reorganization following insult.     

Formation of olfactory memories mediated by nitric oxide

Sheep learn to recognize the odours of their lambs within two hours of giving birth, and this learning involves synaptic changes within the olfactory bulb. Specifically, mitral cells become increasingly responsive to the learned odour, which stimulates release of both glutamate and GABA (gamma-aminobutyric acid) neurotransmitters from the reciprocal synapses between the excitatory mitral cells and inhibitory granule cells. Nitric oxide (NO) has been implicated in synaptic plasticity in other regions of the brain as a result of its modulation of cyclic GMP levels. Here we investigate the possible role of NO in olfactory learning. We find that the neuronal enzyme nitric oxide synthase (nNOS) is expressed in both mitral and granule cells, whereas the guanylyl cyclase subunits that are required for NO stimulation of cGMP formation are expressed only in mitral cells. Immediately after birth, glutamate levels rise, inducing formation of NO and cGMP, which potentiate glutamate release at the mitral-to-granule cell synapses. Inhibition of nNOS or guanylyl cyclase activity prevents both the potentiation of glutamate release and formation of the olfactory memory. The effects of nNOS inhibition can be reversed by infusion of NO into the olfactory bulb. Once memory has formed, however, inhibition of nNOS or guanylyl cyclase activity cannot impair either its recall or the neurochemical release evoked by the learned lamb odour. Nitric oxide therefore seems to act as a retrograde and/or intracellular messenger, being released from both mitral and granule cells to potentiate glutamate release from mitral cells by modulating cGMP concentrations. We propose that the resulting changes in the functional circuitry of the olfactory bulb underlie the formation of olfactory memories.     

Development of 5'-nucleotidase staining in the olfactory bulbs of normal and naris-occluded rats

The distribution of the adenosine-producing ecto-enzyme 5'-nucleotidase was investigated histochemically in the developing rat olfactory bulb. Rat pups underwent either unilateral surgical occlusion of the right external naris or sham surgery on postnatal day 1. At 10, 20, or 30 days postpartum, horizontal sections of the olfactory bulb were reacted histochemically to reveal the locus and intensity of 5'-nucleotidase activity. Relative staining levels were determined by optical densitometry in standardized bulb regions. A marked, age-related increase in staining density was observed. Reaction product was found primarily in neuropil areas. The P10 and P20 control animals did not exhibit right/left differences in bulb staining; however, some laterality was observed in P30 animals. Inter-glomerular and regional variations were observed throughout the developmental period, including (1) differences between neighboring glomeruli; (2) a gradient in the dorsal-ventral axis of the bulb; and (3) a higher staining density in the medial-caudal portion of the bulb. In subjects with occluded nares, asymmetries in right/left bulb 5'-nucleotidase staining patterns were detected throughout development. Bulbs ipsilateral to the blocked nares exhibited increased staining density, suggesting that the procedure enhanced enzymatic activity. Understanding these variations in 5'-nucleotidase staining may be important for a complete understanding of the mechanisms of olfactory bulb maturation and may give insight into the possible role of this enzyme in synaptic malleability during nervous system development and regeneration.     

Distribution and developmental changes of adenylate kinase isozymes in the rat brain: localization of adenylate kinase 1 in the olfactory bulb

Changes in the levels of three adenylate kinase isozymes (AK1, AK2, and AK3) in the rat brain during development were investigated by immunoblot analysis. The levels of AK1 and AK3 of the whole brain increased after birth, while AK2 was detected only in the early embryonic period. In the adult rat brain, high levels of AK1 were present in the olfactory bulb. Immunohistochemical analysis showed that AK1 was found predominantly in the olfactory nerve layer and the glomerular layer. In the olfactory bulb, AK1 gene expression was enhanced in the early postnatal days, whereas it remained low in the cerebellum during the first 10 postnatal days. These results suggest that the AK isozymes are involved in neuronal maturation and regeneration. The understanding of the physiological actions of adenosine and ATP as neurotransmitters/neuromodulaters in the central nervous system has improved. ATP and adenosine receptors have been found to be widely distributed over the whole brain, although the intra- and extracellular metabolism of these compounds has not been well elucidated.     

