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.

脑中中央释放的促肾上腺皮质激素释放因子或激素（丘脑下丘脑CRF或CRH）参与了对压力的行为和情感反应。外侧ha（LHb）是一个上丘脑区域，参与基于价值的决策和压力规避。通过抑制多巴胺介导的奖励电路，LHb的活性增加与成瘾，抑郁，精神分裂症和行为障碍有关。我们发现下丘脑CRF神经传递增加了LHb中神经元的兴奋性。通过其受体CRFR1和随后的蛋白激酶A（PKA），CRF的应用通过影响小电导SK型和大电导BK型K ^+的变化，提高了LHb神经元的固有兴奋性。渠道。CRF还通过内源性大麻素介导的逆行信号传导减少了抑制性的含γ-氨基丁酸（GABAergic）突触传递到LHb神经元。产妇剥夺是一种严重的早期生活压力，它改变了CRF神经回路，并且同样与以后的心理健康异常有关。缺乏母体照料的幼犬的LHb神经元表现出内在兴奋性增加，GABA能传递减少，SK2通道蛋白丰度下降以及PKA活性增加，而Crh或Crhr1没有任何实质性变化表达。此外，母体剥夺削弱了LHb神经元对随后的急性CRF暴露的反应。激活SK通道或抑制突触后PKA活性可防止CRF和母体剥夺对LHb内在兴奋性的影响，从而确定了潜在的药理学指标，可逆转相关疾病患者的中央CRF回路失调。