Adenosine A2A receptors and basal ganglia physiology.

Adenosine A2A receptors are highly enriched in the basal ganglia system. They are predominantly expressed in enkephalin-expressing GABAergic striatopallidal neurons and therefore are highly relevant to the function of the indirect efferent pathway of the basal ganglia system. In these GABAergic enkephalinergic neurons, the A2A receptor tightly interacts structurally and functionally with the dopamine D2 receptor. Both by forming receptor heteromers and by targeting common intracellular signaling cascades, A2A and D2 receptors exhibit reciprocal antagonistic interactions that are central to the function of the indirect pathway and hence to basal ganglia control of movement, motor learning, motivation and reward. Consequently, this A2A/D2 receptors antagonistic interaction is also central to basal ganglia dysfunction in Parkinson's disease. However, recent evidence demonstrates that, in addition to this post-synaptic site of action, striatal A2A receptors are also expressed and have physiological relevance on pre-synaptic glutamatergic terminals of the cortico-limbic-striatal and thalamo-striatal pathways, where they form heteromeric receptor complexes with adenosine A1 receptors. Therefore, A2A receptors play an important fine-tuning role, boosting the efficiency of glutamatergic information flow in the indirect pathway by exerting control, either pre- and/or post-synaptically, over other key modulators of glutamatergic synapses, including D2 receptors, group I metabotropic mGlu5 glutamate receptors and cannabinoid CB1 receptors, and by triggering the cAMP-protein kinase A signaling cascade.

[Changes in neural networks by conditional transgenic approach: a key to our comprehension of neuro-psychiatric disorders in the basal ganglia system]. / Modifications des réseaux neuronaux par transgénèse conditionnelle: une clé pour notre compréhension des pathologies neuro- psychiatriques du système des noyaux de la base.

The striatum, the first relay of the basal ganglia system, is critically involved in motor functions and motivational processes. The dorsal striatum is central to the motor control and motor learning and the ventral striatum or nucleus accumbens is essential for motivation, the reward system and reinforcement by drugs. This system is dysfunctional in movement disorders such as Parkinson's disease and Huntington's disease and in psychiatric disorders including drug addiction. The striatum consists of two populations of neurons projecting at the origin of two distinct paths in the circuit of basal ganglia, and of different populations of interneurons. These two populations of efferent neurons, striatopallidal and striatonigral neurons, are characterized by their projection sites and their differential expression in dopamine receptors and neuropeptides. Their roles in motor control and motivational processes and in the mechanisms of neuroadaptation in the system's pathologies remain mostly unknown. To identify these specific functions, we have developed new animal models wearing molecular or cell "lesions" by a conditional transgenic approach to target a specific population of neurons. By this approach, we demonstrated the inhibitory role of the population of striatopallidal neurons in the motor control and in the process of drug addiction, identified new genes selectively expressed by striatopallidal neurons that could be the target for future therapies and identified the potential role of this population of neurons disturbances in attention-deficit hyperactivity disorder (ADHD).

Modulation of neuronal excitability by intracellular calcium buffering: from spiking to bursting.

We have investigated the detailed regulation of neuronal firing pattern by the cytosolic calcium buffering capacity using a combination of mathematical modeling and patch-clamp recording in acute slice. Theoretical results show that a high calcium buffer concentration alters the characteristic regular firing of cerebellar granule cells and that a transition to various modes of oscillations occurs, including bursting. Using bifurcation analysis, we show that this transition from spiking to bursting is a consequence of the major slowdown of calcium dynamics. Patch-clamp recordings on cerebellar granule cells loaded with a high concentration of the fast calcium buffer BAPTA (15 mM) reveal dramatic alterations in their excitability as compared to cells loaded with 0.15 mM BAPTA. In high calcium buffering conditions, granule cells exhibit all bursting behaviors predicted by the model whereas bursting is never observed in low buffering. These results suggest that cytosolic calcium buffering capacity can tightly modulate neuronal firing patterns leading to generation of complex patterns and therefore that calcium-binding proteins may play a critical role in the non-synaptic plasticity and information processing in the central nervous system.

