FMUP, Faculdade de Medicina - Departamento de Biomedicina, Universidade do Porto, 4200-450, Porto, Portugal.
i3S/IBMC, Instituto de Investigação e Inovação em Saúde e Instituto de Biologia Molecular e Celular - Pain Research Group, Universidade do Porto, 4200-135, Porto, Portugal.
Sci Rep. 2019 Jul 29;9(1):10980. doi: 10.1038/s41598-019-47555-0.
Dysfunction of the prefrontal-hippocampal circuit has been identified as a leading cause to pain-related working-memory (WM) deficits. However, the underlying mechanisms remain poorly determined. To address this issue, we implanted multichannel arrays of electrodes in the prelimbic cortex (PL-mPFC), and in the dorsal hippocampal CA1 field (dCA1) to record the neural activity during the performance of a delayed non-match to sample (DNMS) task. The prefrontal-hippocampal connectivity was selectively modulated by bidirectional optogenetic inhibition or stimulation of local PL-mPFC glutamatergic calcium/calmodulin-dependent protein kinase-II alpha (CaMKIIα) expressing neurons during the DNMS task delay-period. The within-subject behavioral performance was assessed using a persistent neuropathic pain model - spared nerve injury (SNI). Our results showed that the induction of the neuropathic pain condition affects the interplay between PL-mPFC and dCA1 regions in a frequency-dependent manner, and that occurs particularly across theta oscillations while rats performed the task. In SNI-treated rats, this disruption was reversed by the selective optogenetic inhibition of PL-mPFC CaMKIIα-expressing neurons during the last portion of the delay-period, but without any significant effect on pain responses. Finally, we found that prefrontal-hippocampal theta connectivity is strictly associated with higher performance levels. Together, our findings suggest that PL-mPFC CaMKIIα-expressing neurons could be modulated by painful conditions and their activity may be critical for prefrontal-hippocampal connectivity during WM processing.
前额叶-海马回路功能障碍已被确定为与疼痛相关的工作记忆 (WM) 缺陷的主要原因。然而，其潜在机制仍未确定。为了解决这个问题，我们在扣带回皮层（PL-mPFC）和背侧海马 CA1 区（dCA1）植入了多通道电极阵列，以在执行延迟非匹配样本任务（DNMS）期间记录神经活动。在 DNMS 任务延迟期间，通过双向光遗传学抑制或刺激局部 PL-mPFC 谷氨酸能钙/钙调蛋白依赖性蛋白激酶-IIα（CaMKIIα）表达神经元，选择性调节前额叶-海马连接。使用慢性神经病理性疼痛模型 - spared 神经损伤（SNI）评估了个体内的行为表现。我们的结果表明，诱导神经病理性疼痛状态以频率依赖的方式影响 PL-mPFC 和 dCA1 区域之间的相互作用，并且在大鼠执行任务时尤其在 theta 振荡中发生。在 SNI 处理的大鼠中，通过在延迟期的最后部分选择性光遗传学抑制 PL-mPFC CaMKIIα 表达神经元，这种干扰得到了逆转，但对疼痛反应没有任何显著影响。最后，我们发现前额叶-海马 theta 连接与更高的表现水平密切相关。总之，我们的研究结果表明，PL-mPFC CaMKIIα 表达神经元可能受到疼痛条件的调节，其活动对于 WM 处理期间前额叶-海马连接可能至关重要。
