A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress

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Sci. Signal.  06 Mar 2018:
Vol. 11, Issue 520, eaan6480
DOI: 10.1126/scisignal.aan6480

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Stress, the brain, and behavior

Stress hormones, such as CRF (also known as CRH), inhibit the “reward” signals provided by dopamine signaling in the brain after or in anticipation of a given action. Potentially because of this, severe or chronic stress is associated with depression and can impair decision-making, and early-childhood stress is linked to long-term mental health problems and behavioral disorders. Authement et al. found that CRF exposure in slices or maternal deprivation in pups decreased the abundance of K+ channels, which increased the excitation of neurons in the lateral habenula (LHb), a region of the brain that suppresses dopaminergic circuitry. Maternal deprivation in rats blunted the response of LHb neurons to subsequent, acute stress (CRF exposure), indicating some permanence to the circuitry effects. Blocking the kinase PKA, which mediated these effects, might be therapeutic in patients with abnormal, stress-associated LHb activity.


Centrally released corticotropin-releasing factor or hormone (extrahypothalamic CRF or CRH) in the brain is involved in the behavioral and emotional responses to stress. The lateral habenula (LHb) is an epithalamic brain region involved in value-based decision-making and stress evasion. Through its inhibition of dopamine-mediated reward circuitry, the increased activity of the LHb is associated with addiction, depression, schizophrenia, and behavioral disorders. We found that extrahypothalamic CRF neurotransmission increased neuronal excitability in the LHb. Through its receptor CRFR1 and subsequently protein kinase A (PKA), CRF application increased the intrinsic excitability of LHb neurons by affecting changes in small-conductance SK-type and large-conductance BK-type K+ channels. CRF also reduced inhibitory γ-aminobutyric acid–containing (GABAergic) synaptic transmission onto LHb neurons through endocannabinoid-mediated retrograde signaling. Maternal deprivation is a severe early-life stress that alters CRF neural circuitry and is likewise associated with abnormal mental health later in life. LHb neurons from pups deprived of maternal care exhibited increased intrinsic excitability, reduced GABAergic transmission, decreased abundance of SK2 channel protein, and increased activity of PKA, without any substantial changes in Crh or Crhr1 expression. Furthermore, maternal deprivation blunted the response of LHb neurons to subsequent, acute CRF exposure. Activating SK channels or inhibiting postsynaptic PKA activity prevented the effects of both CRF and maternal deprivation on LHb intrinsic excitability, thus identifying potential pharmacological targets to reverse central CRF circuit dysregulation in patients with associated disorders.

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