Role of calcium binding proteins in the control of cerebellar granule cell neuronal excitability: experimental and modeling studies.

Calcium binding proteins, such as calretinin, are abundantly expressed in distinctive patterns in the central nervous system but their physiological function remains poorly understood. Calretinin is expressed in cerebellar granule cells which provide the major excitatory input to Purkinje cells through parallel fibers. Calretinin deficient mice exhibit dramatic alterations in motor coordination and in Purkinje cell firing recorded in vivo through unknown mechanisms. In the present paper, we review the results obtained with the patch clamp recording techniques in acute slice preparation. This data allow us to investigate the effect of a null mutation of the calretinin gene on the intrinsic electroresponsiveness of cerebellar granule cells at a mature developmental stage. Calretinin deficient granule cells exhibit faster action potentials and generate repetitive spike discharge showing an enhanced frequency increase with injected currents. These alterations disappear when 0.15 mM of the exogenous fast calcium buffer BAPTA is infused in the cytosol to restore the calcium buffering capacity. Furthermore, we propose a mathematical model demonstrating that the observed alterations of granule cell excitability can be explained by a decreased cytosolic calcium buffering capacity due to the absence of calretinin. We suggest that calcium binding proteins modulate intrinsic neuronal excitability and may therefore play a role in the information processing in the central nervous system.

Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities.

Gene mutations and gene copy number variants are associated with autism spectrum disorders (ASDs). Affected gene products are often part of signaling networks implicated in synapse formation and/or function leading to alterations in the excitation/inhibition (E/I) balance. Although the network of parvalbumin (PV)-expressing interneurons has gained particular attention in ASD, little is known on PV's putative role with respect to ASD. Genetic mouse models represent powerful translational tools for studying the role of genetic and neurobiological factors underlying ASD. Here, we report that PV knockout mice (PV(-/-)) display behavioral phenotypes with relevance to all three core symptoms present in human ASD patients: abnormal reciprocal social interactions, impairments in communication and repetitive and stereotyped patterns of behavior. PV-depleted mice also showed several signs of ASD-associated comorbidities, such as reduced pain sensitivity and startle responses yet increased seizure susceptibility, whereas no evidence for behavioral phenotypes with relevance to anxiety, depression and schizophrenia was obtained. Reduced social interactions and communication were also observed in heterozygous (PV(+/-)) mice characterized by lower PV expression levels, indicating that merely a decrease in PV levels might be sufficient to elicit core ASD-like deficits. Structural magnetic resonance imaging measurements in PV(-/-) and PV(+/-) mice further revealed ASD-associated developmental neuroanatomical changes, including transient cortical hypertrophy and cerebellar hypoplasia. Electrophysiological experiments finally demonstrated that the E/I balance in these mice is altered by modification of both inhibitory and excitatory synaptic transmission. On the basis of the reported changes in PV expression patterns in several, mostly genetic rodent models of ASD, we propose that in these models downregulation of PV might represent one of the points of convergence, thus providing a common link between apparently unrelated ASD-associated synapse structure/function phenotypes.

Distribution of cells containing mRNA encoding cholecystokinin in the rat central nervous system.

