Data and code from: Cholecystokinin modulates age-dependent thalamocortical neuroplasticity

The thalamocortical pathways exhibit neuroplasticity not only during the critical period but also in adulthood. In this study, we investigated how cholecystokinin (CCK) modulates age-dependent thalamocortical plasticity. Our findings demonstrated that CCK is expressed in thalamocortical neurons and that high-frequency stimulation (HFS) of the thalamocortical pathway triggers the release of CCK in auditory cortex (ACx), as detected by a CCK sensor. HFS of the medial geniculate body (MGB) induced thalamocortical long-term potentiation (LTP) in wild-type young adult mice. However, knockdown of Cck expression in MGB neurons or blockade of the CCK-B receptor (CCKBR) in the ACx abolished HFS-induced LTP. Interestingly, this LTP could not be elicited in juvenile (3-week-old) or aged mice (over 18-month-old) due to distinct mechanisms: the absence of CCKBR in juveniles and the inability to release CCK in aged mice. Notably, exogenous administration of CCK into the ACx rescued LTP in aged mice and significantly improved frequency discrimination. These findings highlight the potential of CCK as a therapeutic intervention for ameliorating neuroplasticity deficits associated with thalamocortical connectivity.

丘脑皮层通路(thalamocortical pathways)不仅在关键发育期，亦于成年阶段展现神经可塑性。本研究旨在探究胆囊收缩素(cholecystokinin, CCK)如何调控年龄依赖性的丘脑皮层可塑性。研究结果表明，CCK在丘脑皮层神经元中存在表达；通过CCK传感器检测发现，对丘脑皮层通路施加高频刺激(high-frequency stimulation, HFS)可触发听觉皮层(auditory cortex, ACx)内CCK的释放。对内侧膝状体(medial geniculate body, MGB)施加HFS，能够在野生型年轻成年小鼠中诱导丘脑皮层长时程增强(long-term potentiation, LTP)。然而，在MGB神经元中敲低Cck基因表达，或是在ACx中阻断胆囊收缩素B受体(CCK-B receptor, CCKBR)，均可消除HFS诱导的LTP。有趣的是，幼年（3周龄）或老年（18月龄以上）小鼠无法诱发该LTP，二者的机制存在差异：幼年小鼠体内缺乏CCKBR，而老年小鼠无法释放CCK。值得关注的是，向ACx中外源性给予CCK可挽救老年小鼠的LTP，并显著提升其频率辨别能力。本研究结果凸显了CCK作为治疗干预手段的潜力，可用于改善与丘脑皮层连接异常相关的神经可塑性缺陷。