Abstract Cortical folding is a defining feature of mammalian brain evolution widely attributed to spatially patterned cell proliferation, neuronal differentiation, and migration that drive regional expansion of the cerebral cortex. Growth-centric models have dominated theories of gyrification for decades; however, cortical morphogenesis is not governed by expansion alone. In this hypothesis-driven review, we reconceptualize cell death as a potential driver of cortical folding. We synthesize evidence indicating that apoptosis is spatiotemporally regulated during healthy brain development, influences cortical size and structure when perturbed, and functions differently in cell type- and layer-specific contexts. Apoptosis has been largely overlooked as an instructive contributor to gyral and sulcal formation. We explore the possibility that spatially patterned apoptosis may directly modulate cell density, radial units, and cortical topology, acting in concert with, rather than a consequence of, proliferation and migration to sculpt the developing brain. We propose that this is a substantial area of investigation given the limited data on spatially patterned apoptosis and gyrification and the evidence that would be required to substantiate this hypothesis. Recognizing the potential for apoptosis as a candidate driver of gyrification expands current developmental models and provides a new testable framework for interpreting both evolutionary cortical expansion and malformations.
Abstract Numerous studies indicate that the brain demonstrates functional lateralization with distinct patterns between males and females, but they primarily have focused on gray matter, with only a handful considering white matter (WM) and sex differences. Utilizing rs-fMRI from the Southwest University Longitudinal Imaging Multimodal (SLIM) dataset, we quantified lateralization of WM as the difference in each region’s synchronization with the left versus right hemisphere, and examined its temporal fluctuations and sex differences. Then, the Louvain community detection algorithm clustered lateralization patterns, and sex differences within each cluster were analyzed. We established the functional connectivity network, assessed its properties, and utilized correlation analysis to examine the relationship between lateralization and network. Our analyses revealed that WM demonstrated a left-lateralized trend in the left hemisphere and a right-lateralized trend in the right hemisphere. Moreover, functional lateralization was more pronounced in males than females. We also categorized the regions into three spatial clusters, revealing sex differences in the lateralization patterns within each cluster. Additionally, lateralization patterns are intricately associated with the functional connectivity network. These findings provide insights into functional lateralization and sex differences, and may inform future investigations of the neural mechanisms associated with functional specialization, cognition, behavior, and neurological disorders.
Abstract Shyness is a prevalent psychological construct that can lead to psychopathology and negative developmental outcomes, yet its neurostructural substrates remain poorly understood, particularly during adolescence—a critical period for social and emotional development. This study examined the brain gray matter volume correlates of shyness and the potential mediating role of basic personality traits in 228 normal adolescents (aged 16–20 years). Participants underwent structural magnetic resonance imaging and completed the Cheek and Buss Shyness Scale and NEO Five-Factor Inventory. Whole-brain voxel-based morphometry and cross-validation prediction analyses revealed a positive association between shyness and gray matter volume in the right dorsolateral prefrontal cortex, a key region implicated in cognitive control and emotion regulation. Among the Big Five traits, only extraversion correlated with right dorsolateral prefrontal cortex gray matter volume and showed a significant indirect association with the gray matter volume–shyness link. Specifically, higher right dorsolateral prefrontal cortex gray matter volume was associated with lower extraversion, which in turn was associated with greater shyness; this indirect association was partial and remained significant after controlling for other personality traits. These results highlight the importance of integrating neural and personality factors in understanding shyness during this critical developmental period and offer potential targets for early identification and intervention.
Abstract The subiculum (SUB) is a major hippocampal output hub that routes information to cortical and subcortical targets, and its long-range projections are considered excitatory. Using enhancer-driven adeno-associated viral vectors to selectively label γ-aminobutyric acid (GABA)-releasing neurons across species, here we show that the dorsal SUB also sends an inhibitory projection to the dorsal part of the medial entorhinal cortex (MEC) in mice and rats. Anterograde tracing in mice revealed that the dorsal SUB contains GABAergic neurons that project sparsely to all layers of the dorsal MEC with enrichment in superficial layers, in contrast to the glutamatergic SUB axons targeting MEC layer V. Slice electrophysiology demonstrated that these GABAergic axons form inhibitory synapses in the MEC. A subset of projecting neurons expressed parvalbumin (PV), whereas somatostatin-positive neurons were infrequent. Consistently, PV neuron-specific anterograde tracing recapitulated the SUB-to-MEC projection. In rats, subicular GABAergic axons were enriched in MEC layer II, and SynaptoTAG2-labeled presynaptic boutons were positive for the vesicular GABA transporter, supporting inhibitory synapse formation. Anterograde tracing of PV neurons similarly recapitulated the laminar axonal distribution in the MEC. These results identify a conserved PV-associated inhibitory SUB-to-MEC projection with specific laminar organization, extending the canonical excitatory view of subicular output.
Abstract The hippocampus integrates spatial information from medial entorhinal cortex (MEC) with non-spatial sensory information from lateral entorhinal cortex (LEC) to form episodic memories. While age-related memory dysfunction is linked to several changes in neuronal function within hippocampal subfields, the effects of aging on MEC and LEC cellular activity patterns are less well-characterized. Here, we investigated MEC and LEC population activity in adult versus aged rats by monitoring the expression of the immediate early gene Arc across two behavioral task sessions with olfactory stimuli separated by a rest period. Aging did not affect the percentage of activated neurons in MEC or their consistent Arc expression patterns across sessions, consistent with stably coding repeated spatial experiences. In contrast, fewer LEC neurons were activated during behavior in aged than adult rats, indicating a specific age-associated hypoactivity in LEC. Additionally, regardless of group, more LEC neurons were activated during the second session compared to the first, which may reflect temporally sensitive LEC neuronal activity increasingly engaged across episodes of experience. These results indicate that aging affects input to the hippocampus in a region-specific manner and are also consistent with observations that suggest that some LEC neurons may provide a temporal tag for episodic memories.