The distribution of cells containing mRNA encoding cholecystokinin was studied in the rat central nervous system by in situ hybridization histochemistry. Cholecystokinin mRNA containing neurons were considerably more numerous than the cholecystokinin-like immunoreactive neurons detected by immunocytochemistry even after colchicine pretreatment and appeared to be heavily, moderately, or lightly labeled. Such neurons were present in the olfactory bulb, olfactory nuclei, layers II-III and V-VI of the cerebral cortex, amygdaloid nuclei, subiculum, hippocampus, claustrum, endopiriform nucleus, several hypothalamic nuclei, most of the thalamic nuclei, ventral tegmental area, substantia nigra, interfascicularis nucleus, linearis rostralis, central gray, Edinger-Westphal nucleus, superior and inferior colliculi, parabrachial nucleus, reticular formation, raphe nuclei, and spinal trigeminal nucleus. This distribution partly confirmed and partly extended the previous immunohistochemical descriptions. Several brain areas such as the thalamus and the colliculi contain cholecystokinin mRNA but are devoid of perikarya exhibiting cholecystokinin-like immunoreactivity. The cerebral cortex and the hippocampus present a far higher density of cholecystokinin mRNA containing cells, including pyramidal neurons, than of perikarya containing cholecystokinin-like immunoreactivity. These results suggest that cholecystokinin or cholecystokinin-related peptides could have a functional role in numerous cerebral pathways including long projections such as cortical or thalamic projections.

Ontogeny of gene expression of adenosine A2 receptor in the striatum: early localization in the patch compartment.

The ontogeny of adenosine A2 receptor mRNA and adenosine A2 binding sites distributions was studied by in situ hybridization histochemistry and receptor autoradiography in pre- and post-natal rat striatum, postnatal dog striatum, and a human fetus striatum and compared to that of dopamine D1 and mu opiate receptors. The early postnatal striatum demonstrated heterogeneous distributions of adenosine A2 receptor mRNA and adenosine A2 binding sites with patches of dense labeling corresponding to dopamine D1 and mu opiate receptors enriched zones. This patchy pattern evolved to the homogeneous distribution observed in the adult. The higher intensity of adenosine A2 receptor mRNA enriched patches correspond at the microscopical level to a higher density of labeled neurons in the patches areas and also to a higher level of expression per labeled patches neuron than in the matrix ones. This demonstrates for the first time that differences in patch/matrix receptor density is at least partly linked to different levels of receptor gene expression.

Caffeine regulates neurotensin and cholecystokinin messenger RNA expression in the rat striatum.

Interactions between dopamine and neurotensin or dopamine and cholecystokinin have been demonstrated in the basal ganglia. Disruption of nigrostriatal dopaminergic transmission results in a dramatic increase in neurotensin messenger RNA and in an induction of cholecystokinin messenger RNA in the striatum. Interaction between striatal dopaminergic and adenosinergic systems have also been reported. Adenosine and the adenosine receptor antagonist, caffeine, regulate gene expression in the striatum. In the present study, in situ hybridization histochemistry was used to investigate the putative regulation of neurotensin and cholecystokinin messenger RNA expression by caffeine in the rat striatum. Using this method, cholecystokinin messenger RNA was undetectable and neurotensin messenger RNA very sparse in the normal striatum. Chronic caffeine administration induced a dramatic increase in neurotensin messenger RNA in the subcallosal region of the caudate-putamen and a moderate increase in the shell sector of the accumbens nucleus. Similarly, caffeine induced a significant striatal expression of cholecystokinin messenger RNA in the dorsolateral and ventrolateral quadrants but was not restricted to the subcallosal area. At the cellular level, this corresponded to a significant labeling of a moderate to high density of medium-sized striatal neurons. These distributions were identical to those of neurotensin and cholecystokinin messenger RNAs observed in the case of disruption of dopaminergic transmission. We therefore concluded that in the intact striatum normally innervated by dopaminergic fibers, caffeine, probably acting through a presynaptic A2 receptor, induced a relative dopamine depletion which in turn led to the induction of neurotensin and cholecystokinin expression in subsets of striatal neurons.

Lesion of the nigrostriatal pathway induces cholecystokinin messenger RNA expression in the rat striatum. An in situ hybridization histochemistry study.

