The organization of serotonergic projections to cerebral cortex in primates: regional distribution of axon terminals.

Serotonergic axons are widely distributed in the primate forebrain and represent the most abundant ascending projection from the reticular formation. Immunocytochemical methods have been utilized to examine the density, laminar distribution and morphology of serotonergic axons in both primary projection (motor, somatosensory) and association areas (dorsolateral prefrontal, area 5) as well as in the hippocampus and in cingulate cortex of rhesus and cynomolgus macaques. Serotonergic axons are present in all areas of cortex examined, and all cortical layers receive serotonergic afferents. However, the intracortical distribution of serotonergic axon terminals is not uniform; rather, different regions of cortex exhibit dissimilarities in both the density and laminar distribution of serotonergic axons. Thus, there are local patterns of serotonin innervation that are characteristic of each cortical area. Highly diverse patterns of serotonin innervation are found in heterotypical areas of cortex; more subtle variations are present among homotypical areas. Two morphologic types of serotonergic axon terminals, fine and beaded, are present in all cortical areas, and they typically exhibit different laminar distributions: in most areas of neocortex, beaded axons predominate in layer I while fine axons predominate in layers II-VI. However, exceptions to this pattern were observed in primary visual cortex and in the hippocampal formation. The distinctive local patterns of serotonin innervation observed in this study indicate that raphe-cortical projections are likely to have differential influences on particular cytoarchitectonic areas of cerebral cortex in the primate. Moreover, the discrete laminar distribution of serotonin axons suggests that serotonergic projections selectively innervate particular neuronal elements in cerebral cortex. The present findings suggest that the two classes of serotonergic axons, fine and beaded, which have different patterns of termination, affect different sets of cortical neurons. In addition, these two serotonergic projections may be associated with different sets of serotonergic receptors and thus produce selective effects on cortical function.     

Amygdaloid projections to the motor,premotor and prefrontal areas of the cat's cerebral cortex: A topographical study using retrograde transport of horseradish peroxidase

The topographic organization of the projections from the amygdaloid complex to the frontal (motor, premotor and prefrontal) cortex has been investigated in the cat by means of the horseradish peroxidase retrograde transport technique. While most of these projections arise from the magnocellular component of the basal nucleus, some arise also from other nuclei, such as the parvocellular basal nucleus, the corticoamygdaloid transition area and the cortical nucleus. The projections from the latter nuclei are directed to the central portions of the prefrontal cortex, both laterally and medially. No clear-cut topographic segregation appeared to exist in the distribution within the magnocellular basal nucleus of the cells of origin of projections to the motor, premotor and prefrontal cortex.The gross topographic arrangement of the amygdalocortical projections seems to reciprocate, to some extent at least, the organization of corticoamygdaloid projections from high-order sensory and polymodal association areas.     

Boundary-limited serotonergic influences on pattern organization in rat sensory cortex

In neonatal rodents, elevated levels of cortical serotonin (5-HT) blur the normally segmented vibrissae-related pattern of thalamocortical afferents (TCAs) in the posteromedial barrel subfield (PMBSF) of primary somatosensory cortex. We employed 5-HT immunocytochemistry or anterograde transport of 1'1'-dioctadecyl-3,3,3',3' tetramethyl-indocarbocyanin (Di-I) to label TCA arbors to study the effects of 5-HT manipulations on space occupied by TCAs within the PMBSF and the total area labeled. In rats treated to increase cortical 5-HT from birth to postnatal day (P) 6, the percentage of PMBSF area occupied by terminal labeling was significantly higher from that in controls (79.0% versus 23.7%, P < 0.05) for the highest levels of cortical 5-HT and was raised, although not significantly, for lower levels of 5-HT. The TCA coverage was significantly correlated with treatment dose. In animals exposed to a selective 5-HT1B agonist, 5-nonyloxytryptamine, or elevated endogenous 5-HT, the total areas of TCA aggregates in the PMBSF and those in visual cortex were similar to the controls. These results suggest that TCAs have a graded response to increasingly higher 5-HT concentrations. The lack of TCA expansion beyond normal cortical areas further implies that 5-HT-induced axon outgrowth is restricted at cortical boundaries.     

