An Investigation into the Role of Melatonin in Papez Circuit and Hypothalamic–pituitary Axis

Background Melatonin hormone is synthesized by the pineal gland and has a well-established role in regulation of the human biological clock and reproduction. These effects are mediated through the hypothalamic–pituitary axis. Many recent studies have expanded the horizon of melatonin role to neuroprotection, memory, sleep regulation, mood, body temperature, and cognition. Many of these physiological processes are mediated by the hypothalamus, thalamus, pituitary gland, and hippocampus. The melatonin acts through activation of its receptors—MT1 and/or MT2. There have been many animal, and few human studies limited to selected areas, for locating the melatonin receptors but a detailed study of melatonin binding sites is lacking. This study was planned to study the melatonin receptor subtypes in anatomical components of the Papez’s circuit—thalamus, hypothalamus, and hippocampus, as well as the hypothalamic–ituitary axis along with the pineal gland. Topographic localization of melatonin receptors can lead to pharmacological manipulation of these anatomic sites specific to the disease process.

Methods This is a cross-sectional immunohistochemical study on 10 brains, sampled within 3 to 4 hours of death from the following areas: thalamus, hypothalamus, pituitary, pineal, and hippocampus. Ethical clearance was taken from the institutional ethical committee. Immunohistochemical staining was done by standard avidin–biotin peroxidize complex technique using specific antibodies against MT1 and MT2 receptors.

Results Pineal gland: MT1 immunoreactivity (IR) was seen in 15 to 30% cells and their neurites. With MT2, 80% were stained. Pineal concretions displayed patchy IR for both MT1 and MT2. Hypothalamus: With MT1 large neurons had polar stippled staining, while fibers demonstrated very mild staining. Forty percent of small-sized neurons and large neurons had IR MT2. Thalamus: In thalamus the white matter (WM) bundles showed intense MT1 IR with IR in few isolated neurons. With MT2 intense, IR was seen in whole tissue in both WM and neurons; 50% of the neurons showed polar stippling. Cingulate cortex: The MT1 showed WM staining in all cerebral layers, while pyramidal and granule cells were stained in deep layers only. MT2 IR was intense with neuronal staining in all layers. Hippocampus: With MT1, WM staining varied from mild to moderate. In moderate staining areas, large pyramidal cells stained in all layers. In light staining areas, 10% of pyramidal cells stained in the layers II, III, and IV. With MT2, moderate staining was seen in WM in whole tissue and pyramidal cells in all layers. Pituitary: MT1 immunopositivity was observed in 90 to 100% of cells of different subgroups in anterior pituitary. In pars tuberalis, IR was observed in parenchymal cells. The pars intermedia showed patchy IR. In pars nervosa and infundibulum, the pituicytes were immunonegative while axons were stained. With MT2, IR observed was identical but more intense.

Conclusion The presence of melatonin receptors provides a neurobiological basis, for role of melatonin in the Papez’s circuit and in regulation of pituitary functions. Differential characterization of MT1 and MT2 receptors in different regions localizes potential areas susceptible to interventions. This opens an exciting door for optimism for many hitherto untreatable conditions.