Odor-induced, activity-dependent transneuronal gene induction in vitro: mediation by NMDA receptors

Expression of tyrosine hydroxylase (TH) by juxtaglomerular (JG) neurons of the olfactory bulb (OB) requires innervation of the bulb by olfactory receptor neurons (ORNs). ORN lesion selectively downregulates TH in JG neurons. In reversible odor deprivation, TH expression is downregulated as the naris is closed and then upregulated upon naris reopening. The mechanism or mechanisms regulating this dependence are unknown. TH expression could be regulated by trophic factor release and/or synaptic activity from ORN terminals. We investigated TH expression in cocultures of dissociated postnatal rat OB cells and embryonic olfactory neuroepithelium (OE) slice explants. TH-positive neurons in control dissociated OB cell cultures alone comprise only a small fraction of the total population of cells present in the culture. However, when OE slice explants are cocultured with dispersed OB cells, there is a mean 2.4-fold increase in the number of TH-positive neurons. ORNs in vivo use glutamate as a neurotransmitter. Broad spectrum excitatory amino acid antagonists (kyurenic acid) or selective antagonists of the NMDA receptor (APV) both prevent induction of TH expression in OE-OB cocultures. Furthermore, pulse application of NMDA stimulates TH expression in OB neurons in the absence of OE. In vitro, OB TH neurons express NMDA receptors, suggesting that NMDA stimulation is acting directly on TH neurons. Exposure of OE explants to natural odorants results in upregulation of TH, presumably through increased ORN activity, which could be blocked by APV. These findings indicate that odorant-stimulated glutamate release by ORN terminals regulates TH expression via NMDA receptors on JG dopaminergic neurons.     

Topographic bulbar projections and dual neural pathways of the primary olfactory neurons in salmonid fishes

A growing body of evidence indicates spatial patterning of molecular expression and physiological activities in the olfactory epithelium and primary afferent circuits of the vertebrate olfactory bulb. Because our previous studies indicate that olfactory receptors specific for amino acids and a bile acid, taurocholic acid, project to segregated coding centres in the olfactory bulb, we further examined the afferent projections and pathways of the primary neuronal responses to putative pheromones by recording the electroencephalogram from various regions of the olfactory bulb. First, using the electro-olfactogram, we determined olfactory sensitivities of six salmonid species to these odorants. Prostaglandin F2 alpha and 15-keto-prostaglandin F2 alpha were potent olfactory stimulants for all tested salmonids, except rainbow trout (Oncorhynchus mykiss). None of the salmonids responded to 17 alpha,20 beta-dihydroxy-4-pregnen-3-one. However, they were sensitive to etiocholan-3 alpha-ol-17-one glucuronide. In all salmonids examined, electroencephalograms to amino acids and taurocholic acid, applied singly or in combination, projected to two segregated regions, the lateroposterior and mid-olfactory bulb, respectively. Neither prostaglandin F2 alpha, 15-keto-prostaglandin F2 alpha nor etiocholan-3 alpha-ol-17-one glucuronide elicited electroencephalograms. These data indicate that, in salmonids, olfactory neurons responsive to amino acids and taurocholic acid project to spatially segregated regions, and thereby generated signals are encoded spatially and temporarily. The results also suggest that olfactory signals due to hormonal pheromones are processed in a manner distinct from those for amino acids and bile acids, and may possibly be mediated by extrabulbar primary olfactory fibres bypassing the bulb.     

Differential expression of Fos protein in the brain of female mice dependent on pup sensory cues and maternal experience.

Immunoreactivity for Fos protein following 30 min of sensory and behavioral experience with foster pups was measured in different brain areas of nulliparous female Balb/c mice who were intact, ovariectomized, or selectively depleted of olfactory bulb noradrenaline. Fos expression was also investigated in intact nulliparous female mice undergoing distal exposure to pup sensory cues. Behavioral interaction with pups increased Fos immunoreactivity in the olfactory areas (anterior olfactory nucleus, piriform cortex, corticomedial amygdala, and entorhinal cortex) as well as in the medial preoptic area, and this occurred regardless of whether females were intact or ovariectomized. Noradrenaline depletion of the olfactory bulb prevented Fos induction in primary olfactory areas, but not in the medial preoptic area, whereas distal exposure to pup cues enhanced Fos expression in the olfactory areas but not in the medial preoptic area. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Developmental expression of galanin-like immunoreactivity by members of the avian sympathoadrenal cell lineage

