Fig. 9.

Dyn/KOR dysregulation of LHb neuronal activity following MD. The figure depicts our proposed model of Dyn/KOR differential regulation of LHb neuronal excitability in Ih- and Ih+ LHb neurons in control un-stressed rats (A) and its loss following MD (B). Dyn/KOR stimulation uniformly and presynaptically suppresses glutamatergic transmission (glutamate release) in LHb neurons while its effects on GABA release can be either a decrease (predominant effect) or even an increase (in small subset of neurons). We hypothesize that the preferential reduction of presynaptic glutamate release by KOR stimulation that can equally decrease the postsynaptic excitatory function of AMPARs and NMDARs in Ih- neurons as well as a selective projection-specific KOR-induced increases in GABA release could contribute to KOR-induced reduction of Ih-neuronal excitability. On the other hand, KOR-induced reduction of presynaptic GABA release onto Ih+ neurons is the main determinant for the excitatory actions of KOR signaling in Ih+ neurons. We also hypothesize that GABA release onto Ih+ neurons may be potentiated by presynaptic and postsynaptic NMDAR activity where KOR-induced reduction of glutamate release and the subsequent reduced NMDAR activity could result in less release of GABA from presynaptic terminals onto Ih+ neurons. In this model, we favor the idea that Ih- neurons are GABAergic interneurons, therefore the inhibitory action of KOR on Ih- neurons in addition to excitatory effect of KOR stimulation on Ih+ neurons (glutamatergic projection neurons) will increase the excitatory output of LHb to downstream targets. We further hypothesize that MD stress engages Dyn/KOR signaling and upregulates this pathway with homeostatic decrease in KOR expression in response to Dyn hypertrophy. This loss of proper KOR signaling may contribute to MD-induced enhancement of presynaptic glutamate and GABA release onto LHb neurons although MD-induced postsynaptic potentiation of glutamatergic transmission could still facilitate the shift of E/I balance towards excitation in LHb neurons.