In situ hybridization histochemistry was used to investigate the putative regulation of cholecystokinin messenger RNA expression by dopamine in the rat striatum. Using this method, cholecystokinin messenger RNA was undetectable in the normal rat striatum. Dopamine depletion caused by a 6-hydroxydopamine injection in the medical forebrain bundle induced, two and four weeks after the injection, an increase of cholecystokinin messenger RNA expression in the ipsilateral striatum. The labeling was mostly restricted to the dorsolateral quadrant. At the cellular level, this corresponded to a slight but significant labeling of a moderate density of striatal neurons which most probably represent a subpopulation of medium-sized spiny neurons. Conversely, treatment with either haloperidol or SCH23390 for two weeks did not induce any detectable changes in cholecystokinin messenger RNA expression in the striatum while, as expected, an increase in the striatal enkephalin messenger RNA content was observed. These results suggest that the dopaminergic nigrostriatal pathway directly, or indirectly, regulates the expression of cholecystokinin messenger RNA in the striatum.

Inactivation of adenosine A2A receptor impairs long term potentiation in the accumbens nucleus without altering basal synaptic transmission.

The nucleus accumbens is considered to be critically involved in the control of complex motivated behaviors. By modulating its glutamatergic excitatory input, mesolimbic dopaminergic afferents have been implicated in the reinforcing properties of drugs of abuse. However, they might not represent the only path for influencing the accumbens output. The aim of this study was to investigate possible modulation of synaptic transmission at this glutamatergic synapse by adenosine receptors. The standard field potential recording technique was used on brain slices from wild-type and A2A receptor-deficient mice. Neither the stimulus-response relationship nor paired-pulse facilitation was altered in the mutant mice. In both genotypes, the activation of A1 receptors by 2-chloro-N6-cyclopentyladenosine reduced the field excitatory postsynaptic potential (fEPSP) slope to a similar extent. In wild-type slices, activation or blockade of A2A receptors by 2-[4-(carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine and 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol, respectively, did not modify the synaptic transmission. Moreover, a long lasting pre-activation of these A2A receptors did not influence the A1 receptor-mediated reduction in fEPSP slope. Long term potentiation (LTP) of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA) receptor-mediated synaptic transmission could be elicited in both wild-type and A2A receptor-deficient mice. However, LTP appeared to be quantitatively modulated by the A2A receptor pathway since the level of potentiation was reduced in A2A receptor-deficient mice as well as in slices of wild-type mice in which the A2A receptor pathway was blocked. The involvement of the cAMP-dependent protein kinase was supported by the reduction in potentiation level in slices of wild-type mice treated with adenosine 3',5'-cyclic monophosphorothiotate, 8-(4-chlorophenylthio)-Rp isomer, an inhibitor of this enzyme. These data provide evidence that the adenosine acting at the A2A receptor is implicated in events directly or indirectly related to LTP induction in the accumbens whereas it is not involved in the regulation of the basal AMPA receptor-mediated excitatory synaptic transmission.

Homolateral cerebrocortical changes in neuropeptide and receptor expression after minimal cortical infarction.

A cortical infarct of 2 mm diameter was obtained in the parietal cortex after a craniotomy, disruption of the dura mater and topical application of 3 M KCl. It has been shown previously that the presence of a small cortical infarct induces an increase in immediate early gene messenger RNA expression followed by an increase in neuropeptide and glutamic acid decarboxylase messenger RNA expression. Glutamate, acting at N-methyl-D-aspartate receptors, is held responsible for these changes, since they are blocked by pretreatment with dizocilpine. In the present study, we have analysed the consequences of the dramatic changes in messenger RNA expression on the level of immediate early gene products c-fos and zif 268, and on that of neuropeptides by using immunohistochemistry. After just 1 h, an increase in c-fos- and zif 268-like immunoreactivity is observed in the entire cortical hemisphere homolateral to the infarct, and is no longer detected after 6 h. An increase in cholecystokinin octapeptide-, substance P-, neuropeptide Y- and somatostatin-like immunoreactivity is observed in the entire cortical hemisphere homolateral to the infarct after three days, and is no longer detected after 30 days. To investigate if these dramatic increases in neuropeptide immunoreactivities may have functional consequences, we studied the level of cholecystokinin receptors by autoradiographic binding using [125I]cholecystokinin-8S and in situ hybridization for the detection of cholecystokinin-b receptor messenger RNA. A decrease in cholecystokinin binding sites and cholecystokinin-b receptor messenger RNA is observed in the entire cortical hemisphere homolateral to the infarct after three days, and is no longer detected after nine days. This study shows that a topical stimulation has diffuse effects, reaching regions far from the site of the lesion, and some of them are still strongly present after nine days. The increase in neuropeptide messenger RNAs is followed by an increase in the protein products of these genes, which may modify the neurotransmission. As a corollary to this, a decrease in cholecystokinin binding sites occurs. This may have further consequences on signal transduction pathways. This decrease in cholecystokinin binding sites is associated with a decrease in the cholecystokinin-b receptor messenger RNA, and this is the first example of a decrease in messenger RNA levels in this experimental model.

