Faculty Bibliography

In CA1 pyramidal neurons (CA1-PYRs), plateau potentials control synaptic plasticity and the emergence of place cell identity. Here, we show that dendritic inhibition terminates plateaus in an all-or-none manner in CA1-PYRs recorded in acute hippocampal slices from mice of either sex. Plateaus were initially resistant to inhibition but became increasingly susceptible to termination as they progressed. Two subtypes of dendrite-targeting oriens-lacunosum moleculare (OLM) interneurons, accessed in transgenic mice based on the expression of the genes Ndnf or Chrna2 (OLM^Ndnf and OLM^α2, respectively), could terminate plateau potentials. OLM^Ndnf generated slower postsynaptic currents that terminated plateaus more effectively than OLM^α2 Voltage-gated Ca²⁺ channels (VGCCs) were necessary for plateaus, which were prolonged by blocking small-conductance Ca²⁺-activated K⁺ channels (SK). A single-compartment model with these two conductances recapitulated core experimental findings and provided a mechanistic explanation for terminations. Plateaus arose from VGCCs maintained in the active state by sustained Ca²⁺ influx, a positive feedback loop that was quasi-balanced by I_SK Inhibition terminated plateaus by driving the membrane potential below a dynamic threshold to deactivate VGCCs and end the positive feedback loop. Similar all-or-none termination dynamics were observed for plateaus evoked under cholinergic modulation. Lastly, two-photon Ca²⁺ imaging showed that plateaus evoke large dendritic Ca²⁺ transients that were graded by terminations. Overall, our results demonstrate how the feedback inhibitory circuit interacts with intrinsic cellular mechanisms to regulate plateau potentials and shape dendritic Ca²⁺ signals in CA1-PYRs.Significance Statement Plateau potentials are critical biophysical events that drive memory-related synaptic plasticity in the hippocampus, yet their underlying regulatory mechanisms remain incompletely understood. Here, we reveal that synaptic inhibition can abruptly terminate plateaus in CA1 pyramidal neurons. This all-or-none termination results from a nonlinear interaction between voltage-gated Ca2+ channels and SK channels. Using intersectional genetics, we identify two dendrite-targeting interneuron subtypes that differentially modulate plateau duration. Two-photon Ca2+ imaging further shows that plateau termination converts these binary events into graded dendritic Ca2+ signals. Overall, these results demonstrate that feedback inhibition regulates the duration of plateaus, adding a critical layer of control over dendritic computation.

A social hierarchy is an ordered ranking of individuals that arises through their interactions and governs relative access to resources and social influence. This form of social organization is pervasive across animal species and has a crucial role in shaping survival and reproductive outcomes. Across species, the routes to high status vary widely. As social groups become more complex, the basis of hierarchy shifts from simple residency rules to fighting-based dominance and finally to alliance-based systems. In this Review, we first examine the neuroendocrine and subcortical mechanisms that support status transitions in residency-based hierarchies. We then discuss plasticity within hypothalamic and mesolimbic circuits that underlie fighting-outcome-based social learning, through which fighting-based hierarchies emerge. Finally, we explore alliance-based hierarchies in cognitively complex species, in which individuals attain status through coalition formation, cooperation and reputation. We review evidence that cortical regions encode information about the strengths, emotions, experiences and intentions of other individuals and use this to navigate complex social interactions and attain status. As social hierarchies have shifted from primarily fighting-based to increasingly alliance-based strategies over evolutionary time, neural control of status has, thus, transitioned from subcortical social behaviour circuits to a more elaborated cortical network in humans.

