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.

Bessel beams are commonly used in two-photon microscopy to extend the depth of field and thereby achieve functional volumetric imaging of the living brain. In practice, this approach suffers from background signals and limited lateral resolution due to the Bessel beam's strong side lobes. We introduce and demonstrate a new approach to side lobe suppression based on non-degenerate two-photon excitation, in which dual wavelength illumination produces an imaging point-spread function that is the product of the two coaxial Bessel beams. This technique can reduce the main side lobe intensity of a Bessel beam by 50% or more. We illustrate the approach conceptually with an analytical paraxial model and use detailed physical simulation to show that the approach is effective in the presence of the symmetry-breaking aberrations that amplify side lobes in high NA systems. We experimentally demonstrated the technique using a refractive axicon and the pump and tunable beams of a femtosecond laser. This work establishes non-degenerate two-photon excitation as a practical and broadly applicable strategy for improving point spread-function quality in high-resolution volumetric microscopy.

Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge, in part because tau lacks well-defined druggable sites and accumulates as heterogeneous intracellular aggregates that are difficult to access and clear. Here, we present 1D9-LIRΔTP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance through the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIRΔTP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In neurons derived from patients with frontotemporal dementia (FTD) and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIRΔTP53INP2 promoted autophagy-lysosome-mediated tau degradation. It readily crossed the blood-brain barrier and improved motor function in JNPL3 tauopathy mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.

Maternal aggression enables lactating females to protect their vulnerable young^1,2, yet its rapid emergence after birth and swift decline when pups are absent remain poorly understood. Our study reveals the critical role of the pathway from posterior amygdala cells expressing oestrogen receptor alpha (PA^Esr1) to the ventrolateral part of ventromedial hypothalamus cells expressing neuropeptide Y receptor 2 (VMHvl^Npy2r) in the rise and fall of maternal aggression. Projection-specific manipulations and recordings show that PA^Esr1 cells projecting to the VMHvl are naturally active during attack and are required for maternal aggression. During lactation, PA-to-VMHvl^Npy2r synapses potentiate and VMHvl^Npy2r cell excitability increases, enabling heightened aggression. PA^Esr1 neurons express abundant oxytocin receptors, allowing oxytocin to boost PA output; after pup removal, declining oxytocin levels reduce PA drive and dampen maternal aggression, a deficit restored by pup reunion or optogenetic elevation of oxytocin. These findings reveal multiple forms of plasticity in a defined PA^Esr1-VMHvl^Npy2r circuit that collectively implement the adaptive, need-based control of maternal aggression.

We report a 71-year-old woman who developed disabling orthostatic tremor and severe orthostatic hypertension following cosmetic neck lift surgery. Autonomic testing demonstrated exaggerated pressor responses and excessive orthostatic catecholamine release, consistent with sympathoadrenal overactivation due to impaired carotid baroreflex function. This case highlights a potential autonomic complication of aesthetic neck surgery.

Intercompartmental water exchange in brain and other biological tissue can be probed in vivo with diffusion MRI (dMRI). We assess the accuracy of a recently proposed method for estimating a mean exchange rate by performing Monte Carlo simulations of random walkers through a packing of permeable, randomly placed, parallel cylinders to model water exchange within axonal fiber bundles. The diffusivity and kurtosis of the full system are calculated for a broad range of diffusion times and model parameters. The mean exchange rate is estimated from the logarithmic derivative of the kurtosis with respect to the diffusion time and compared with the exchange rate predicted by the Kärger model (KM), which is exact in certain limits. The mean exchange rate is also compared with the reciprocal exchange time obtained by conventional fitting of the kurtosis time dependence to a two-compartment KM, with a high correlation being found between the two quantities. The estimates from the logarithmic derivative are in good agreement with the KM predictions when the exchange time is long in comparison to the compartment traversal times, which corresponds to barrier-limited exchange. Compared to the standard procedure of fitting the kurtosis to the KM over a broad range of diffusion times, using the logarithmic derivative reduces the data acquisition burden by only requiring a narrow range of times and increases generality in that number of compartments need not be specified. This method may be useful for estimating the mean exchange rate from the kurtosis time dependence measured with dMRI.

INTRODUCTION/BACKGROUND:Affiliate stigma may cause depressive symptoms among Asian American dementia caregivers, yet few studies have examined the underlying mechanisms or cross-ethnic differences. METHODS:We analyzed data from 338 older dementia caregivers (176 Chinese Americans, 162 Korean Americans; mean age 68.8 years) who completed measures of affiliate stigma, social isolation, loneliness, and depressive symptoms. RESULTS:for interaction < 0.01). DISCUSSION/CONCLUSIONS:These findings identify affiliate stigma as an important risk factor for dementia caregivers' depressive symptoms, operating through both objective and emotional forms of social disconnection. Culturally sensitive efforts to reduce caregivers' stigma and social disconnection may improve mental health outcomes in Asian American communities.

As vertebrates transitioned from water to land, locomotion shifted from undulatory swimming to limb-based movement. How spinal circuits and their cell types evolved to support this transition remains unclear. We leverage frog metamorphosis, which recapitulates this transition within a single organism, to define how spinal circuits generate aquatic versus terrestrial motor patterns. At swim stages, spinal architecture is uniform, with a transcriptionally and anatomically homogeneous motor and interneurons. As limbs develop and their movement complexifies, spinal circuits expand in neuron number and subtype diversity. This expansion is most pronounced for V1 inhibitory neurons, which increase ∼70-fold and diversify into transcriptionally distinct subtypes. Disrupting transcription factors defining emerging motor and V1 populations reveals molecular segregation between swim and limb circuits, highlighting the role of subtype diversity in motor coordination. A multifold increase in inhibitory neuron diversity thus underlies the tail-to-limb locomotor transition, providing a framework for spinal circuit adaptation during vertebrate evolution.

Individuals with Down syndrome (DS) are at risk for early-onset Alzheimer's disease (AD), marked by neurodegeneration in hippocampal and basal forebrain circuits. Early-life interventions offer therapeutic potential, including maternal choline supplementation (MCS). MCS improves cognitive outcomes and neuroplasticity in rodent models of neurodevelopmental and neurodegenerative disorders, yet cell-type specific molecular effects remain unknown. We investigated the effect of MCS upon the onset of septohippocampal degeneration at 6 months of age in the Ts65Dn mouse model of DS/AD. Using laser capture microdissection and single population RNA-sequencing, transcriptomic changes were profiled within hippocampal CA1 and CA3 pyramidal neurons and dentate gyrus granule cells comparing trisomic and disomic offspring. Bioinformatic analysis revealed MCS-mediated downregulation of apoptotic pathways and upregulation of cognition-related functions across all populations, alongside cell-specific responses. These findings highlight MCS as a promising strategy for modulating disease-relevant pathways in a hippocampal cell-type-specific manner during early neurodegeneration in DS/AD.

UNLABELLED:= 123), we found that people’s willingness to exert effort is positively associated with outcome expected value under both risk and ambiguity. Additionally, people exert more effort when outcome distribution uncertainty increases in risky situations, but are insensitive to ambiguity, except when facing extreme ambiguity. Our results demonstrate an unexpected dissociation. Humans will engage in effort-based information-seeking, even for non-instrumental information, when facing risk. In contrast, they show a much lower willingness to expend effort to resolve non-instrumental ambiguity. SUPPLEMENTARY INFORMATION:The online version contains supplementary material available at 10.1038/s41598-026-43803-2.