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

Abstract

Centrally released corticotropin releasing factor or hormone (extrahypothalamic CRF or CRH) in the brain is involved in 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, increased activity of the LHb is associated with addiction, depression, schizophrenia and behavior disorders. Here, 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- and large-conductance SK- and BK-type K+ channels. CRF also reduced inhibitory GABAergic synaptic transmission onto LHb neurons through endocannabinoid (eCB)-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 significant changes in Crh or Crhr1 expression. Notably, 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.

Factors of sex and age dictate the regulation of GABAergic activity by corticotropin-releasing factor receptor 1 in the medial sub-nucleus of the central amygdala

“…One investigation of presumed-adolescent male Sprague Dawley rats (125-150g) has demonstrated that CRF superfusion into the CeA results in neuronal hyperpolarization (Rainnie et al, 1992), however, this study did not directly examine synaptic transmission. A more recent study in the lateral habenula showed a CRFR1-induced reduction in GABA transmission in post-weanling rats (Authement et al, 2018), opposite of what has been established in the adults within the CeA (Bajo Sex and age influence CRFR1 function in the CeM 5 Nie et al, 2004;Roberto et al, 2010). These findings suggest a potential developmental shift in CRFR1-regulation of GABA transmission, however age and sex as biological factors have not been systematically investigated.…”

Histone deacetylase inhibition reduces ventral tegmental area dopamine neuronal hyperexcitability involving AKAP150 signaling following maternal deprivation in juvenile male rats

“…The number of APs induced by depolarization at each intensity was counted and averaged for each experimental group. AP threshold, medium after hyperpolarization (mAHP), and fast after hyperpolarization (fAHP) amplitudes were measured at the current step that was sufficient to generate the first AP/s as previously described (Authement et al, 2018). Briefly, AP threshold was measured at the beginning of the upward rise of the AP.…”

The Multi-Circuit Neuronal Hyperexcitability Hypothesis of Psychiatric Disorders

“…Again, the answer lies in the dynamics of brain circuitry. What theoretically happens in clinical depression is that persistent hyperactivity in negative (feel bad) neural circuits both directly and indirectly drives a persistent hyperactivation of a small epithalamic structure called the habenula [142][143][144][145]. Increased firing in the habenula inhibits the firing of large populations of neurons that release the "feel good" neurotransmitters serotonin and dopamine [146][147][148].…”