Early-onset cortico-cortical synchronization in the hemiparkinsonian rat model.

Changes in synchronized neuronal oscillatory activity are reported in both cortex and basal ganglia of Parkinson's disease patients. The origin of these changes, in particular their relationship with the progressive nigrostriatal dopaminergic denervation, is unknown. Therefore, in the present study we studied interregional neuronal synchronization in motor cortex and basal ganglia during the development of dopaminergic degeneration induced by a unilateral infusion of 6-hydroxydopamine (6-OHDA) into the rat medial forebrain bundle. We performed serial local field potential recordings bilaterally in the motor cortex and the subthalamic nucleus of the lesioned hemisphere prior to, during, and after development of the nigrostriatal dopaminergic cell loss. We obtained signal from freely moving rats in both resting and walking conditions, and we computed local spectral power, interregional synchronization (using phase lag index), and directionality (using Granger causality). After neurotoxin injection the first change in phase lag index was an increment in cortico-cortical synchronization. We observed increased bidirectional Granger causality in the beta frequency band between cortex and subthalamic nucleus within the lesioned hemisphere. In the walking condition, the 6-OHDA lesion-induced changes in synchronization resembled that of the resting state, whereas the changes in Granger causality were less pronounced after the lesion. Considering the relatively preserved connectivity pattern of the cortex contralateral to the lesioned side and the early emergence of increased cortico-cortical synchronization during development of the 6-OHDA lesion, we suggest a putative compensatory role of cortico-cortical coupling.

What drives MRI-measured cortical atrophy in multiple sclerosis?

BACKGROUND: Cortical atrophy, assessed with magnetic resonance imaging (MRI), is an important outcome measure in multiple sclerosis (MS) studies. However, the underlying histopathology of cortical volume measures is unknown. OBJECTIVE: We investigated the histopathological substrate of MRI-measured cortical volume in MS using combined post-mortem imaging and histopathology. METHODS: MS brain donors underwent post-mortem whole-brain in-situ MRI imaging. After MRI, tissue blocks were systematically sampled from the superior and inferior frontal gyrus, anterior cingulate gyrus, inferior parietal lobule, and superior temporal gyrus. Histopathological markers included neuronal, axonal, synapse, astrocyte, dendrite, myelin, and oligodendrocyte densities. Matched cortical volumes from the aforementioned anatomical regions were measured on the MRI, and used as outcomes in a nested prediction model. RESULTS: Forty-five tissue blocks were sampled from 11 MS brain donors. Mean age at death was 68±12 years, post-mortem interval 4±1 hours, and disease duration 35±15 years. MRI-measured regional cortical volumes varied depending on anatomical region. Neuronal density, neuronal size, and axonal density were significant predictors of GM volume. CONCLUSIONS: In patients with long-standing disease, neuronal and axonal pathology are the predominant pathological substrates of MRI-measured cortical volume in chronic MS.

The Short Physical Performance Battery does not correlate with daily life gait quality and quantity in community-dwelling older adults with an increased fall risk.

BACKGROUND: Both the Short Physical Performance Battery (SPPB) and daily life gait quality and quantity obtained from wearable sensors are used to measure functional status in older adults. It is generally assumed that they are interrelated and exchangeable, but this has not yet been established. Interchangeability of these measures would pave the way for remote monitoring of functional status. RESEARCH QUESTION: Are the SPPB and daily life gait quality and quantity measures correlated in community-dwelling older adults? METHODS: The SPPB and gait quality and quantity data of 229 community-dwelling adults of 65 years or older were collected. The SPPB is a combined score of the Three Stage Balance test, Four Meter Walk test, and Five Times Sit to Stand test and ranges from 0 to 12. Participants wore a tri-axial inertial sensor for one week to assess gait quality (e.g. gait stability and smoothness) and quantity (e.g. number of strides). Correlation coefficients between SPPB scores and gait quality and quantity measures were assessed using Spearman's correlation. RESULTS: The median age of the study population was 76.2 years (IQR 72.6-81.0), and 76 % were women (n=175). The median SPPB score was 10 (IQR 8-11). Spearman's correlation coefficients between the SPPB and gait quality and quantity measures were all below 0.3. SIGNIFICANCE: A possible explanation for the observed weak correlations is that the SPPB reflects one's maximal capacity, while gait quality and quantity reflect the submaximal performance in daily life. The SPPB and gait quality and quantity seem therefore distinct constructs with complementary value, rather than interchangeable. A more comprehensive understanding of functional status might be achieved by combining the SPPB assessment of standardized activities with the evaluation of inertial sensor measurements obtained during daily life activities.