Episignatures are increasingly valuable for variant interpretation in rare neurodevelopmental disorders, especially when optimized to capture the impact of specific variant types and locations across a gene. Here, we generated a next-generation DNA methylation (DNAm) episignature for Kabuki syndrome type 1 (KS1) using the largest cohort studied to date, aiming to clarify the epigenomic and phenotypic effects of diverse KMT2D variant types and positions. Genome-wide DNAm profiles were obtained for 110 individuals with KMT2D variants and 854 controls using microarrays and long-read sequencing (LRS). Differentially methylated loci were enriched in genes involved in embryonic and nervous system development and were leveraged to construct a support-vector machine classifier for detecting pathogenic KMT2D variants. The classifier achieved 97% sensitivity and 100% specificity in validation cohorts and outperformed in silico tools, demonstrating stronger concordance with clinical presentation. Missense variants in the C-terminal region (exon 48) of KMT2D and the N-terminal plant homeodomain (PHD)-type zinc fingers were predominantly classified as pathogenic, highlighting regions enriched for pathogenic variants. Missense variants in the central region (exons 31-39) were more often predicted benign for KS1, consistent with potential association with a different syndrome, highlighting the classifier's specificity for KS1. Test performance was consistent across array and LRS platforms, and classifier scores reflected levels of mosaicism detected by LRS. The KS1 episignature also positively classified pathogenic KDM6A variants associated with KS2. These findings represent a significant advance in the evolution of episignature development, demonstrating diagnostic and interpretive value of a KS1 signature in resolving uncertain or complex cases.

The capacity of hippocampal circuits to transform inputs into downstream outputs is fundamental to navigation and memory, yet the circuit-level mechanisms that enable this flexibility in adapting to experience remain unclear. Here we approach this problem by performing large-scale (up to 1,024 channel) recordings across the hippocampal-retrosplenial cortex (RSC) circuit in behaving mice, enabling simultaneous access to spiking activity in dentate gyrus (DG), CA3, CA2, CA1 and RSC. On the basis of a linear dimensionality-reduction technique known as partial canonical correlation analysis, we identify low-dimensional communication subspaces¹ between two regions while accounting for influences from a third area. These subspaces captured distinct input-output transformations in the CA1 region, linking upstream hippocampal activity (DG, CA3 and CA2) to downstream cortical targets (RSC). Intrinsic firing properties and anatomical location constrained subspace memberships-members were mapped to deep sublayers of the CA3-CA1-RSC axis during both spatial and non-spatial tasks. These subspaces could recombine overlapping neuronal pools to support distinct interareal interactions across changing experiences and brain states. Reactivation patterns of CA1-CA3 subspaces, but not those of CA1-RSC, during post-experience sleep correlated with replay, reflecting a plasticity-stability balance in the input-output transformation along the hippocampal-retrosplenial axis. Our findings suggest a model in which hippocampal-neocortical communication reconfigures predetermined circuit motifs to flexibly encode experiences.

Protease-activated receptor 2 (PAR₂) mediates oral cancer pain. Patients with metastatic (N + ) cancers report greater pain. PAR₂ is activated by N-terminal proteolytic cleavage. Here we show that proteases encoded by genes overexpressed in N+ cancers from patients with pain (matrix metallopeptidase 1, MMP1 and serine protease 23, PRSS23) elicit protease-specific receptor redistribution (trafficking) and signaling that differs from that promoted by proteases encoded by genes not differentially expressed (transmembrane serine protease matriptase, ST14 and cathepsin S, CTSS). Mixtures of the proteases prepared to model the oral cancer microenvironment revealed that ST14-mediated PAR₂ activation predominated at low protease concentrations. At high concentrations, MMP1 and PRSS23 prevailed over the greater potency of ST14. We propose that PAR₂ activation in oral N+ cancers from patients with pain is driven by high levels of MMP1 and PRSS23. Our study informs design of signaling and location-specific antagonists to provide more efficacious analgesia.

Vocalizations are ancient behaviours that require the complex coordination of breath and display. Understanding how laryngeal anatomy shapes vocalization provides insights into this diversity, its mechanisms and their evolution. Rodents are ideal for exploring this variation because of their diverse mechanisms and vocal structures. Here, we describe the laryngeal morphology and sound production mechanisms underlying the vocalizations of Alston's singing mouse (Scotinomys teguina) and compare these results to those of other vocalizing mammals. We reconstructed the three-dimensional laryngeal morphology with micro-computed tomography, recorded laryngeal sound production using high-speed video and investigated frequency control using surgical ablations. We found that singing mice use a whistle mechanism that uniquely relies on the inflation of an enlarged air sac called the ventral pouch. Song frequency can be controlled by pouch volume, airflow and cricothyroid muscle action. Singing mouse laryngeal morphology and vocal mechanism are distinct from those of other Neotomids; singing mice appear to use inflation-mediated whistles for both distant and close exchanges. Inflatable air sacs have evolved repeatedly for sound modulation and filtering. Our results indicate a novel role for these structures in being required to generate sound. Together, our results expand on an emerging story of how biomechanic and morphological variation contributes to vocal diversity.