The SH2 domain-containing 5-phosphatase SHIP2 is expressed in the germinal layers of embryo and adult mouse brain: increased expression in N-CAM-deficient mice.

The germinative ventricular zone of embryonic brain contains neural lineage progenitor cells that give rise to neurons, astrocytes and oligodendrocytes. The ability to generate neurons persists at adulthood in restricted brain areas. During development, many growth factors exert their effects by interacting with tyrosine kinase receptors and activate the phosphatidylinositol 3-kinase and the Ras/MAP kinase pathways. By its ability to modulate these pathways, the recently identified Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 2, SHIP2, has the potential to regulate neuronal development. Using in situ hybridization technique with multiple synthetic oligonucleotides, we demonstrated that SHIP2 mRNA was highly expressed in the ventricular zone at early embryonic stages and subventricular zones at latter stages of brain and spinal cord and in the sympathetic chain. No significant expression was seen in differentiated fields. This restricted expression was maintained from embryonic day 11.5 to birth. In the periphery, large expression was detected in muscle and kidney and moderate expression in thyroid, pituitary gland, digestive system and bone. In the adult brain, SHIP2 was mainly restricted in structures containing neural stem cells such as the anterior subventricular zone, the rostral migratory stream and the olfactory tubercle. SHIP2 was also detected in the choroid plexuses and the granular layer of the cerebellum. The specificity of SHIP2 expression in neural stem cells was further demonstrated by (i) the dramatic increase in SHIP2 mRNA signal in neural cell adhesion molecule (N-CAM)-deficient mice, which present an accumulation of progenitor cells in the anterior subventricular zone and the rostral migratory stream, (ii) the abundant expression of 160-kDa SHIP2 by western blotting in proliferating neurospheres in culture and its downregulation in non-proliferating differentiated neurospheres. In conclusion, the close correlation between the pattern of SHIP2 expression in the brain and the proliferative and early differentiative events suggests that the phosphatase SHIP2 may have important roles in neural development.

Homolateral cerebrocortical increase of immediate early gene and neurotransmitter messenger RNAs after minimal cortical lesion: blockade by N-methyl-D-aspartate antagonist.

A small surgical lesion of the parietal cortex induces an increase in the expression of several messenger RNAs varying from 172 to 980% in the entire homolateral cerebral cortex, as detected by quantitative in situ hybridization histochemistry. The messenger RNAs encoding the immediate early genes of the leucine zipper family (c-fos, c-jun, jun-B), the Zinc finger family (zif268), the glucocorticoid receptor family (NGFI-B) and the interferon family (PC4) are increased within 2 h after the lesion and return to normal levels at 6 h. The messenger RNAs encoding cholecystokinin, neuropeptide Y, somatostatin and the synthetizing enzyme of the neurotransmitter GABA, glutamate decarboxylase, are elevated within one day and return to normal levels after six days. An intraperitoneal injection of the N-methyl-D-aspartate receptor antagonist dizocilpine maleate, 30 min before surgery, prevented either the induction of immediate early gene expression or the increase of neuropeptide and glutamate decarboxylase messenger RNA expression. This study demonstrates that a minimal cortical lesion induces extensive changes in gene expression and that the mechanism(s) leading to these changes involves the action of glutamate at the N-methyl-D-aspartate receptor. These modifications may be of importance in explaining diffuse changes not related to neuronal circuitry in several conditions.