Plasticity in fast synaptic inhibition of adult oxytocin neurons caused by switch in GABA(A) receptor subunit expression.

We found that magnocellular oxytocin neurons in adult female rats exhibit an endogenous GABA(A) receptor subunit switch around parturition: a decrease in alpha1:alpha2 subunit mRNA ratio correlated with a decrease in allopregnanolone potentiation and increase in decay time constant of the GABA(A) receptor-mediated IPSCs in these cells. The causal relationship between changes in alpha1:alpha2 mRNA ratio and the ion channel kinetics was confirmed using in vitro antisense deletion. Further, GABA(A) receptors exhibited a tonic inhibitory influence upon oxytocin release in vivo, and allopregnanolone helped to restrain oxytocin neuron in vitro firing only before parturition, when the alpha1:alpha2 subunit mRNA ratio was still high. Such observations provide evidence for the physiological significance of GABA(A) receptor subunit heterogeneity and plasticity in the adult brain.

Expression of amphetamine sensitization is associated with recruitment of a reactive neuronal population in the nucleus accumbens core.

RATIONALE: Repeated exposure to psychostimulant drugs causes a long-lasting increase in the psychomotor and reinforcing effects of these drugs and an array of neuroadaptations. One such alteration is a hypersensitivity of striatal activity such that a low dose of amphetamine in sensitized animals produces dorsal striatal activation patterns similar to acute treatment with a high dose of amphetamine. OBJECTIVES: To extend previous findings of striatal hypersensitivity with behavioral observations and with cellular activity in the nucleus accumbens and prefrontal cortex in sensitized animals. MATERIALS AND METHODS: Rats treated acutely with 0, 1, 2.5, or 5 mg/kg i.p. amphetamine and sensitized rats challenged with 1 mg/kg i.p. amphetamine were scored for stereotypy, rearing, and grooming, and locomotor activity recorded. c-fos positive nuclei were quantified in the nucleus accumbens and prefrontal cortex after expression of sensitization with 1 mg/kg i.p. amphetamine. RESULTS: Intense stereotypy was seen in animals treated acutely with 5 mg/kg amphetamine, but not in the sensitized group treated with 1 mg/kg amphetamine. The c-fos response to amphetamine in the accumbens core was augmented in amphetamine-pretreated animals with a shift in the distribution of optical density, while no effect of sensitization was seen in the nucleus accumbens shell or prefrontal cortex. CONCLUSIONS: A lack of stereotypy in the sensitized group indicates a dissociation of behavioral responses to amphetamine and striatal immediate-early gene activation patterns. The increase in c-fos positive nuclei and shift in the distribution of optical density observed in the nucleus accumbens core suggests recruitment of a new population of neurons during expression of sensitization.

Augmented reinforcer value and accelerated habit formation after repeated amphetamine treatment.

Various processes might explain the progression from casual to compulsive drug use underlying the development of drug addiction. Two of these, accelerated stimulus-response (S-R) habit learning and augmented assignment of motivational value to reinforcers, could be mediated via neuroadaptations associated with long-lasting sensitization to psychostimulant drugs, i.e. augmented dopaminergic neurotransmission in the striatum. Here, we tested the hypothesis that both processes, which are often regarded as mutually exclusive alternatives, are present in amphetamine-sensitized rats. Amphetamine-sensitized rats showed increased responding for food under a random ratio schedule of reinforcement, indicating increased incentive motivational value of food. In addition, satiety-specific devaluation experiments under a random interval schedule of reinforcement showed that amphetamine-sensitized animals exhibit accelerated development of S-R habits. These data show that both habit formation and motivational value of reinforcers are augmented in amphetamine-sensitized rats, and suggest that the task demands determine which behavioral alteration is most prominently expressed.

