Diversity of Layer 3 Pyramidal Neuron Properties Across Areas of the Primate Neocortex.

Lhx2 Regulates Distinct Dendritic Architecture of Pyramidal Neurons across Primary Sensory Areas

Distinct neocortical regions subserve different sensory functions, yet the cellular features that distinguish neurons across cortical areas remain poorly understood. Layer (L)2/3 pyramidal neurons (PyNs) are generated at similar developmental times throughout the cortex, but whether their morphological and functional properties are shaped by areal identity programs is unclear. Here, we compared L2/3 PyNs in mouse primary somatosensory (S1) and primary visual (V1) cortices (both male and female). We observed pronounced areal differences where V1 neurons exhibited smaller and less complex dendritic arbors and displayed increased intrinsic excitability relative to their counterparts in S1. These differences were present in both juvenile and adult stages, indicating that they emerge early and persist over time. Given prior evidence implicating the transcription factor LHX2 in dendritic arborization, we tested its contribution to these differences. Loss of Lhx2 in E15.5 V1 progenitors did not alter neuronal morphology in V1, in contrast to our previous findings in S1. We found that E15.5 progenitors display lower levels of LHX2 protein in V1 than in S1; therefore, we overexpressed Lhx2 in V1 progenitors and found increased dendritic branching complexity in V1 L2/3 PyNs. Together, these findings identify LHX2 as a molecular regulator that contributes to area-specific structural differentiation of L2/3 PyNs. Our results show that PyNs arising from different regions of the dorsal pallium diverge in morphology and physiology according to the cortical area, suggesting that regionally patterned transcriptional programs help establish functional specialization across the neocortex.

Distinct tuning properties of human hippocampal neurons along the longitudinal axis during working memory

Working memory (WM) is among the most sophisticated and fundamental capabilities of the mammalian brain. While the roles of prefrontal and sensory areas are heavily explored, there is little knowledge on how the hippocampus (HPC) contributes to this process. Here, we studied human HPC neuronal activities during a verbal WM task and reveal that neurons in the posterior HPC (PH) show more robust rate-modulations during WM. On the other hand, anterior HPC (AH) neurons are more prominently modulated by the phase of local and frontal cortex θ and αβ oscillations, a phenomenon that is accompanied by enhanced phase-synchronization between frontal cortex and HPC. Moreover, absence of correlational correspondence suggested that rate and phase are independent coding mechanisms. These results open a window to explore the functional dissociations along the primate HPC antero-posterior axis, a phenomenon long known to exist in the rodent brain. Furthermore, we suggest that combination of a variety of coding mechanisms in the human HPC neuronal population supports execution of WM. Graphical abstract

Pharmacological and Physiological Characteristics of Synaptic Transmissions From the Medial Prefrontal Cortex Onto Noradrenergic Neurons and Inhibitory Interneurons in the Mouse Locus Coeruleus.

A prefrontal cortex-piriform cortex circuit mediates diminished interest.

Diminished interest constitutes a core behavioral deficit across multiple neuropsychiatric conditions, yet its neural mechanism remains poorly understood. Here, we identify projection-biased and transcriptionally distinct subsets of glutamatergic neurons in the ventromedial prefrontal cortex (vmPFC) that preferentially innervate the anterior piriform cortex (APC) and posterior piriform cortex (PPC). By establishing a behavioral paradigm that selectively captures interest-related behaviors, we reveal that the vmPFCglu-PPC, but not the vmPFCglu-APC, circuit governs interest-related engagement without affecting olfactory function. This regulation is encoded by AMPAR-dependent burst firing in PPC neurons. Chronic stress selectively weakens this cortico-cortical pathway, reducing glutamatergic transmission and impairing burst firing in PPC neurons, thereby leading to deficits in interest-related behavior in mice. Targeted reactivation of the vmPFCglu-PPC circuit rescues these behavioral impairments. Collectively, our findings uncover a previously unrecognized cortical pathway dedicated to interest encoding and establish a circuit-level framework for explaining the selective vulnerability of interest under chronic stress.

Responsiveness of cerebral cortex to hippocampal inputs depends on brain region and brain state

Gamma oscillations (30–90 Hz) are a prominent signature of cortical network state, but whether they facilitate or hinder inter-areal communication remains unresolved. The communication-through-coherence hypothesis posits that gamma enhances transmission between areas, whereas recent computational work suggests that high-amplitude gamma oscillations may instead filter incoming inputs and reduce their impact. To distinguish between these accounts, we used a well-defined physiological input—sharp-wave ripple (SWR) complexes—to probe cortical responsiveness via two parallel monosynaptic pathways: from ventral CA1 to prefrontal cortex (PFC), and from dorsal CA1 to retrosplenial cortex (RSC). By classifying the cortical state immediately preceding each ripple as low- or high-amplitude gamma, we found that PFC responses to ripples were significantly larger during low-amplitude gamma states, an effect carried by the ventral CA1–PFC pathway and driven primarily by ripples during quiet wakefulness. RSC showed no such state-dependent modulation. A mean-field model of PFC reproduced the enhanced responsiveness during low-amplitude gamma and revealed that this modulation depends on the excitatory–inhibitory balance of the afferent input and on the level of recurrent excitation—providing a mechanistic explanation for the distinct behaviors of PFC and RSC, which differ in their local recurrent connectivity. Extending the model to a chain of cortical areas predicted that low-amplitude gamma supports robust propagation of activity across regions, whereas high-amplitude gamma confines it locally. Together, these results argue that low-amplitude gamma, rather than strong gamma synchronization, constitutes a favorable substrate for communication between brain areas.

Pyramidal cell types and circuit organization of the mouse insular cortex reveal functional specializations.

The insular cortex integrates interoceptive and exteroceptive information to mediate bodily homeostasis, emotion and learning. However, the cellular and circuit substrates governing insular functions are poorly understood compared to primary cortices. Here we quantify dendritic morphology together with projections, electrical properties and/or local inputs of 1,130 mouse insular pyramidal neurons. Neurons are mapped onto a quantitative Nissl-derived model of the insula. Using improved algorithms, we define 21 morphological, 12 electrical and 9 input neuronal types, some unique to the insula. Several types exhibit elaborate dendrites, reminiscent of primate cortical neurons. Furthermore, morphological properties constrain and often predict inputs, electrical properties, projection targets or molecular markers. Eight morphological types are differentially distributed between the functionally distinct anterior and posterior insula, facilitating a quantitative demarcation between these subregions. Certain types receive intra-insular excitatory inputs originating far beyond cortical columns, which functionally bridge a long-range thalamus-to-amygdala circuit linking sensory information to valence behaviorally. Our work establishes a structure-and-function foundation for investigating the insula.