Distribution of the nociceptin and nocistatin precursor transcript in the mouse central nervous system.

The distribution of prepronociceptin messenger RNA, the recently identified endogenous ligand of the ORL1 receptor (opioid receptor-like-1), has been studied in the adult mouse central nervous system using in situ hybridization. Prepronociceptin is a new peptide precursor that generates, upon maturation, at least three bioactive peptides: nociceptin, noc2 and the recently described nocistatin. Considering both the density of labeled neurons per region and their intensity of labeling, the distribution of prepronociceptin messenger RNA-containing neurons can be summarized as follows: the highest level of prepronociceptin messenger RNA expression was detected in the septohippocampal nucleus, bed nucleus of the stria terminalis, central amygdaloid nucleus, and in selective thalamic nuclei such as the parafascicular, reticular, ventral lateral geniculate and zona incerta. High to moderate levels of prepronociceptin messenger RNA expression were detected in the lateral, ventral and medial septum, and were evident in brainstem structures implicated in descending antinociceptive pathways (e.g., the gigantocellular nucleus, raphe magnus nucleus, periaqueductal gray matter), and also observed in association with auditory relay nuclei such as the inferior colliculi, lateral lemniscus nucleus, medioventral preolivary nucleus and lateral superior nucleus. A moderate level of prepronociceptin messenger RNA expression was observed in the medial preoptic nucleus, ventromedial preoptic nucleus, periventricular nucleus, pedonculopontine tegmental nucleus, solitary tract nucleus and spinal trigeminal nucleus. A weak level of prepronociceptin messenger RNA expression was present in some areas, such as the cerebral cortex, endopiriform cortex, hippocampal formation, medial amygdaloid nucleus, anterior hypothalamic area, medial mammillary hypothalamic nuclei, retrorubral field and substantia nigra pars compacta. No labeled cells could be found in the caudate-putamen, nucleus accumbens and ventral tegmental area. The present data confirm that nociceptin is expressed in a broad array of regions of the central nervous system. In good correlation with the presently known physiological actions of nociceptin, they include, amongst others, brain areas conveying/integrating pain and auditory sensory afferences.

Immunocytochemical detection of GABAergic nerve cells in the human striatum and cerebellum using a gamma-aminobutyric acid antiserum.

We have adapted the immunocytochemical technique which allows direct detection of gamma-aminobutyric acid (GABA) which has enabled us to visualize GABA-immunoreactive nerve cell bodies, fibers and terminals in post-mortem human striatum and cerebellum. A high density of GABA-immunoreactive nerve cell bodies is detected in the striatum. They are mostly medium-sized with a mean cross-sectional area of 236 +/- 80 ?m(2) but some larger nerve cell bodies with a mean cross-sectional area of 547 +/- 104 ?m(2) are also present. These neurons are most probably essentially spiny neurons type I and type II identified in the human striatum by the Golgi method. In the cerebellum, Purkinje, stellate, Golgi and basket cells are GABA-immunoreactive. In the dentatus nucleus of the cerebellum a high density of presumptive synaptic GABA-immunoreactive terminals surround the GABA-negative neurons. As predicted by animal studies the present results demonstrate that GABAergic neurons are widely distributed in the human striatum and cerebellum. They demonstrate also that GABA-immunocytochemistry can be successfully performed on post-mortem human tissue fixed by immersion after short post-mortem delay and that application of this technique may lead to a better understanding of pathological conditions involving the GABAergic transmission.

