Hypothalamic vasopressinergic and orexinergic pathways converge with midbrain aminergic inputs on LHb intrinsic GABAergic system regulated by neurosteroid signaling: implications for contingency‐dependent motivated behavior

Abstract

We have recently reported the existence of a vasopressinergic input from the hypothalamic paraventricular nucleus (PVN) to the medial division of the lateral habenula (LHbM), reporting to a subpopulation of putative GABAergic interneurons there. Stimulation of this pathway influences escape behaviors in the rat. Here, we identify additional hunger‐related orexinergic and reward‐related midbrain aminergic (dopaminergic and serotoninergic) inputs converging on this habenular cell group, and uniquely expressing the estrogen receptor ERalpha. The origins of each of the projection types were determined by fluorogold retrograde tracing. Orexinergic, dopaminergic and serotonergic projections originate in lateral hypothalamus (LH), ventral tegmental area (VTA) and substantia nigra (SN), and dorsal raphe (DR), respectively. They share, with the vasopressinergic inputs from the PVN, sex‐steroid responsivity, i.e. they express androgen receptors (ARs) and aromatase, the latter visualizable in axon terminals within the habenula. The distinct LHbM cell population onto which these inputs converge are likely to be functionally GABAergic, as determined by in situ hybridization histochemistry identifying the expression of gad1, gad2, Slc6A1, Slc6A11, Slc32A1 within them. This cell group also expresses mRNA encoding receptors for serotonin, dopamine, vasopressin, and orexin. Of physiological importance, AR and aromatase expression in the input neurons from PVN, LH, VTA/SN and DR are dependent on both estrogen levels, in female rats, and history of sexual activity, in male rats. Castration‐induced behavioral changes in passive vs active coping strategies before a predator were also observed. We postulate that all four pathways studied here contribute to the hormonal/homeostatic control of behavioral motivation in a coordinated or convergent fashion, through the use of estrogen as a co‐transmitter impingent on LHbM neurons. These findings are relevant within a broader physiological context, reflecting the influence of hunger and thirst circuitry on contingency‐dependent motivated behavior.Support or Funding InformationPartially supported by: DGAPA‐UNAM‐PAPIIT‐IN216214, CONACYT‐CB‐176919 & CB‐238744 to LZ and NIMH‐IRP‐1ZIAMH002386 to LEE. LZ is a Fulbright visiting scholar, also supported by PASPA‐DGAPA‐UNAM fellowships for her sabbatical research stay hosted by LEE of SMN‐NIMH‐NIH‐USA.