Anatomical evidence for direct connections between the shell and core subregions of the rat nucleus accumbens.

The nucleus accumbens is thought to subserve different aspects of adaptive and emotional behaviors. The anatomical substrates for such actions are multiple, parallel ventral striatopallidal output circuits originating in the nucleus accumbens shell and core subregions. Several indirect ways of interaction between the two subregions and their associated circuitry have been proposed, in particular through striato-pallido-thalamic and dopaminergic pathways. In this study, using anterograde neuroanatomical tracing with Phaseolus vulgaris-leucoagglutinin and biotinylated dextran amine as well as single-cell juxtacellular filling with neurobiotin, we investigated the intra-accumbens distribution of local axon collaterals for the identification of possible direct connections between the shell and core subregions. Our results show widespread intra-accumbens projection patterns, including reciprocal projections between specific parts of the shell and core. However, fibers originating in the core reach more distant areas of the shell, including the rostral pole (i.e. the calbindin-poor part of the shell anterior to the core) and striatal parts of the olfactory tubercle, than those arising in the shell and projecting to the core. The latter projections are more restricted to the border region between the shell and core. The density of the fiber labeling within both the shell and core was very similar. Moreover, specific intrinsic projections within shell and core were identified, including a relatively strong projection from the rostral pole to the rostral shell, reciprocal projections between the rostral and caudal shell, as well as projections within the core that have a caudal-to-rostral predominance. The results of the juxtacellular filling experiments show that medium-sized spiny projection neurons and medium-sized aspiny neurons (most likely fast-spiking) contribute to these intra-accumbens projections. While such neurons are GABAergic, the intrastriatal projection patterns indicate the existence of lateral inhibitory interactions within, as well as between, shell and core subregions of the nucleus accumbens.

The distribution of hypothalamic and extrahypothalamic vasotocinergic cells and fibers in the brain of a lizard, Gekko gecko: presence of a sex difference.

The distribution of vasotocin in the brain of the lizard Gekko gecko was studied with immunocytochemical methods. Vasotocinergic cells were found in the nucleus supraopticus, the nucleus paraventricularis, the bed nucleus of the stria terminalis, and in the rhombencephalon. Vasotocinergic fibers were found in the preoptic area, the lateral and ventral hypothalamus, and in many extrahypothalamic brain areas. Furthermore, evidence was obtained of a conspicuous sex difference with regard to vasotocinergic innervation of the lateral septum, the ventrocaudal telencephalon (nucleus sphericus), and the periaqueductal gray; in these areas vastocinergic innervation is much denser in males than in females. The results are discussed in relation to the sexually dimorphic vasopressinergic innervation of the rat brain. It is suggested that the vasotocinergic fiber system in the sexually dimorphic brain areas in Gekko gecko is related to the bed nucleus of the stria terminalis.

Compartmental organization of the ventral striatum of the rat: immunohistochemical distribution of enkephalin, substance P, dopamine, and calcium-binding protein.

In the caudate-putamen of the rat a patch/matrix organization can be recognized on the basis of the immunohistochemical distribution of several markers, which include enkephalin, substance P, dopamine, and calcium-binding protein. In the present experiments the distributional relations of these markers were investigated in the nucleus accumbens. The distribution of enkephalin fibers shows different inhomogeneities according to their location in the nucleus. Rostrally, heavily labeled areas stand out against a moderately stained background, whereas caudally, in medial and ventral parts of the nucleus, lightly stained areas delineate regions in the moderately stained neuropil. In the distribution of substance P, areas with high staining intensity were observed in the medial and ventral parts of the nucleus accumbens. Inhomogeneities in the distribution of strong dopamine immunoreactivity consist of weakly immunoreactive areas throughout the rostrocaudal extent of the nucleus accumbens and extremely heavily labeled areas in the medial and ventral parts of the nucleus. Calcium-binding protein immunoreactivity can only be detected in dorsal parts of the nucleus. The generally intense immunostaining for calcium-binding protein is interspersed with "blanks" of weak immunoreactivity. The heavily and moderately labeled enkephalin areas each maintain specific relations with inhomogeneities in the distribution of substance P, dopamine, and calcium-binding protein. Rostrally, the heavily labeled enkephalin areas coincide with areas strongly immunostained for calcium-binding protein and with lightly stained areas in the dopamine and substance P immunoreactivity patterns. In the same region lightly stained areas in the enkephalin distribution match heavily labeled substance P areas. Caudally, in the border region of the nucleus accumbens and the caudate-putamen, the heavily labeled enkephalin areas are either related to "blanks" or to the intense staining regions in the calcium-binding protein immunoreactivity distribution. The moderately labeled enkephalin areas caudomedially in the nucleus accumbens are in register with the heavily labeled regions in the distribution of substance P and with the extremely heavily labeled regions in the distribution of dopamine. Relations with connectivity are discussed and the inhomogeneities are compared to those in the caudate-putamen. It is concluded that in the ventral striatum either one patch and one matrix compartment exist with different immunohistochemical relationships or there are several compartments with different immunohistochemical characteristics and different input-output relations.

