Sahyoun Gabriella M, Do Trang Dao, Anqueira-Gonzàlez Amanda, Hornblass Ava, Canetta Sarah E
Division of Developmental Neuroscience, Department of Psychiatry, Columbia University Irving Medical Center and the New York State Psychiatric Institute, New York, New York, USA.
Department of Behavioral Neuroscience, Barnard College, New York, New York, USA.
Dev Neurosci. 2025;47(2):127-138. doi: 10.1159/000539584. Epub 2024 Jun 3.
Developmental windows in which experiences can elicit long-lasting effects on brain circuitry and behavior are called "sensitive periods" and reflect a state of heightened plasticity. The classic example of a sensitive period comes from studies of sensory systems, like the visual system, where early visual experience is required for normal wiring of primary visual cortex and proper visual functioning. At a mechanistic level, loss of incoming visual input results in a decrease in activity in thalamocortical neurons representing the affected eye, resulting in an activity-dependent reduction in the representation of those inputs in the visual cortex and loss of visual perception in that eye. While associative cortical regions like the medial prefrontal cortex (mPFC) do not receive direct sensory input, recent findings demonstrate that changes in activity levels experienced by this region during defined windows in early development may also result in long-lasting changes in prefrontal cortical circuitry, network function, and behavior. For example, we recently demonstrated that decreasing the activity of mPFC parvalbumin-expressing (PV) interneurons during a period of time encompassing peripuberty (postnatal day P14) to adolescence (P50) led to a long-lasting decrease in their functional inhibition of pyramidal cells, as well as impairments in cognitive flexibility. While the effects of manipulating mPFC PV interneuron activity were selective to development, and not adulthood, the exact timing of the sensitive period for this manipulation remains unknown.
To refine the sensitive period in which inhibiting mPFC PV cell activity can lead to persistent effects on prefrontal functioning, we used a chemogenetic approach to restrict our inhibition of mPFC PV activity to two distinct windows: (1) peripuberty (P14-P32) and (2) early adolescence (P33-P50). We then investigated adult behavior after P90. In parallel, we performed histological analysis of molecular markers associated with sensitive period onset and offset in visual cortex, to define the onset and offset of peak-sensitive period plasticity in the mPFC.
We found that inhibition of mPFC PV interneurons in peripuberty (P14-P32), but not adolescence (P33-P50), led to an impairment in set-shifting behavior in adulthood manifest as an increase in trials to reach criterion performance and errors. Consistent with a pubertal onset of sensitive period plasticity in the PFC, we found that histological markers of sensitive period onset and offset also demarcated P14 and P35, respectively. The time course of expression of these markers was similar in visual cortex.
Both lines of research converge on the peripubertal period (P14-P32) as one of heightened sensitive period plasticity in the mPFC. Further, our direct comparison of markers of sensitive period plasticity across the prefrontal and visual cortex suggests a similar time course of expression, challenging the notion that sensitive periods occur hierarchically. Together, these findings extend our knowledge about the nature and timing of sensitive period plasticity in the developing mPFC.
Developmental windows in which experiences can elicit long-lasting effects on brain circuitry and behavior are called "sensitive periods" and reflect a state of heightened plasticity. The classic example of a sensitive period comes from studies of sensory systems, like the visual system, where early visual experience is required for normal wiring of primary visual cortex and proper visual functioning. At a mechanistic level, loss of incoming visual input results in a decrease in activity in thalamocortical neurons representing the affected eye, resulting in an activity-dependent reduction in the representation of those inputs in the visual cortex and loss of visual perception in that eye. While associative cortical regions like the medial prefrontal cortex (mPFC) do not receive direct sensory input, recent findings demonstrate that changes in activity levels experienced by this region during defined windows in early development may also result in long-lasting changes in prefrontal cortical circuitry, network function, and behavior. For example, we recently demonstrated that decreasing the activity of mPFC parvalbumin-expressing (PV) interneurons during a period of time encompassing peripuberty (postnatal day P14) to adolescence (P50) led to a long-lasting decrease in their functional inhibition of pyramidal cells, as well as impairments in cognitive flexibility. While the effects of manipulating mPFC PV interneuron activity were selective to development, and not adulthood, the exact timing of the sensitive period for this manipulation remains unknown.
To refine the sensitive period in which inhibiting mPFC PV cell activity can lead to persistent effects on prefrontal functioning, we used a chemogenetic approach to restrict our inhibition of mPFC PV activity to two distinct windows: (1) peripuberty (P14-P32) and (2) early adolescence (P33-P50). We then investigated adult behavior after P90. In parallel, we performed histological analysis of molecular markers associated with sensitive period onset and offset in visual cortex, to define the onset and offset of peak-sensitive period plasticity in the mPFC.
We found that inhibition of mPFC PV interneurons in peripuberty (P14-P32), but not adolescence (P33-P50), led to an impairment in set-shifting behavior in adulthood manifest as an increase in trials to reach criterion performance and errors. Consistent with a pubertal onset of sensitive period plasticity in the PFC, we found that histological markers of sensitive period onset and offset also demarcated P14 and P35, respectively. The time course of expression of these markers was similar in visual cortex.
