Input‐specific regulation of discrete populations of Lateral Habenula neurons by Kappa opioid receptors

Abstract

The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of reward circuitry. Increased activity of the LHb is associated with drug addiction and stress-related mood disorders. Dynorphin (DYN)/Kappa opioid receptor (KOR) signaling is an endogenous mediator of stress response in reward circuitry. Previously, we have shown a novel functional role of DYN/KOR signaling within LHb and its dysregulation by a severe early life stress (maternal deprivation, MD). Specifically, KOR stimulation has distinct effects on LHb neuronal excitability in distinct neuronal populations identified by the presence of hyperpolarizing current (Ih) that were absent following MD. Namely, KOR stimulation through the KOR agonist, U50,488, significantly decreases excitability of Ih negative (Ih-) LHb neurons while simultaneously increasing excitability of Ih positive (Ih+) LHb neurons. Additionally, KOR-induced alteration in LHb excitability is dependent on both presynaptic glutamatergic and GABAergic signaling likely through presynaptic KORs on inputs to LHb neurons. Given that LHb inputs from the entopeduncular nucleus (EP) and lateral hypothalamus (LH) have been implicated in stress-induced mood disorders through modulation of LHb excitability, we hypothesize that the presynaptic effects of KOR stimulation on LHb neuronal activity may be driven by one or both of these inputs. Using selective in vitro optical stimulation of either EP or LH inputs to LHb neurons in brain slices from rats, our pilot study suggests that KOR activation of EP and LH inputs may differentially affect optically evoked action potential generation across Ih- and Ih+ LHb subpopulations. Moreover, our data from MD rats suggest that there may be an imbalance of excitation to inhibition at EP synapses onto LHb neurons. Given that MD increases immunolabeled DYN (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb, we also investigated MD-induced modulation of a KOR-specific downstream signaling (p38 MAPK). Our molecular data indicate that decreased KOR expression may be a homeostatic response to higher basal activation of KORs by MD-induced increases in DYN and p38 expression in the LHb. Ih- and Ih+ neurons molecular identification is further investigated following electrophysiological recordings by combining ionophoresis labeling during electrophysiology experiments and post-hoc immunohistochemistry to verify the glutamatergic (VGLUT+) and GABAergic (somatostatin, SST+ or parvalbumin, PV) nature of LHb neurons. Collectively, our current studies provide evidence for input- and cell-specific regulation of LHb neurons by KOR signaling that could be modulated by MD and highlights a future hotspot for pharmacological intervention of KOR-mediated mood disorders through dysregulation of specific LHb neural circuits.