The distribution of dopamine immunoreactivity in the forebrain and midbrain of the lizard Gekko gecko: an immunohistochemical study with antibodies against dopamine.

The distribution of dopamine (DA) immunoreactivity in the forebrain and the midbrain of the lizard Gekko gecko was studied by using recently developed antibodies against DA. Dopamine-containing cells were found around the glomeruli of the olfactory bulb, in several parts of the periventricular hypothalamic nucleus, in the periventricular organ, the ependymal wall of the infundibular recess, the lateral hypothalamic area and the pretectal posterodorsal nucleus of the diencephalon, and in the ventral tegmental area, the substantia nigra, and the presumed reptilian equivalent of the mammalian A8 cell group of the mesencephalon. Dopaminergic fibers and terminals were observed throughout the whole brain, but particularly in the diencephalon and the telencephalon. The nucleus accumbens appears to have the most dense innervation, but also the striatum, amygdaloid complex, olfactory tubercle, septum, and dorsal ventricular ridge (especially its superficial zone) show numerous DA-containing fibers and terminals. Except for the lateral cortex, cortical areas are not densely innervated by DA fibers. In several respects DA distribution in the gekkonid brain differs from that in other reptiles studied. For instance, in the Gekko the dorsal ventricular ridge is densely innervated by DA fibers, whereas in turtles and crocodiles the same structure shows only weak catecholaminergic histofluorescence. When compared to the distribution of DA immunoreactivity in mammals, it appears that the DA system in the gekkonid telencephalon resembles the distribution of DA in the limbic forebrain and striatum of mammals. Whether these similarities in distribution of DA also imply similarities in function will be discussed.

Prenatal development of GABA-ergic neurons in the neocortex of the rat.

The present study shows that in the prenatal rat neocortex the GABA immunoreactive neurons are not limited to the marginal, subplate, and intermediate zones, but are also found in all fetal zones of the cerebral anlage. The first GABA-ergic cells are observed on embryonic day 14 in the plexiform primordium. On embryonic day 15, a second population of GABA-ergic cells is observed in the intermediate zone. Beginning on day 16 of gestation and continuing throughout gestation, GABA-ergic neurons are observed in the marginal zone, the subplate zone, the cortical plate, and the ventricular and subventricular zones. Furthermore, while the number of GABA-ergic cells in the cortical plate increases, GABA-ergic neurons in the intermediate zone and subventricular zone decrease in number after embryonic day 19.

The dopaminergic innervation of the ventral striatum in the rat: a light- and electron-microscopical study with antibodies against dopamine.

Dopamine (DA) in the dorsal and ventral striatum is associated with different aspects of locomotor activity control. The ventral striatum may form an interface between the limbic system and the extrapyramidal motor system. The distribution of dopaminergic fibers in this interface position was studied in detail with a method applying antibodies against DA. Furthermore, the ultrastructural morphology of the DA fibers was examined by means of immuno-electron microscopy. The results show that DA immunoreactivity is distributed over the ventral striatum in a highly compartmentalized fashion. In the dorsal striatum few compartments were found. The DA fibers in the ventral striatum establish mainly symmetric synaptic contacts, preferably with dendritic shafts and spines. The results are discussed in relation to previous data concerning the light and electron-microscopic identification of catecholaminergic fibers in the ventral and dorsal striatum.