The relation between the vocal capacities of animals and those of humans is a long-standing topic of interest for scientists, philosophers, and lay people alike. While similar neural and physiological substrates underlie the production of vocal signals in humans and animals, the most celebrated and prototypical aspects of language are cognitive phenomena that go far beyond speech sensorimotor processes. These include a subset of features that have begun to be systematically investigated in nonhuman animals, namely: (i) the presence of statistical laws, (ii) hierarchical syntactic rules, and (iii) the capacity for meaning and reference. Here we review recent progress describing and quantifying language-like structure in animal vocalizations. We highlight agreement and disagreement about the similarities that may exist between human language and animal vocal repertoires, with an eye toward what these phenomena may reveal about the evolution of language and its neural control.

BACKGROUND:Familial dysautonomia (FD) is a hereditary neurodevelopmental disorder caused by aberrant splicing of the ELP1 gene, leading to a tissue-specific reduction in ELP1 protein expression. Preclinical models indicate that increasing ELP1 levels can mitigate disease manifestations. A blood-based ELP-1 protein assay may provide a reliable way to monitor gene target engagement. DESIGN AND METHODS/METHODS:Using a newly developed radioimmunoassay, we quantified ELP1 protein levels in peripheral blood samples collected from 59 homozygous FD patients carrying the IVS20 + 6T>C mutation and 66 heterozygous carriers. To assess the reproducibility of the measurement, replicate samples were collected in 43 participants. Longitudinal variability was evaluated in 22 participants who underwent repeat sampling 1 year later. RESULTS: = 0.827, p < 0.001). An ELP1 threshold of 492 pg/mL yielded a sensitivity of 80.2% (CI of 70.6 to 87.2%) and a specificity of 98.2% (95% CI of 90%-99%) with a positive likelihood ratio of 46.5, indicating that individuals with FD were over 46 times more likely to have ELP1 levels below this threshold compared to non-affected carriers. CONCLUSION/CONCLUSIONS:Blood ELP1 levels are robust and reproducible, with concentrations below 492 pg/mL strongly indicative of disease. Moreover, given their longitudinal stability, ELP1 can serve as a marker of target engagement to evaluate the efficacy of gene-targeted therapies aimed at correcting ELP1 gene splicing and protein production.

The autonomic nervous system (ANS) plays a vital role in health care for both acute care and chronic diseases. The traditional view of the ANS is to divide it into individual organ systems and study the separate components with a reductionist approach, which has been proven insufficient. Here, we argue that a holistic network-level view of the ANS is critical for generating new insights and deepening our understanding of its complex and dynamic functions. In this review, we treat the ANS as such a coordinated and dynamic network. We advocate for studying its interactions with major organ systems and the central nervous system using continuous and longitudinal monitoring in ambulatory and at-home settings rather than clinic-based snapshots. We first briefly review ANS physiology, then outline our network perspective, and finally highlight cutting-edge research directions and emerging engineering innovations in ANS monitoring, modeling, and modulation that benefit from this network-level view.

MR imaging is increasingly used in evaluation of patients with known or suspected hypertrophic cardiomyopathy (HCM), as it provides useful information on cardiac structure, function, and tissue characterization that is complementary to echocardiography. While the adverse effect of left ventricle (LV) outflow tract obstruction on blood flow patterns is well characterized by the midsystolic drop in LV ejection velocities and flow, flow patterns in HCM with mid-LV obstruction, with or without apical aneurysm, are less well characterized. MR imaging can provide additional information on alterations of blood flow patterns in these HCM phenotypes and "paradoxic" flows associated with apical aneurysms.