So far, no clear correlation has been found between the effects of dopamine D1 receptor agonists on motor behavior in primate models of Parkinson's disease and their ability to stimulate adenylate cyclase in rats, the benzazepine SKF 83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H- 3-benzazepine) being the most striking example. Since this discrepancy might be attributed to: (A) the different species used to study these effects or (B) the interaction of SKF 83959 with other catecholamine receptors, the aims of this study were: (1) to study the ability of SKF 83959 to stimulate adenylate cyclase in cultured human and monkey glial cells equipped with dopamine D1 receptors and (2) to evaluate the affinity for and the functional interaction of SKF 83959 with other catecholamine receptors. Binding studies revealed that SKF 83959 displayed the highest affinity for the dopamine D1 receptor (pKi=6.72) and the alpha2-adrenoceptor (pKi=6.41) and moderate affinity for the dopamine D2 receptor and the noradrenaline transporter. In monkey and human cells, SKF 83959 did not stimulate cyclic adenosine monophosphate (cAMP) formation to a significant extent, but antagonized very potently the dopamine-induced stimulation of cAMP formation in both cell types. The compound stimulated basal dopamine outflow and inhibited depolarization-induced acetylcholine release only at concentrations > 10 microM. Finally, SKF 83959 concentration dependently increased electrically evoked noradrenaline release, indicating that it had alpha2-adrenoceptor blocking activity and interfered with the noradrenaline transporter. In conclusion, SKF 83959 is a potent dopamine D1 receptor and alpha2-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 83959 in primates are not mediated by striatal dopamine D1 receptors coupled to adenylate cyclase in a stimulatory way.     

Oncoprotein v-Myb and retinoic acid receptor alpha are mutual antagonists

The expression of nitric oxide synthase (NOS) in the olfactory bulb was compared between two mouse strains, CD-1 and BALB/c, that differ in the connectivity within their olfactory glomeruli, their content of tyrosine hydroxylase, and their response to olfactory deafferentation. Labelled cells were qualitatively and quantitatively analyzed by both immunohistochemistry for NOS and histochemistry for nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase (ND). Both periglomerular cells and short-axon cells were observed with both techniques employed, and their colocalization in the same neurons demonstrated that ND is a reliable marker for NOS-expressing cells in the mouse olfactory bulb (OB). The histochemical technique differentiates two types of glomeruli: ND-positive and ND-negative. Olfactory glomeruli in the CD-1 strain were about 7% larger than those in the BALB/c animals. While the density of NOS/ND-containing periglomerular cells was similar between both strains studied, more NOS/ND-labelled cells were observed in the ND-positive glomeruli (P = 0.002). Since periglomerular cells in the BALB/c strain do not receive direct olfactory receptors synapses, the present results indicate that such inputs do not regulate the expression of NOS and ND activity in the periglomerular cells. The different densities of NOS/ND-expressing periglomerular cells may indicate that nitric oxide is implicated in a differential modulation of the odor response within both types of chemically distinct glomeruli in the mouse olfactory bulb.     

Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS

Glial cell line-derived neurotrophic factor (GDNF), the most potent trophic factor yet described for both dopaminergic neurons of the substantia nigra and spinal motorneurons, has recently been shown to signal through a multireceptor complex composed of a novel glycosylphosphatidylinositol-anchored GDNF receptor-alpha (GDNFR-alpha) and the receptor tyrosine kinase product of the c-ret proto-oncogene (RET). Despite its importance, the individual expression patterns and the relationships between domains of expression of the different components of this trophic system are not understood. We show here by in situ hybridization that GDNF mRNA is expressed in the normal adult rat brain in several targets of substantia nigra neurons, including striatum, nucleus accumbens, thalamic nuclei, olfactory tubercle, hippocampus, cerebellum, and cingulate cortex as well as in the internal granular cell layer of the olfactory bulb. Within the basal ganglia we observe a pronounced segregation of regions expressing GDNF from those expressing GDNF receptors, suggesting that within these structures GDNF is functioning in its anticipated role as a target-derived trophic factor. In addition, the expression of GDNF and both GDNF receptors within the cerebellum, hippocampus, and olfactory bulb may indicate a paracrine mode of action. Importantly, we also see expression of RET mRNA in cellular populations within the cerebellum and the glomerular layer of the olfactory bulb, as well as in the subthalamic nucleus, which lack GDNFR-alpha expression, indicating that RET functions either independently of GDNFR-alpha or with GDNFR-alpha presented in trans. Conversely, GDNFR-alpha is widely expressed in many regions in which RET expression is absent, suggesting that GDNFR-alpha may associate with additional signaling receptors. Finally, RET and GDNFR-alpha show distinct patterns of regulated expression in the brain after kainic acid stimulation and in the sciatic nerve after nerve transection. Taken together these findings indicate that GDNF, RET, and GDNFR-alpha utilize multiple mechanisms to comprise physiologically relevant trophic circuits for different neuronal populations.