Development and organization of the descending serotonergic brainstem-spinal projections in the sea lamprey

The organization and development of the descending spinal projections from serotonergic rhombencephalic neurons in the larval sea lamprey were investigated by double labeling, tract-tracing methods and immunocytochemistry against serotonin. The results showed that two serotonergic populations of the isthmic and vagal reticular regions present reticulospinal neurons from the beginning of the larval period. Of the three serotonergic subpopulations recognized in the isthmic reticular group [Abalo, X.M., Villar-Cheda, B., Meléndez-Ferro, M., Pérez-Costas, E., Anadón, R., Rodicio, M.C., 2007. Development of the serotonergic system in the central nervous system of the sea lamprey. J. Chem. Neuroanat. 34, 29-46], only two - the medial and ventral subpopulations - project to the spinal cord, with most of the projecting cells in the caudal part of the medial isthmic subpopulation. Occasional cells projecting to the spinal cord were observed in the ventral subpopulation. The vagal reticular serotonergic nucleus situated in the caudal rhombencephalon also presents cells with descending projections. The early development of the brainstem serotonergic projections to the spinal cord appears to be a conserved trait in all vertebrates studied. Although a serotonergic hindbrain-spinal projection system appears to have been present before the divergence of agnathans and gnathostomes, no serotonergic cells were observed in the raphe region in lamprey. Moreover, proportionally more rostral hindbrain serotonergic cells contribute to the spinal serotonergic projections in the sea lamprey than in jawed vertebrates.     

The mode of projections of single locus coeruleus neurons to the cerebral cortex in rats

Axonal distributions of single locus coeruleus neurons within the cerebral cortex were examined with antidromic stimulation technique combined with cortical lesions (frontal lobotomy and lobectomy). In urethan-anesthetized rats, stimulating electrodes were implanted in 10 points extending over nearly the entire cerebral cortex, and antidromic responses of single locus coeruleus neurons to stimulation of these stimulus sites were analysed. Fifty percent of locus coeruleus neurons examined were activated antidromically from at least one cortical point in the cerebral cortex. The pattern and extent of axonal distributions of single locus coeruleus neurons in the cortex appeared to vary from cell to cell. From the results obtained in rats with the cortical lesions, it is concluded that in addition to locus coeruleus neurons with intracortical axons running from rostral to caudal, there are the neurons projecting to the occipital cortex without innervating the frontal cortex and those projecting simultaneously to the frontal and occipital cortex with two axonal branches. There was no topographic order between the recording sites within the locus coeruleus and the projection sites in the cortex.     

The vestibulothalamic projections in the cat studied by retrograde axonal transport of horseradish peroxidase

Summary Horseradish peroxidase (HRP) was injected or iontophoretically ejected in various thalamic nuclei in 63 adult cats. In 11 other animals HRP was deposited outside the thalamic territory. The number and distribution of labelled cells within the vestibular nuclear complex (VC) were mapped in each case. To a varying degree all subgroups of VC appear to contribute to the vestibulothalamic projections. Such fibres are distributed to several thalamic areas. From the present investigation it appears that generally speaking, there exist three distinct vestibulothalamic pathways with regard to origin as well as to site of termination of the fibres. One projection appears to originate mainly in caudal parts of the medial (M) and descending (D) vestibular nuclei and in cell group z. This pathway terminates chiefly in the contralateral medial part of the posterior nucleus of the thalamus (POm) including the magnocellular part of the medial geniculate body (Mgmc), the ventrobasal complex (VB) and the area of the ventral lateral nucleus (VL) bordering on VB. A second projection originates mainly in the superior vestibular nucleus (S) and in cell group y and terminates mainly in the contralateral nucleus centralis lateralis (CL) and the adjoining nucleus paracentralis (Pc). A third, more modest, pathway originates chiefly in the middle M and D, with a minor contribution from S and cell group y, and terminates in the contralateral ventral nucleus of the lateral geniculate body (GLV). There is some degree of overlap between the origin of these three vestibulothalamic pathways.Abbreviations B.c. brachium conjunctivum - CeM nucleus centralis medialis thalami - CL nucleus centralis lateralis thalami - CM nucleus centrum medianum - D nucleus vestibularis descendons - f cell group f - g cell group g - GLD corpus geniculatum laterale dorsalis - GLV corpus geniculatum laterale ventralis - i.e. nucleus intercalatus - L nucleus vestibularis lateralis - LD nucleus lateralis dorsalis thalami - LIM lamina medullaris interna - Lim nucleus limitans - LP nucleus lateralis posterior thalami - M nucleus vestibularis medialis - MD nucleus medialis dorsalis thalami - MGmc corpus geniculatum mediale, pars magnocellularis - MGp corpus geniculatum mediale, pars principalis - N.cu.e. nucleus cuneatus externus - N.f.c. nucleus fasciculi cuneati - N.mes. V nucleus mesencephalicus nervi trigemini - NR nucleus ruber - N.tr.s. nucleus tractus solitarius - N. VII nervus facialis - N. VIII nervus statoacusticus - PC pedunculus cerebri - Pc nucleus paracentralis thalami - Pf nucleus parafascicularis - p.h. nucleus prepositus hypoglossi - PO posterior thalamic group - PO1 lateral part of PO - POm medial part of PO - Prt nucleus pretectalis - Pul pulvinar - R nucleus reticularis thalami - S nucleus vestibularis superior - Sg nucleus suprageniculatus - SN substantia nigra - Sv nucleus supravestibularis - Tr.s. tractus solitarius - VA nucleus ventralis anterior thalami - VL nucleus ventralis lateralis thalami - VPL nucleus ventralis posterior lateralis - VPL1 lateral part of VPL - VPLm medial part of VPL - VPM nucleus ventralis posterior medialis - x cell group x - y cell group y - z cell group z - V nucleus motorius nerve trigemini - X nucleus dorsalis nerve vagi - XII nucleus nervi hypoglossi     

