Whyte Alonzo J, Trinoskey-Rice Gracy, Davies Rachel A, Woon Ellen P, Foster Stephanie L, Shapiro Lauren P, Li Dan C, Srikanth Kolluru D, Gil-Henn Hava, Gourley Shannon L
Departments of Pediatrics and Psychiatry, Emory University School of Medicine, Atlanta, Georgia 30329.
Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329.
J Neurosci. 2021 Jul 7;41(27):5923-5936. doi: 10.1523/JNEUROSCI.0781-20.2021.
Repeated cocaine exposure causes dendritic spine loss in the orbitofrontal cortex, which might contribute to poor orbitofrontal cortical function following drug exposure. One challenge, however, has been verifying links between neuronal structural plasticity and behavior, if any. Here we report that cocaine self-administration triggers the loss of dendritic spines on excitatory neurons in the orbitofrontal cortex of male and female mice (as has been reported in rats). To understand functional consequences, we locally ablated neuronal β1-integrins, cell adhesion receptors that adhere cells to the extracellular matrix and thus support dendritic spine stability. Degradation of β1-integrin tone: (1) caused dendritic spine loss, (2) exaggerated cocaine-seeking responses in a cue-induced reinstatement test, and (3) impaired the ability of mice to integrate new learning into familiar routines, a key function of the orbitofrontal cortex. Stimulating Abl-related gene kinase, overexpressing Proline-rich tyrosine kinase, and inhibiting Rho-associated coiled-coil containing kinase corrected response strategies, uncovering a β1-integrin-mediated signaling axis that controls orbitofrontal cortical function. Finally, use of a combinatorial gene silencing/chemogenetic strategy revealed that β1-integrins support the ability of mice to integrate new information into established behaviors by sustaining orbitofrontal cortical connections with the basolateral amygdala. Cocaine degenerates dendritic spines in the orbitofrontal cortex, a region of the brain involved in interlacing new information into established behaviors. One challenge has been verifying links between cellular structural stability and behavior, if any. In this second of two related investigations, we study integrin family receptors, which adhere cells to the extracellular matrix and thereby stabilize dendritic spines (see also DePoy et al., 2019). We reveal that β1-integrins in the orbitofrontal cortex control food- and cocaine-seeking behaviors. For instance, β1-integrin loss amplifies cocaine-seeking behavior and impairs the ability of mice to integrate new learning into familiar routines. We identify likely intracellular signaling partners by which β1-integrins support orbitofrontal cortical function and connectivity with the basolateral amygdala.
反复接触可卡因会导致眶额皮质中的树突棘丢失，这可能是药物接触后眶额皮质功能不良的原因之一。然而，一个挑战一直是验证神经元结构可塑性与行为之间的联系（如果存在的话）。在这里，我们报告可卡因自我给药会引发雄性和雌性小鼠眶额皮质中兴奋性神经元上的树突棘丢失（正如在大鼠中所报道的那样）。为了了解其功能后果，我们局部消融了神经元β1整合素，这是一种将细胞粘附到细胞外基质并因此支持树突棘稳定性的细胞粘附受体。β1整合素水平的降低：（1）导致树突棘丢失，（2）在提示诱导的复吸试验中夸大了对可卡因的寻求反应，（3）损害了小鼠将新学习融入熟悉日常行为的能力，这是眶额皮质的一项关键功能。刺激Abl相关基因激酶、过表达富含脯氨酸的酪氨酸激酶以及抑制含Rho相关卷曲螺旋的激酶可纠正反应策略，揭示了一个控制眶额皮质功能的β1整合素介导的信号轴。最后，使用组合基因沉默/化学遗传学策略表明，β1整合素通过维持眶额皮质与基底外侧杏仁核的连接来支持小鼠将新信息整合到既定行为中的能力。可卡因会使眶额皮质中的树突棘退化，眶额皮质是大脑中一个参与将新信息交织到既定行为中的区域。一个挑战一直是验证细胞结构稳定性与行为之间的联系（如果存在的话）。在这两项相关研究的第二项中，我们研究了整合素家族受体，它们将细胞粘附到细胞外基质并由此稳定树突棘（另见DePoy等人，2019年）。我们发现眶额皮质中的β1整合素控制对食物和可卡因的寻求行为。例如，β1整合素的缺失会放大对可卡因的寻求行为，并损害小鼠将新学习融入熟悉日常行为的能力。我们确定了β1整合素支持眶额皮质功能以及与基底外侧杏仁核连接的可能细胞内信号伙伴。
