Anatomical studies of hypothalamic thyrotropin-releasing hormone : Implications for motivated states

Sammanfattning: The survival of every animal as an organism and species depends on three motivated states: ingestive, defensive and reproductive. Regulation of these states is coordinated by the hypothalamus through the coordination of three principal output pathways: behavioural, endocrine and autonomic. An additional key component required for motivated behaviour is arousal. Imbalances within this intricate system have widespread clinical consequences as observed in e.g. endocrine disorders. A messenger molecule implicated in all three output pathways is the peptide, Thyrotropin-Releasing Hormone (TRH). While TRH has primarily been studied as a releasing factor in the hypothalamopituitary- thyroid axis, it is now well recognized that TRH also has a variety of neuromodulatory effects beyond pituitary regulation. The processes affected by TRH include the sleep-wake cycle, lactation, food intake and thermogenesis. The aim of this thesis was investigate the circuitry and mechanisms underlying the effects of hypothalamic TRH in arousal, lactation and metabolism. In paper I, we explored the effect of TRH on cells in the lateral hypothalamic area (LHA) that express the peptide hypocretin (a.k.a. orexin), which exerts potent arousal-promoting actions. We found that TRH depolarized and increased the firing rate of hypocretin neurons through activation of cation currents. By double-label immunofluorescence, we observed close appositions between TRH-immunoreactive (-ir) nerve terminals and hypocretin-ir cell bodies. These results identify a new potential modulator of hypocretin cell firing, and suggest that hypocretin cell excitation may contribute to the arousalenhancing actions of TRH. In paper II, the population of cells located in the LHA that expresses TRH was anatomically defined and histochemically characterized. Occupying most of the ventrolateral hypothalamus in its full rostro-caudal axis, the TRH-ir population in the LHA displayed little co-existence with other hypothalamic neuronal markers, suggesting a unique neuronal population. The TRH-ir cells were innervated by terminals containing Agouti Gene-Related Peptide and α-Melanocyte- Stimulating Hormone, suggesting that they form a downstream target for the hypothalamic metabolic sensor in the arcuate nucleus. In paper III, a population of cells located in the dorsomedial arcuate nucleus was demonstrated, which discharge in rhythmic oscillations. Oscillator neurons were histochemically identified as tuberoinfundibular dopamine (TIDA) neurons, which provide tonic inhibition of pituitary prolactin release. The oscillation was shown to be robustly synchronized between neurons via electrotonic gap junction coupling. Terminals containing TRH were observed in close apposition to TIDA cells, and when TRH was applied oscillating TIDA neurons switched from phasic to tonic discharge. These results suggest a novel mode of regulation of lactation where a change in TIDA network from oscillations to tonic discharge switches dopamine function from an antagonist to an agonist. Furthermore, our findings suggest that the lactation-releasing actions of TRH may take place at the hypothalamic, rather than the pituitary level.