Cytoarchitecture, fiber connections, and some histochemical aspects of the interpeduncular nucleus in the rat
Authors: Groenewegen H. J. , Ahlenius S. , Haber S. N. , Kowall N. W. , Nauta W. J. H. 
Published: January 2005

The organization of afferent and efferent connections of the interpeduncular nucleus (IP) has been examined in correlation with its subnuclear parcellation by using anterograde and retrograde tracing techniques. Based on Nissl, myelin, and acetylcholinesterase staining five paired and three unpaired IP subnuclei are distinguished. The unpaired division includes the rostral subnucleus (IP‐R), the apical subnucleus (IP‐A), and the central subnucleus (IP‐C). The subnuclei represented bilaterally are the paramedian dorsal medial (IP‐DM) and intermediate subnuclei (IP‐I) and the laterally placed rostral lateral (IP‐RL), dorsal lateral (IP‐DL), and lateral subnuclei (IP‐L). Immunohistochemical techniques showed cell bodies and fibers and terminals immunoreactive for substance P, leuenkephalin, metenkephalin, or serotonin to be differentially distributed over the different IP subnuclei. Substance P‐positive perikarya were found in IP‐R, enkephalin neurons in IP‐R, IP‐A, and the caudodorsal part of IP‐C, and serotonin‐containing cell bodies in IP‐A and the caudal part of IP‐L.

Efferent IP projections were studied both by injecting tritiated leucine in IP and by injecting HRP or WGA‐HRP in the presumed termination areas. The results indicate that the major outflow of IP is directed caudalward to the median and dorsal raphe nuclei and the caudal part of the central gray substance, i.e., the dorsal tegmental region. The projection appears to terminate mainly in the raphe nuclei, around the ventral and dorsal tegmental nuclei of Gudden, and in the dorsolateral tegmental nucleus. The descending projection to the dorsal tegmental region originates in virtually all IP subnuclei, but the main contribution comes from IP‐R and the lateral subnuclei IP‐RL, IP‐DL, and IP‐L. Sparser projections to the dorsal tegmental region originate in IP‐C and IP‐I, whereas the contribution of IP‐A is only minimal. The projections from IP‐R are mainly ipsilateral and those from IP‐DM are mainly contralateral. IP fibers to the median and dorsal raphe nuclei originate predominantly in IP‐R and IP‐DM, and to a lesser extent in IP‐C, IP‐I, IP‐RL, and IP‐DL.

A much smaller contingent of IP fibers ascends to diencephalic and telencephalic regions. A relatively minor projection, stemming from IP‐RL and IP‐DL, reaches the lateral part of the mediodorsal nucleus, the nucleus gelatinosus, and some midline thalamic nuclei. These IP fibers follow either the habenulo‐interpeduncular pathway or the mammillothalamic tract. An other group of ascending IP fibers follows the medial forebrain bundle, providing offsets to the supramammillary region, the medial and lateral hypothalamus, the nucleus of the diagonal band, and the lateral septum. A few of these fibers continue in the fornix to the cornu Ammonis and fascia dentata of the hippocampus. Retrograde tracing experiments revealed that this part of the ascending IP system stems from neurons in IP‐A and the caudal part of IP‐L.

Regarding the afferent connections of the interpeduncular nucleus, in the present study most emphasis has been placed on the anterograde tracing of these projections. The nucleus derives its main input from the medial habenular nucleus and the dorsal tegmental region. The habenula projects in moderate‐to‐heavy volume to all IP subnuclei, with the exception of IP‐A, which receives a relatively sparse habenular input. Similarly, afferents from the dorsal tegmental region reach the entire IP, but this projection exhibits a more complex differential distribution. It most massively involves the contralateral IP‐R and IP‐DM, and IP‐DL and IP‐L bilaterally. Less prominent are its distributions to IP‐A, IP‐C, IP‐I, and IP‐RL. More rostra1 parts of the central gray substance, including the dorsal raphe nucleus, project heavily to the contralateral IP‐DM, and to IP‐RL and IP‐DL bilaterally. The median raphe nucleus sends a strong projection to IP‐C and IP‐I and a minor projection to IP‐L. Injections in the parabigeminal region labeled a very restricted but distinct projection to a dorsal part of IP‐RL bilaterally. Within IP itself indications were found of reciprocal connections between IP‐A and IP‐R. Autoradiographic tracing of descending fibers to IP from the nucleus of the diagonal band and the lateral hypothalamus revealed only very sparse projections, mainly distributed to IP‐C, IP‐I, and IP‐L. The present study demonstrates that the inputs and outputs of the various subnuclei of IP are interrelated in a most complex way. Nevertheless, the massive projection from the medial habenular nucleus to IP and the close reciprocal connection of IP with the raphe nuclei and the dorsal tegmental nuclei suggests an important modulatory role of IP in the transmission of impulses descending from the limbic forebrain via the medial habenular nucleus to the sources of serotoninergic and other mesencephalic projections affecting most if not all principal subdivisions of the cerebral hemisphere.