The lateral prefrontal cortex (LPFC) serves as a critical hub for higher-order cognitive and executive functions in the human brain, coordinating brain networks whose disruption has been implicated in many neurological and psychiatric disorders. While transcranial brain stimulation treatments often target the LPFC, our current understanding of connectivity profiles guiding these interventions based on electrophysiology remains limited. Here, we present a high-resolution probabilistic map of bidirectional effective connectivity between the LPFC and widespread cortical and subcortical regions. This map is derived from intracranial evoked potential analysis of 48,797 intracranial direct electrical stimulation runs across 759 implantations in 724 patients with refractory epilepsy (368 male, 354 female, two unspecified; mean age 24±13.5 years). We mapped probabilistic connectivity between brain parcels with adaptive resolution - higher resolution in the LPFC in the hemisphere of interest and lower elsewhere - maintaining statistical power while achieving 95% average confidence interval of ∼0.03 for connectivity probability estimates. In addition, the significance threshold (p-value) for probabilistic connectivity was obtained from surrogate distributions. Overall, we observed remarkable symmetry between afferent and efferent connectivity patterns of the LPFC, with a slight preference for efferent connections (mean slope = 0.92±0.09, mean R² = 0.93±0.025). For example, connections between the inferior frontal gyrus (IFG) and anterior cingulate showed notable directional asymmetry. The IFG strongly projected to most brain networks compared to other LPFC regions, with the strongest connectivity to the ventral attention network (0.26±0.01 compared to values between 0.15 and 0.21 in other LPFC regions). Posterior DLPFC demonstrated stronger connectivity to brain networks compared to anterior DLPFC regions (eg. 0.21±0.01 vs 0.15±0.01 for connectivity to ventral attention network), with the exception of the limbic cortex. All LPFC subregions strongly projected to the fronto-parietal (greater than 0.17) and ventral attention (greater than 0.15) networks, with moderate connections to the default network (between 0.1 and 0.15, with the maximum corresponding to superior DLPFC). Finally, latency analysis suggested that the left LPFC's influence on ipsilateral emotion-related regions is primarily polysynaptic, with particularly strong pathways from IFG to amygdala (0.16±0.02) and hippocampus (0.12±0.01). Taken together, these comprehensive connectivity maps provide a new detailed electrophysiological foundation for understanding the functional anatomy of LPFC and guiding targeted brain stimulation protocols.

While cognitive function remains stable for majority of the lifespan, many functions sharply decline in later life. Women have higher rates of neurodegenerative diseases that involve memory loss, including Alzheimer's disease. This sex disparity may be due to longer life expectancies when compared to men; women outlive men by roughly 5 years globally. Despite this, most preclinical work compares aged male rodents to young adult counterparts, making it difficult to determine the relative contributions of advanced age and sex to memory function and neurodegeneration. We used male and female rats throughout old age (PND590-734) to examine the extent to which both sex and advanced age would impact trace fear memory and associated neural changes, including expression of the immediate early gene zif268, perineuronal nets (PNN) amount, and lysine-48 (K48) polyubiquitin protein tagging in brain regions necessary for trace fear memory: the prelimbic cortex (PL), the dorsal hippocampus (DH), and the basolateral amygdala (BLA). While both advanced age and biological sex impacted trace fear memory, they had no effect on acquisition or context fear retrieval. Advanced age was associated with decreased zif268 expression in the PL and DH, while biological sex had no influence. PNN amount corresponded with advanced aged in the PL, but not in the DH or BLA, and was not influenced by sex. Neither biological sex nor advanced age impacted K48 polyubiquitin levels in any region. Overall, these results suggest that advanced age has a more pronounced effect on memory impairment and associated neural changes than biological sex.

Theta oscillation is considered a temporal scaffold for hippocampal computations that organizes the activity of spatially tuned cells known as place cells. Late phases of theta support prospective spatial representation via phase 'precession'. In contrast, some studies have hypothesized that early phases of theta may subserve both retrospective spatial representation via phase 'procession' and the encoding of new associations. Here, combining virtual reality, electrophysiology and computational modeling, we provide experimental evidence for such a functionally multiplexed phase code and describe how distinct spatial inputs control its manifestation. Specifically, when rats continuously learned new associations between external landmark (allothetic) cues and self-motion (idiothetic) cues, phase 'precession' remained intact, allowing continuous prediction of future positions. Conversely, phase 'procession' was diminished, matching the putative role in encoding at the early theta phase. This multiplexed phase code may serve as a general circuit logic for alternating different computations at a sub-second scale.

Hippocampal place cells (PCs) are important for spatial coding and episodic memory. PCs' representations are modulated upon transitioning between environments (global remapping) but also change with repeated exposure to familiar spaces (representational drift). To gain insights into the mechanistic basis for this unique balance between circuit plasticity and stability, we used voltage imaging to longitudinally record the subthreshold and spiking activity of pyramidal neurons (PNs) and somatostatin-positive (SST) interneurons in CA1 during virtual navigation. A fraction of cells from both populations showed spatial representations, but many SSTs were speed-tuned or fired uniformly across space. Intracellular recordings revealed increased theta power and asymmetric ramp-like depolarization in PN place fields, while SSTs exhibited symmetric depolarization with no theta increase. Longitudinal recordings across weeks demonstrated representational drifts in both populations, although SSTs exhibited remarkably stable firing and subthreshold properties. Transition to a novel environment induced remapping in both populations, accompanied by increase in SST activity and reduction in PNs. These results provide new insights into how hippocampal circuits balance representational stability with experience-dependent plasticity.

The precise structural and functional characteristics of input circuits targeting histaminergic neurons remain poorly understood. Here, using a rabies virus retrograde tracing system combined with fluorescence micro-optical sectioning tomography, we construct a 3D monosynaptic long-range input atlas of male mouse histaminergic neurons. We identify that the hypothalamus, thalamus, pallidum, and hippocampus constitute major input sources, exhibiting diverse spatial distribution patterns and neuronal type ratios. Notably, a specific layer distribution pattern and co-projection structures of upstream cortical neurons are well reconstructed at single-cell resolution. As histaminergic system is classically involved in sleep-wake regulation, we demonstrate that the lateral septum (predominantly supplying inhibitory inputs) and the paraventricular nucleus of the thalamus (predominantly supplying excitatory inputs) establish monosynaptic connections, exhibiting distinct functional dynamics and regulatory roles in rapid-eye-movement sleep. Collectively, our study provides a precise long-range input map of mouse histaminergic neurons at mesoscopic scale, laying a solid foundation for future systematic study of histaminergic neural circuits.