Evidence for a multi-compartmental histochemical organization of the nucleus accumbens in the rat.

In the present study, the compartmental organization of the nucleus accumbens was investigated by comparing the pattern of leu-enkephalin immunoreactivity with that of the opioid receptor ligand, naloxone, an established marker for the compartmental organization of the neostriatum. Both patterns have a nonhomogeneous, patch-like appearance throughout the rostrocaudal extent of the nucleus and show a good, mutual correspondence. In the core of the nucleus accumbens as well as in the border region between the nucleus accumbens and the caudate-putamen, leu-enkephalin-rich areas are in register with opioid receptor-dense areas. In the shell region the precise relationship between the enkephalin and the naloxone patterns could not be established. A comparison of the connectivity patterns and neurochemical characteristics of the opioid receptor-dense compartments in the nucleus accumbens with those in the caudate-putamen reveals major discrepancies between these two striatal subdivisions. We therefore conclude that, rather than a bicompartmental patch/striosome-matrix organization, the nucleus accumbens has a multicompartmental organization.

Ultrastructural characteristics of enkephalin-immunoreactive boutons and their postsynaptic targets in the shell and core of the nucleus accumbens of the rat.

The present study compared the ultrastructural morphology of enkephalin-immunoreactive boutons and their postsynaptic targets in different territories of the nucleus accumbens in the rat. The synaptic bouton profiles were identified by antibodies directed against [leu5]enkephalin. Ninety-five percent of the synaptic contacts were symmetric in configuration and the remaining 5% were asymmetric. Axosomatic contacts comprised 6% of all enkephalin-immunoreactive junctions and were distributed equally in all parts of the nucleus. Most (76%) synaptic terminals contacted dendrites but they contacted proportionally fewer dendrites in the shell (71%) than in the core (78%). Moreover, enkephalin-immunoreactive synaptic boutons in the shell (19%) and caudal enkephalin-rich areas (17%) of the core contacted twice as many spines than in the remaining parts of the core (8.5%). In the core, long pallidum-like dendrites were occasionally found ensheathed in enkephalin-immunoreactive terminal boutons. We conclude that the differential arrangement of enkephalinergic contacts in the shell and core could have important functional consequences, especially when considered in relation to other known morphological and neurochemical differences between these regions.

Development of the dopaminergic innervation in the prefrontal cortex of the rat.

The pre- and postnatal development of the dopaminergic innervation in the prefrontal cortex (PFC) of the rat is described from embryonic day 14 through postnatal day 90. By embryonic day 15 the dopamine (DA)-containing fibers reach the anlage of the lateral neocortex; 2 days later the first fibers have reached the subplate of the future prefrontal cortex. The process of entering the cortical plate starts just before birth. Prenatally, some dopaminergic fibers can be observed in the marginal zone of both the lateral and the medial wall of the hemisphere. Within 48 hours after birth a large number of dopaminergic fibers can be observed in the marginal zone, i.e., the future layer I, in some subareas of the PFC. A transient appearance of DA-positive fibers is noticed in the late embryonic and early postnatal periods especially in the marginal zone and possibly in the superficial layers of the pregenual cingulate cortex. Changes in the morphology of DA fibers at P4 suggest that the actual DA innervation starts at this age. From postnatal day 6 the different subareas of the PFC can be recognized according to the characteristics of the topographical distribution of the dopaminergic fibers. Until postnatal day 60 the density of the dopaminergic fibers continues to increase. No difference in density and topography was observed between postnatal days 60 and 90.

Opioid receptor ligand binding in the human striatum: II. Heterogeneous distribution of kappa opioid receptor labeled with [3H]bremazocine.

