Cellular mechanism underlying lateral habenula hyperactivation in acute and early-life stress models

Title: A role for corticotropin-releasing factor (CRF) signalling in the lateral habenula and its modulation by early-life stress.

Journal: Sci. Signal. 11, eaan6480 (2018)

Link: https://stke.sciencemag.org/content/11/520/eaan6480.long

Comments:

Previous studies have shown that mice with social defeat stress exhibit lateral habenula (LHb) hyperactivity, characterized by increased firing rate and inflammatory response. However, the cellular mechanism underlying the role of stress in LHb chronic activation remained elusive.

To address this, the current study applied extracellular CRF to rat slices to mimic acute stress. CRF is a stress hormone known to participate in stress-induced activation of the HPA axis, as well as extrahypothalamic brain areas implicated in mental illness such as LHb. CRF increased firing rate and lowered action potential threshold, increased cytosolic Ca2+ levels which led to changes in small-conductance (SK) and large-conductance (BK) Ca2+-sensitive voltage-gated K+ channels. Rats with maternal deprivation (MD), a model of early-life stress, had an altered CRF signalling circuit which was unresponsive to acute CRF exposure. Moreover, due to MD, they had low SK2 protein levels, reduced GABAergic transmission, and increased activity of PKA, all leading to LHb hyperactivity.

This study identified the cellular mechanisms underlying LHb hyperexcitability in response to stress and therefore identified potential targets for pharmacological treatment of LHb-associated stress disorders.