Increase of substance P and met-enkephalin in a severely atrophied striatum without clinical expression of chorea.

In a severely demented patient, with a family history of dementia, a severe striatal atrophy was observed. Neither this patient, nor his relatives, had choreoathetosis but he displayed rigidity and bradykinesia. A selective increase of the number of detectable striatal substance P and met-enkephalin neurones was found. These neurones also exhibited a striking increase of the intensity of these peptides' immunoreactivities. Simultaneously, the dense networks of substance P and met-enkephalin nerve fibres were well preserved in the globus pallidus and the substantia nigra. The absence of choreoathetosis, despite severe striatal atrophy, is described in several basal ganglia diseases. Our results are in contrast with the well established reductions of substance P and enkephalins in the atrophied striatum as well as in the globus pallidus and the substantia nigra reported in classical cases of Huntington's disease expressing choreoathetosis.

Neurotensin containing neurones in the human hippocampus of the adult and during development.

Marked age-related changes are noted in the neurotensin distribution of the human hippocampus. Different neuronal structures containing neurotensin are detected by immunohistochemistry during postnatal brain growth from birth to 4 years but no later. They are the neurotensin-immunoreactive pyramidal cells of the subiculum and presubiculum. Their axonal fibres are seen in the alveus and the fimbria. There are also the neurotensin-immunoreactive granular cells of the hilus. The varicosities of the mossy fibres are detected among the pyramidal cells of the CA3 and CA2 subfields of the Ammon's horn. After 4 years of age, only the varicosities are shown by immunohistochemistry, thus there is probably an important decrease in the neurotensin concentration in the cell bodies of the granular cells and also in the pyramidal neurons of the subiculum and presubiculum.

High concentration of somatostatin-14 neurones in the infant human hippocampus.

The distribution of somatostatin-14 immunoreactivity (SRIF-14-IR) was studied in the hippocampal formation of the human infant. The most prominent accumulation of SRIF-14-IR cell bodies and processes occurred in the CA1 subfield of the stratum oriens in the Ammon's horn, in the hilus of the area dentata, in the deeper layers of the subicular complex and in the entorhinal cortex. SRIF-14-IR neurones are also detected in the angular bundle though they are rare in the alveus and absent in the fimbria.

Transient neurotensin in the cat inferior olive during development.

By immunohistochemistry, a large number of neurotensin immunoreactive nerve terminals are found in the kitten inferior olive of the medulla oblongata. They are present in the dorsal lamella of the principal olive, in the ventrolateral outgrowth and in the medial part of the caudal dorsal accessory olive. They are absent in the medial accessory olive. They disappear in the adult cat. Neurotensin immunoreactivity is absent in the developing rat inferior olive. This localization in the cat suggests a neuronal origin in the mesencephalon, mainly in the red nucleus. These results confirm our recent report on a transient large neurotensinergic innervation of the human developing principal olive.

Cholecystokinin distribution in the human striatum and related subcortical structures.

The distribution of cholecystokinin immunoreactive nerve cell bodies and processes is reported in the human striatum and adjacent structures such as the claustrum, the pallidum, the bed nucleus of the stria terminalis and the substantia innominata. Cholecystokinin-positive terminals are present in the striatum where they are arranged in a patchy pattern. Cholecystokinin-positive somata are observed in the claustrum and in the bed nucleus of the stria terminalis but not in the striatum, the pallidum or the substantia innominata. Dense networks of cholecystokinin-positive woolly fibres are present in the bed nucleus of the stria terminalis and the substantia innominata. These results suggested that cholecystokinin is involved in the compartmental organization of the human striatum. This compartmentalization has functional and pathological implications. Involvement of the cholecystokinin system in some basal ganglia diseases is therefore expected. Presence of neuronal cholecystokinin in the accumbens nucleus, bed nucleus of the stria terminalis and substantia innominata also suggests that this peptide may interact at different levels in the human limbic system.