Topographical organization of the projections from the cerebral cortex to the head of the caudate nucleus. A horseradish peroxidase study in the cat

The topographical organization of the projections from the cerebral cortex to the head of the caudate nucleus was studied in the cat using the horseradish peroxidase method. Various amounts of horseradish peroxidase were injected into several sites of the head portion of the caudate nucleus at about the frontal level where its cross section was widest. Injections of small amounts of horseradish peroxidase retrogradely labeled neurons in rather limited cortical areas bilaterally, showing the localized organization of the projections. Neurons in the lateral portions of the ventral bank of the cruciate sulcus and in the dorsal bank (areas 4 gamma and 4 delta) were labeled after horseradish peroxidase injections into the dorsolateral part of the head of the caudate nucleus. Neurons in the intermediate portions of the ventral bank (areas 6 a delta and 6 infra fundum) were strongly labeled after dorsolateral or ventrointermediate injections, and neurons in the medial portion (area 6a beta), after dorsomedial, dorsointermediate, ventrointermediate or central injections. These findings indicate that areas 4 gamma and 4 delta project to the dorsolateral part of the caudate nucleus, areas 6a delta and 6 infra fundum to the lateral half, and area 6a beta to a more medial portion. Other findings revealed that the gyrus proreus projects to the medial part of the caudate nucleus and the anterior cingulate gyrus to the dorsal region.     

Functional organization of thalamic projections to the motor cortex. An anatomical and electrophysiological study in the rat

In rats, horseradish peroxidase crystals were injected in motor cortical foci functionally identified by means of the motor effects evoked by electrical stimulations. The location in the thalamus of the neurons linked to different motor cortical foci was studied. Thalamic neurons were retrogradely labeled in both "motor" (ventralis lateralis and ventralis medialis) and "non-motor" nuclei: centralis lateralis, lateralis posterior, mediodorsalis and posterior thalamic nuclear group, as well as the ventrobasal complex. The ventrobasal complex was labeled after horseradish peroxidase injections in hindlimb and trunk motor areas. The ascending projections toward the motor cortex from both "motor" and "non-motor" thalamic nuclei are organized more precisely and more elaborately than previously reported. The motor cortical afferents from the nucleus ventralis lateralis are organized in three planes, rostrocaudally, dorsoventrally and mediolaterally. An inverted relation exists in the rostrocaudal plane between the nucleus ventralis lateralis and the motor cortex: the caudal motor cortex region (hindlimb) receives fiber inputs from the rostral region of the nucleus ventralis lateralis, whereas the caudal zone of the nucleus ventralis lateralis projects to the rostral motor cortex region (forelimb and vibrissae). A dorsoventral organization has also been observed in the rostral region of the nucleus ventralis lateralis: the ventral aspect is the source of fibers directed to the distal hindlimb region, whereas fibers originating from the dorsal aspect are directed to the proximal hindlimb area. A mediolateral relationship exists between medial and lateral sides of the nucleus ventralis lateralis and, respectively, proximal and distal forelimb cortical areas. There is some overlap between the various nuclear regions thus delineated. Four functional zones were found in the lateral half of the nucleus ventralis medialis and were classified according to their projection to the motor cortex; these are involved in motor control of the proximal and distal forelimb, vibrissae and ocular movements. The projection is topographically organized according to both an inverted rostrocaudal and a direct dorsoventral-mediolateral arrangement. Caudally, dorsal and ventral nuclear parts project to rostromedial (vibrissae) and rostrolateral (distal forelimb) regions of the motor cortex, respectively. More rostral nuclear zones project to more caudal (proximal forelimb, eye) cortical regions. There is little overlap between these four nuclear subdivisions. The nucleus centralis lateralis projects to vibrissae and proximal, as well as distal, forelimb areas.(ABSTRACT TRUNCATED AT 400 WORDS)     