Selective kappa opioid receptor autoradiography with [3H]bremazocine (BRM) was used to examine regional and subregional kappa receptor distribution patterns at five rostrocaudal levels through the human striatum. [3H]BRM binding densities were measured in the individual striatal nuclei and in subregions therein. The distribution of [3H]BRM binding sites was found to have a strongly heterogeneous character. At the regional level a rostral-to-caudal decrease in [3H]BRM binding densities was observed. Also, a dorsal-to-ventral differentiation was seen, with higher values in the ventral striatum, especially in the nucleus accumbens, and lower values in the dorsal parts of the caudate nucleus and putamen. These findings suggest an association of kappa receptor function with limbic-related processes in the ventral striatum. Along the ventral edge of the nucleus accumbens and putamen, specific domains with extremely high [3H]BRM binding values were identified.

Regional and cellular distribution of serotonin 5-hydroxytryptamine2a receptor mRNA in the nucleus accumbens, olfactory tubercle, and caudate putamen of the rat.

This paper describes the regional and cellular distribution of serotonin 5-hydroxytryptamine2a (5-HT2a) receptor mRNA in (sub)regions of the rat striatum by using in situ hybridization. Our results indicate that 5-HT2a mRNA is distributed heterogeneously in this brain region. Regional densitometry of autoradiograms from striatal sections hybridized with isotope-labeled cRNA probes showed that mRNA levels were highest in the olfactory tubercle, lower in the nucleus accumbens, and lowest in the caudate-putamen. In the nucleus accumbens, the average mRNA levels in the shell were higher than those in the core. These data suggest a particular relevance for the 5-HT2a receptor for olfactory tubercle- and shell-related functions. Therefore, in the nucleus accumbens and the olfactory tubercle, the cellular localization of 5-HT2a mRNA was investigated by determining the colocalization of 5-HT2a mRNA with enkephalin mRNA or dynorphin mRNA. 5-HT2a mRNA was found in enkephalinergic as well as dynorphinergic neurons. Thus, there does not seem to be a differential distribution of this receptor in the output routes of the ventral striatum. In all of the subregions investigated (core, medial shell, and lateral shell of the nucleus accumbens and the olfactory tubercle), only subpopulations of the total enkephalinergic and dynorphinergic populations were found to contain 5-HT2a mRNA. For enkephalin, the percentage colocalization was higher in the lateral shell (61%) compared with the other subregions (38-45%). For dynorphin, the percentage colocalization was higher in the olfactory tubercle (68%) than in the other subregions (34-43%). The differences in (sub)regional mRNA levels and in colocalization with opioids suggest a considerable regional differentiation in the effects of 5-HT2a-mediated neurotransmission in the striatum.

Densitometrical analysis of opioid receptor ligand binding in the human striatum--I. Distribution of mu opioid receptor defines shell and core of the ventral striatum.

Changes in opioid neurotransmission have been implicated in several basal ganglia-related neurological and psychiatric disorders. To gain a better insight into the opioid receptor distribution in the normal human striatum, we examined in post mortem brain the distribution of the mu opioid receptor using ligand binding of [3H]O-ala2-N-methyl-phe4, gly-ol5-enkephalin. Our results indicate at the regional level the presence of a dorsal-to-ventral high-to-low density gradient in the striatum, with lowest densities in the ventral one-third of the putamen and in the nucleus accumbens. At the subregional level, the nucleus accumbens shows two major types of heterogeneities. First, low vs intermediate binding densities distinguish the core and shell subdivisions, respectively. The low-density core and intermediate-density shell regions extend into the putamen and are therefore characteristic for the entire ventral striatum. The second type of heterogeneity is formed by small areas located along the ventral contours of the nucleus accumbens and putamen that display the highest binding density of the entire striatum. Since these areas can also be recognized in the distribution patterns of other markers and in the cytoarchitecture, they appear to possess a separate identity. To emphasize their special neurochemical characteristics we propose the description "neurochemically unique domains in the accumbens and putamen". The present results, with the difference between core and shell of the ventral striatum as the most prominent outcome, together with the notion that the connectional relationships and neurochemical organization of the striatum are very heterogeneous, suggest a strong regional functional differentiation for mu receptor function in the human striatum.

The pre- and postnatal development of the dopaminergic cell groups in the ventral mesencephalon and the dopaminergic innervation of the striatum of the rat.