Both lines of research converge on the peripubertal period (P14-P32) as one of heightened sensitive period plasticity in the mPFC. Further, our direct comparison of markers of sensitive period plasticity across the prefrontal and visual cortex suggests a similar time course of expression, challenging the notion that sensitive periods occur hierarchically. Together, these findings extend our knowledge about the nature and timing of sensitive period plasticity in the developing mPFC.
经历能够对大脑回路和行为产生持久影响的发育窗口被称为“敏感期”，反映了一种高度可塑性的状态。敏感期的经典例子来自对感觉系统的研究，比如视觉系统，在该系统中，早期视觉经验是初级视觉皮层正常布线和正常视觉功能所必需的。在机制层面，传入视觉输入的丧失会导致代表受影响眼睛的丘脑皮质神经元活动减少，从而导致这些输入在视觉皮层中的表征因活动而减少，以及该眼睛的视觉感知丧失。虽然像内侧前额叶皮层（mPFC）这样的联合皮质区域不接受直接的感觉输入，但最近的研究结果表明，该区域在早期发育的特定窗口期间所经历的活动水平变化，也可能导致前额叶皮质回路、网络功能和行为的长期变化。例如，我们最近证明，在从青春期前（出生后第14天，P14）到青春期（P50）的一段时间内，降低mPFC中表达小白蛋白（PV）的中间神经元的活性，会导致它们对锥体细胞的功能抑制长期减少，以及认知灵活性受损。虽然操纵mPFC PV中间神经元活性的影响对发育具有选择性，而非对成年期有选择性，但这种操纵的敏感期的确切时间仍然未知。
为了确定抑制mPFC PV细胞活性可导致对前额叶功能产生持久影响的敏感期，我们采用化学遗传学方法，将对mPFC PV活性的抑制限制在两个不同的窗口：（1）青春期前（P14 - P32）和（2）青春期早期（P33 - P50）。然后，我们在P90之后研究成年后的行为。同时，我们对与视觉皮层敏感期开始和结束相关的分子标记进行了组织学分析，以确定mPFC中峰值敏感期可塑性的开始和结束。
我们发现，在青春期前（P14 - P32）而非青春期（P33 - P50）抑制mPFC PV中间神经元，会导致成年后转换行为受损，表现为达到标准表现的试验次数和错误增加。与PFC中敏感期可塑性在青春期开始一致，我们发现敏感期开始和结束的组织学标记分别也划定在P14和P35。这些标记的表达时间进程在视觉皮层中相似。
两条研究路线都指向青春期前阶段（P14 - P32）是mPFC中敏感期可塑性增强的时期之一。此外，我们对前额叶和视觉皮层中敏感期可塑性标记的直接比较表明，它们的表达时间进程相似，这对敏感期是分层发生的观点提出了挑战。总之，这些发现扩展了我们对发育中的mPFC中敏感期可塑性的性质和时间的认识。
经历能够对大脑回路和行为产生持久影响的发育窗口被称为“敏感期”，反映了一种高度可塑性的状态。敏感期的经典例子来自对感觉系统的研究，比如视觉系统，在该系统中，早期视觉经验是初级视觉皮层正常布线和正常视觉功能所必需的。在机制层面，传入视觉输入的丧失会导致代表受影响眼睛的丘脑皮质神经元活动减少，从而导致这些输入在视觉皮层中的表征因活动而减少，以及该眼睛的视觉感知丧失。虽然像内侧前额叶皮层（mPFC）这样的联合皮质区域不接受直接的感觉输入，但最近的研究结果表明，该区域在早期发育的特定窗口期间所经历的活动水平变化，也可能导致前额叶皮质回路、网络功能和行为的长期变化。例如，我们最近证明，在从青春期前（出生后第14天，P14）到青春期（P50）的一段时间内，降低mPFC中表达小白蛋白（PV）的中间神经元的活性，会导致它们对锥体细胞的功能抑制长期减少，以及认知灵活性受损。虽然操纵mPFC PV中间神经元活性的影响对发育具有选择性，而非对成年期有选择性，但这种操纵的敏感期的确切时间仍然未知。
为了确定抑制mPFC PV细胞活性可导致对前额叶功能产生持久影响的敏感期，我们采用化学遗传学方法，将对mPFC PV活性的抑制限制在两个不同的窗口：（1）青春期前（P14 - P32）和（2）青春期早期（P33 - P50）。然后，我们在P90之后研究成年后的行为。同时，我们对与视觉皮层敏感期开始和结束相关的分子标记进行了组织学分析，以确定mPFC中峰值敏感期可塑性的开始和结束。
我们发现，在青春期前（P14 - P32）而非青春期（P33 - P50）抑制mPFC PV中间神经元，会导致成年后转换行为受损，表现为达到标准表现的试验次数和错误增加。与PFC中敏感期可塑性在青春期开始一致，我们发现敏感期开始和结束的组织学标记分别也划定在P14和P35。这些标记的表达时间进程在视觉皮层中相似。
两条研究路线都指向青春期前阶段（P14 - P32）是mPFC中敏感期可塑性增强的时期之一。此外，我们对前额叶和视觉皮层中敏感期可塑性标记的直接比较表明，它们的表达时间进程相似，这对敏感期是分层发生的观点提出了挑战。总之，这些发现扩展了我们对发育中的mPFC中敏感期可塑性的性质和时间的认识。