Topographic organization of projections from the amygdala to the visual cortex in the macaque monkey

The topography of amygdaloid projections to the visual cortices in the macaque monkey was examined by injecting the fluorescent tracers Fast Blue and Diamidino Yellow at different locations in the occipital and temporal lobes and mapping the distribution of retrogradely labeled cells in the amygdala. Injections involving regions from rostral area TE to caudal area V1 all resulted in labeled cells within the basal nucleus of the amygdala. Relatively few double-labeled cells were observed even when the two injections were separated by less than 3 mm. The projections were rostrocaudally organized such that projections to caudal visual areas originated from dorsal and caudal portions of the magnocellular division of the basal nucleus while projections to more rostrally situated visual areas originated in more rostral and ventral portions of the basal nucleus. When injections involved rostral and medial portions of area TE, retrogradely labeled cells were observed in the accessory basal and lateral nuclei in addition to the basal nucleus. These data confirm that the amygdala gives rise to feedback projections to all levels of the "ventral stream" visual pathway. The projections do not appear to be diffusely distributed since few double-labeled cells were observed. The largest cells of the basal nucleus, those located in the magnocellular division, project the farthest in the visual system and innervate all occipital and temporal levels. The smaller cells, in the intermediate and parvicellular regions, project to more rostral and medial portions of the visual cortex. These results suggest that the amygdala may have substantial modulatory control over sensory processing at all stages of the ventral-stream visual cortical hierarchy.     

The organization of the projection from the cerebral cortex to the striatum in the rat

The detailed organization of the corticostriate projection has been investigated in the brain of the rat using the technique of retrograde transport of horseradish peroxidase following the placement of small, iontophoretic injections of horseradish peroxidase conjugated to lectin throughout all major regions of the striatum (caudate-putamen, nucleus accumbens and olfactory tubercle). The results demonstrate that all major regions of the cerebral cortex project to the striatum on both sides of the brain with an ipsilateral predominance. The cells of origin of both the ipsilateral and contralateral corticostriate projections lie mainly in lamina V (especially lamina Va) with very small numbers in lamina III of the neocortex and mesocortex, and in the deep laminae of the allocortex. The results show that each striatal locus receives inputs from several cortical regions, i.e. there is extensive overlap in the corticostriate projection, and that, in general terms, each cortical region projects onto a longitudinally oriented region of the striatum. In particular, the major subdivisions of the cerebral cortex--the neocortex, mesocortex and allocortex--project onto defined but partially overlapping regions of the striatum: the neocortex projects to the caudate-putamen; the mesocortex projects mainly to the medial and ventral regions of the caudate-putamen but also to the ventral striatum (nucleus accumens and olfactory tubercle); and the allocortex projects mainly to the ventral striatum but also to the medial and ventral parts of the caudate-putamen. Within each of these major projection systems there is a further organization, with the constituent parts of each major cortical region projecting to smaller longitudinal components of the major projection fields. Each neocortical area projects to a longitudinal region of the dorsal striatum (caudate-putamen): the sensory and motor areas project topographically onto the dorsolateral striatum such that the rostral sensorimotor cortex (head areas) projects to central and ventral regions and the more caudal sensorimotor cortex (limb areas) projects to dorsal regions of the dorsolateral striatum; the visual area projects to the dorsomedial striatum; and the auditory area projects to the medial striatum. Each mesocortical area projects to a longitudinal area of the striatum: the most posteromedial mesocortex (the retrosplenial area) projects to the dorsomedial striatum; more anterior and lateral parts of the mesocortex project to more ventral parts of the striatum: and the most lateral mesocortex (the agranular insular and perirhinal areas) project to the ventrolateral striatum.(ABSTRACT TRUNCATED AT 400 WORDS)     

Vestibular projections to the nucleus intercalatus of Staderini mapped by retrograde transport of horseradish peroxidase

Medullary afferent projections to the nucleus intercalatus of Staderini have been studied by retrograde transport of horseradish peroxidase (HRP) from highly localized injections. This nucleus receives afferent projections particularly from the medial and descending vestibular nuclei as well as from the nucleus praepositus hypoglossi of both sides. The nucleus intercalatus of Staderini represents therefore an area of integration for the vestibular systems of both sides.     

