Zlotnik, V. | Search bioRxiv

bioRxiv2026

Prolonged developmental programming of somatostatin neurons defines adolescent remodeling of the prelimbic, but not barrel, cortex

Higher order association cortices like the prefrontal cortex (PFC) mature over a longer developmental window than sensory cortices, but whether genetically defined interneuron populations follow this region-wide delayed trajectory remains unclear. We compared the postnatal development of somatostatin-expressing interneurons in a higher-order cortical region (prelimbic cortex; PLC) and a sensory cortical region (somatosensory barrel cortex; S1BF) across adolescence using complementary structural, electrophysiological, and circuit analyses. We found that the maturation of SST neurons within these two cortical regions differs across time. S1BF SST neurons exhibited relatively linear maturation, whereas PLC SST neurons underwent continued dendritic remodeling, nonlinear intrinsic maturation, and age-dependent refinement of inhibitory output onto pyramidal neurons. Multivariate analyses likewise supported a more linear developmental trajectory in S1BF and a more prolonged, heterogeneous trajectory in PLC. This suggests divergent maturation of the PLC and S1BF and supports a broader, longer window of critical cellular plasticity in the PLC than in sensory cortices. Together, this reflects an extended developmental program at the level of a genetically defined inhibitory cell type. Because SST neurons are positioned to regulate pyramidal neuron output via control of dendritic integration, their delayed maturation is a crucial reflection of overall circuit function. These findings provide a cellular framework for the prolonged plasticity and developmental vulnerability known to be characteristic of adolescent prelimbic cortex. Significance statementWithin the brain, higher order association cortex remains plastic long after sensory cortex has matured, but the cellular basis for this prolonged developmental window has remained unknown. We find that developmental timing is encoded within genetically defined microcircuits. Prelimbic somatostatin circuits continue to remodel after sensory somatostatin circuits have largely stabilized through changes in cell shape, action potential firing dynamics, and inhibitory signaling. This work points to a specific prelimbic inhibitory cell type that matures more slowly, and less linearly, than its counterparts in other brain regions, and may help explain why prelimbic circuits remain vulnerable during adolescence, representing a biological substrate for extended adolescent remodeling in prelimbic cortex, and potentially the overall extensive flexibility, but also cognitive susceptibility, seen during adolescence.

neuroscience↗

bioRxiv2025

Genetic diversity shapes behavioral outcomes and reveals sex differences in mice exposed to early life stress

Understanding how genetic variability shapes responses to environmental and developmental factors is critical for advancing translational neuroscience. However, most preclinical studies rely on inbred mouse strains that do not capture the genetic complexity of human populations. One key area of translational research focuses on identifying the neural and behavioral consequences of early life trauma. Rodent models of childhood neglect, such as maternal separation with early weaning (MSEW), have been used in isogenic mouse strains like C57BL/6J (B6) to identify behavioral domains and neural loci of deficits stemming from exposure to MSEW. To understand how genetic diversity may contribute to the outcomes produced by MSEW, and thus inform future studies on the topic, we utilized the Jackson Laboratory Diversity Outbred (DO) line, a population derived from eight founder strains that exhibit broad genetic and phenotypic heterogeneity. We first compared MSEW effects on social behavior in DO mice versus B6 mice, because we have previously found social behavior deficits in B6 mice with a history of MSEW. Indeed, we established that MSEW incited social motivation deficits in DO mice, in a sex-specific manner. We then expanded our investigation of DO mice to test MSEW-related changes in anxiety-like behavior, fear learning and expression, and reward-seeking. Results revealed that MSEW produces distinct, sex-specific phenotypes: female DO mice displayed reduced social motivation and elevated anxiety-like behavior, while male DO mice showed attenuated CS-evoked fear expression and diminished reward-seeking behavior. Additionally, immunohistochemical analysis revealed increased Fos expression in the paraventricular nucleus of the hypothalamus (PVN) in MSEW-exposed DO mice, both at baseline and following acute stress. These findings highlight the importance of incorporating genetically diverse models to better capture the nuances of early life adversity-related outcomes relevant to human populations.

neuroscience↗