Faculty Bibliography

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.

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.

OBJECTIVE:To validate the carotid web (CW) risk stratification assessment described in previous works within a larger cohort of patients with symptomatic and incidentally found asymptomatic CWs. METHODS:A retrospective analysis of our institution's electronic medical records identified all patients with a diagnosis of CW from 2017 to 2024. We included symptomatic patients and those with asymptomatic CWs, that is, incidentally found webs without history of stroke or transient ischemic attack. Patient charts were reviewed for demographics, imaging, comorbidities, and a diagnosis of stroke after diagnosis of asymptomatic CW. All angles were measured as described in previous work on a sagittal reconstruction of neck CT angiography in which the common carotid artery (CCA), external carotid artery, and internal carotid artery (ICA) were well visualized, together with the CW itself. Principal component analysis and logistic regression were performed to evaluate the association between high-risk angles and stroke risk.  RESULTS: Twenty-six symptomatic and 26 asymptomatic patients were identified. Of note, the number of patients with hypertension, hyperlipidemia, and smoking history was 17 (65.0%), 16 (62.0%), and 8 (31.0%) for symptomatic patients and 18 (69.0%), 17 (65.0%), and 15 (58.0%) for asymptomatic patients. All angular measurements showed statistically significant associations with stroke status. The CCA-web-pouch angle showed the strongest association (p=2.07×10⁻⁴), followed by the CCA-pouch-tip angle (p=3.23×10⁻⁴), ICA-web-pouch angle (p=0.004), and ICA-pouch-tip angle (p=0.005). Each additional high-risk angle increased the odds of stroke by 9.47-fold (p<0.0001). The associated probability of stroke increased from 6.3% with no high-risk angles to 39.1% with one high-risk angle and further to 85.9% with two high-risk angles. The model demonstrated high sensitivity, correctly identifying 84.6% of positive cases, and high specificity, correctly identifying 88.5% of negative cases. The F1 score was 0.863, indicating good overall model performance.  CONCLUSION: Given this successful stratification of CWs into high- and low-risk groups, the utilization of geometric CW parameters may play a role in improving patient selection for intervention in the setting of incidentally diagnosed CW. .

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.

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.

In a dynamic environment, sensory systems must filter out irrelevant information to construct a stable percept. Animals who rely on smell need to identify and discriminate odors despite fluctuations in concentration, yet odor receptor activation is strongly concentration dependent. Here we explored how odor signals are transformed within the mouse olfactory bulb (OB) by developing an all-optical approach to identify the connectivity between odor receptor channels (glomeruli) and the mitral and tufted cells (MTCs), while monitoring their odor responses. We found that the glomeruli and MTCs activated earliest in a sniff robustly represented odor identity across concentrations, whereas MTCs connected to later activated glomeruli were concentration dependent. Furthermore, probing the responsiveness of MTCs to glomerular input found a short temporal window of excitability at a sniff's onset, followed by prolonged odor-evoked inhibition. Our findings demonstrate, in awake animals, that the OB implements a rapid temporal filter, which is responsible for stabilizing identity across concentrations while decorrelating responses between odors.

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.

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.