In the adult rat the striatum is a compartmentalized structure, which is reflected in the inhomogeneous distribution of dopamine. As a first step to test the hypothesis that dopamine plays an organizational role in the development of the striatum, the ontogeny of the dopaminergic system was studied in detail with immunocytochemical methods employing antibodies against dopamine. Rat embryos, fetuses, pups and adults were perfusion-fixed with glutaraldehyde on all prenatal days from E11 onward, postnatally on P2, P4, P6, P7, P8, P13, P14, P20, P21, and in adult age. On E13 the first dopaminergic cells are detected in the ventral prosencephalon. On E14 two dopaminergic cell groups are present in the ventral mesencephalon, and fibres of these cells reach the ventrolateral part of the ganglionic eminence. In the next two days both the cell groups and their projections rapidly increase in size. On E17 the afferent dopaminergic fibres to the striatum become aligned and form huge bundles that are closely associated with the fascicles of the internal capsule. Rostrally, the development of the striatal dopaminergic innervation shows a clear ventrolateral to dorsomedial gradient, whereas more caudally the dopaminergic fibres innervate the striatum from a ventromedial position. The lateral parts of the otherwise compact mesencephalic cell groups consist of loosely arranged cells. From E17 onward these cells become arranged into a dorsal and a ventral group. Just before birth, on E21, the primordia of the dopaminergic cell groups in the substantia nigra pars compacta and pars reticulata can be observed. On E19 several centres with extensive fibre ramifications along the dorsolateral margin of the caudate putamen represent the first signs of the inhomogeneous distribution of dopaminergic fibres in the dorsal striatum seen during the next two weeks. In the following pre- and postnatal days these so-called dopaminergic "patches" also appear more medially. By the third postnatal week most of the patches are no longer detectable, and only the most dorsolaterally located ones, i.e. in the region where they first were detected on E19, remain visible through to the adult stage. Prenatally, no varicosities can be observed in the dopaminergic fibres. The first varicosities appear after birth. Their number increase rapidly during the first and second postnatal weeks and reaches near adult levels on P20. The development of the striatal dopaminergic innervation, and that of the "patches" in particular, is discussed in relation to the development of the mesencephalic dopaminergic cell groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Detailed mapping of serotonin 5-HT1B and 5-HT1D receptor messenger RNA and ligand binding sites in guinea-pig brain and trigeminal ganglion: clues for function.

The similar pharmacology of the 5-HT1B and 5-HT1D receptors, and the lack of selective compounds sufficiently distinguishing between the two receptor subtypes, have hampered functional studies on these receptors. In order to provide clues for differential functional roles of the two subtypes, we performed a parallel localization study throughout the guinea-pig brain and the trigeminal ganglia by means of quantitative in situ hybridization histochemistry (using [35S]-labelled riboprobes probes for receptor messenger RNA) and receptor autoradiography (using a new radioligand [3H]alniditan). The anatomical patterns of 5-HT1B and 5-HT1D receptor messenger RNA were quite different. While 5-HT1B receptor messenger RNA was abundant throughout the brain (with highest levels in the striatum, nucleus accumbens, olfactory tubercle, cortex, hypothalamus, hippocampal formation, amygdala, thalamus, dorsal raphe and cerebellum), 5-HT1D receptor messenger RNA exhibited a more restricted pattern; it was found mainly in the olfactory tubercle, entorhinal cortex, dorsal raphe, cerebellum, mesencephalic trigeminal nucleus and in the trigeminal ganglion. The density of 5-HT(1B/1D) binding sites (combined) obtained with [3H]alniditan autoradiography was high in the substantia nigra, superior colliculus and globus pallidus, whereas lower levels were detected in the caudate-putamen, hypothalamus, hippocampal formation, amygdala, thalamus and central gray. This distribution pattern was indistinguishable from specific 5-HT1B receptor labelling in the presence of ketanserin under conditions to occlude 5-HT1D receptor labelling; hence the latter were below detection level. Relationships between the regional distributions of the receptor messenger RNAs and binding sites and particular neuroanatomical pathways are discussed with respect to possible functional roles of the 5-HT1B and 5-HT1D receptors.