Stinson Hannah E, Ninan Ipe
Department of Neurosciences and Psychiatry, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.
bioRxiv. 2025 Jan 3:2025.01.03.631193. doi: 10.1101/2025.01.03.631193.
The medial habenula (MHb)-interpeduncular nucleus (IPN) pathway plays an important role in information transferring between the forebrain and the midbrain. The MHb-IPN pathway has been implicated in the regulation of fear behavior and nicotine addiction. The synapses between the ventral MHb and the IPN show a unique property, i.e., an enhancement of synaptic transmission upon activation of GABA receptors. This GABA receptor-mediated potentiation of ventral MHb-IPN synaptic transmission has been implicated in regulating fear memory. Although IPN is known to contain parvalbumin (PV) and somatostatin (SST) GABAergic neurons and vesicular glutamate transporter 3 (VGLUT3)-expressing neurons, it is unknown how GABA receptor activation affects ventral MHb-mediated glutamatergic transmission onto these three subtypes of IPN neurons. Our studies show robust glutamatergic connectivity from ventral MHb to PV and SST neurons in the IPN, while the ventral MHb-mediated glutamatergic transmission in IPN VGLUT3 neurons is weak. Although activation of GABA receptors produces a robust potentiation of ventral MHb-mediated glutamatergic transmission in PV neurons, we observed a modest effect in IPN SST neurons. Despite the diminished basal synaptic transmission between ventral MHb and IPN VGLUT3 neurons, activation of GABA receptors causes transient conversion of non-responding ventral MHb synapses into active synapses in some IPN VGLUT3 neurons. Thus, our results show strong ventral MHb connectivity to GABAergic IPN neurons compared to VGLUT3-expressing IPN neurons. Furthermore, GABA receptor activation produces a differential effect on ventral MHb-mediated glutamatergic transmission onto PV, SST, and VGLUT3 neurons in the IPN.
内侧缰核（MHb）-脚间核（IPN）通路在前脑和中脑之间的信息传递中起重要作用。MHb-IPN通路与恐惧行为调节和尼古丁成瘾有关。腹侧MHb与IPN之间的突触具有独特特性，即GABA受体激活后突触传递增强。这种GABA受体介导的腹侧MHb-IPN突触传递增强与恐惧记忆调节有关。虽然已知IPN包含小白蛋白（PV）和生长抑素（SST）γ-氨基丁酸能神经元以及表达囊泡谷氨酸转运体3（VGLUT3）的神经元，但尚不清楚GABA受体激活如何影响腹侧MHb介导的谷氨酸能传递至IPN这三种神经元亚型。我们的研究表明，从腹侧MHb到IPN中的PV和SST神经元存在强大的谷氨酸能连接，而腹侧MHb介导的IPN中VGLUT3神经元的谷氨酸能传递较弱。虽然GABA受体激活在PV神经元中产生强大的腹侧MHb介导的谷氨酸能传递增强，但我们在IPN的SST神经元中观察到适度的效应。尽管腹侧MHb与IPN的VGLUT3神经元之间的基础突触传递减弱，但GABA受体激活在一些IPN的VGLUT3神经元中导致无反应的腹侧MHb突触短暂转变为活跃突触。因此，我们的结果表明，与表达VGLUT3的IPN神经元相比，腹侧MHb与IPN的γ-氨基丁酸能神经元有更强的连接。此外，GABA受体激活对腹侧MHb介导的谷氨酸能传递至IPN中的PV、SST和VGLUT3神经元产生不同的影响。
