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Afferent and efferent connections of the interpeduncular nucleus with special reference to circuits involving the habenula and raphe nuclei

Grant number: 17/08960-4
Support type:Regular Research Grants - Publications - Scientific article
Duration: June 01, 2017 - November 30, 2017
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Martin Andreas Metzger
Grantee:Martin Andreas Metzger
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


The habenula is an epithalamic structure differentiated into two nuclear complexes, medial (MHb) and lateral habenula (LHb). Recently, MHb together with its primary target, the interpeduncular nucleus (IP), have been identified as major players in mediating the aversive effects of nicotine. However, structures downstream of the MHb-IP axis, including the median (MnR) and caudal dorsal raphe nucleus (DRC), may contribute to the behavioral effects of nicotine. The afferent and efferent connections of the IP have hitherto not been systematically investigated with sensitive tracers. Thus, we placed injections of retrograde or anterograde tracers into different IP subdivisions or the MnR and additionally examined the transmitter phenotype of some major IP and MnR afferents by combining retrograde tract tracing with immunofluorescence and in situ hybridization techniques.Besides receiving topographically organized inputs from MHb and also LHb, we found that the main theme of IP connectivity are strong reciprocal interconnections with midline structures, including the MnR/DRC, nucleus incertus, supramammillary nucleus, septum, and laterodorsal tegmental nucleus. The bidirectional connections between IP and MnR and the LDTg inputs to the IP proved to be mostly GABAergic. Regarding a possible topography of IP outputs, all IP subnuclei gave rise to descending projections, whereas ascending projections, including focal projections to the ventral hippocampus, ventrolateral septum, and LHb mostly originated from the dorsocaudal IP. Our findings indicate that IP is closely associated to a distributed network of midline structures, all of them considered key modulators of hippocampal theta activity. Thus, IP forms a node that links MHb and LHb with this network and the hippocampus. Moreover, the rich predominantly GABAergic interconnections between IP and MnR support a cardinal role of this bidirectional pathway in the behavioral response to nicotine.Key words: medial habenula, raphe nuclei, hippocampus, nicotine, aversion, teta rhythm (AU)