A role for neurotrophin-3 in targeting developing cholinergic axon projections to cerebral cortex

This study examined the relationship between expression of neurotrophin-3 (NT-3) and the ingrowth of cholinergic axonal projections in cerebral cortex. Patterns of expression of NT-3 (defined by beta-galactosidase reporter expression in heterozygous offspring of transgenic NT-3(lacZneo/+) mice) revealed that limbic cortical regions (including frontal, cingulate, and insular cortex, as well as the dentate gyrus) express NT-3 and that these cortical regions receive early and relatively dense cholinergic axons (stained for acetylcholinesterase, AChE). Using the dentate gyrus as a model system, studies revealed that expression of the NT-3 reporter parallels, and precedes by approximately 2 days, the ingrowth of AChE positive cholinergic axons. Studies of forebrain organotypic slice cultures demonstrate that basal forebrain-derived cholinergic axons extend into cortical regions in a pattern that mimics the pattern of expression of the NT-3 reporter. Similarly, chimeric co-cultures, combining wild type septum with a slice of hippocampus from heterozygous NT-3(lacZneo/+) mice, demonstrate that cholinergic axons grow into regions of the dentate gyrus that express the NT-3 reporter. Hemisphere slice cultures made from NT-3 knockout mice reveal cholinergic axonal growth into cortex, but these axons do not form the regional pattern characteristic of slice cultures made from wild type or heterozygous NT-3(lacZneo/+) mice. Further, chimeric co-cultures made using slices of wild type septum combined with slices of hippocampus from NT-3 knockout mice demonstrate robust cholinergic axonal growth into the hippocampus, but the cholinergic axons do not form the characteristic preterminal pattern associated with the dentate gyrus. Slice cultures from limbic cortical tissue from the NT-3 null mice do not display exaggerated levels of cell death. In aggregate, these data support the hypothesis that expression of NT-3 by cortical neurons serves to attract basal forebrain cholinergic projections to their target cells in cerebral cortex.     

Afferent projections to the cerebellar flocculus in the pigmented rat demonstrated by retrograde transport of horseradish peroxidase

The horseradish peroxidase (HRP) retrograde transport method was used to identify brainstem afferents to the cerebellar flocculus in the pigmented rat. Injections of the enzyme were made through recording microelectrodes, making it possible to localize the injection site by physiological criteria. Clearly, the largest number of afferents arise from the bilateral vestibular and perihypoglossal nuclei and from the contralateral dorsal cap (of Kooy) of the inferior olive. Additionally, a substantial number arise bilaterally from: (1) the nucleus reticularis tegmenti pontis (NRTP); (2) several of the cranial motor nuclei including the abducens, retrofacial and facial nuclei and the nucleus ambiguus; (3) the rostral part of the lateral reticular nucleus (subtrigeminal nucleus); (4) the raphe pontis and raphe magnus and (5) neurons intercalated among the medial longitudinal fasciculus (MLF) just rostral to the hypoglossal nucleus and another group rostral to the abducens nucleus. The basilar pontine nuclei contained a large number of lightly labeled neurons in all flocculus injections which were discretely located within the dorsolateral, lateral and medial divisions. These areas were labeled bilaterally but with a slight contralateral preponderance. Injection into the flocculus, but involving the adjacent ventral paraflocculus, produced a heavier labeling of pontine neurons with a slightly different distribution. Therefore, we tentatively conclude that the flocculus receives input from these pontine visual centers (dorsolateral, lateral and medial nuclei), perhaps through collateral projections from neurons projecting to the paraflocculus. The present study demonstrates strong similarities between the rat and other species studied (e.g., rabbit, cat, monkey) in terms of the brainstem nuclei projecting to the flocculus. Most noticeable in quantitative terms are the pathways known to mediate vestibular (vestibular and perihypoglossal nuclei) and visual (optokinetic) information (e.g., NRTP). Additionally, we can provide morphological evidence that the midline and paramedian pontine tegmentum, identified in the cat and monkey as containing saccade-related neurons, send large numbers of projections to the rat flocculus. Given these similarities, the rat may be a suitable animal model in which to study the pathways underlying visual-vestibular interaction and saccadic mechanisms in the flocculus.