The tuberomammillary nucleus projections in the control of learning, memory and reinforcement processes: Evidence for an inhibitory role

The tuberomammillary nucleus (TM), a cluster of magnocellular cells in the posterior hypothalamus, is the main source of neuronal histamine in the brain. Although this nucleus is well described in terms of anatomy and neurochemistry, only little is known about its function. Our earlier work showed that the TM projection system may be involved in behavioral asymmetries and behavioral recovery after unilateral manipulations of the brain. Using horseradish peroxidase (HRP) labeling we found an increase in strength (structure and/or activity) in the crossed and uncrossed tuberomammillary-striatal projections in the course of recovery from behavioral asymmetries produced by unilateral removal of the rats' vibrissae, which were in the same direction as the asymmetries found in projections from the substantia nigra to the striatum. Experiments performed with unilateral lesions of the TM region provide evidence for an involvement of the TM system in reinforcement mechanisms. Unilateral destruction of the TM with direct current (DC) or ibotenic acid was found to increase the rate of lateral hypothalamic self-stimulation ipsilateral to the lesion site, suggesting that the TM (particularly the E2 subgroup in its rostral part) may function as a reinforcement inhibiting neural substrate. Experiments performed with bilateral DC or ibotenic acid lesions of the TM region suggest a role of the nucleus in learning and mnemonic processes. A bilateral electrolytic or neurotoxic lesion of the TM region was found to facilitate the performance of adult and behaviorally impaired aged rats in a variety of learning tasks, including a habituation paradigm, aversively motivated learning tasks and water mazes. Examination of the site of the neurotoxic lesion in the TM region with immunohistochemical techniques revealed a marked decline of histamine-staining neurons mainly in the rostral part of the TM nucleus, suggesting that the facilitatory effects on reinforcement and mnemonic processes might be related to the destruction of TM intrinsic histaminergic cells. In summary, the present results indicate that the TM nucleus is involved in neural plasticity and functional recovery following damage to the CNS and may function as an inhibitory neural substrate in the control of reinforcement and mnemonic processes.