Faculty Bibliography

Alzheimer's disease (AD) arises from complex multilevel interactions between genetic, epigenetic, and environmental factors. Recent studies suggest that exposure to the environmental and occupational toxicant formaldehyde (FA) may play a significant role in AD development. However, the effects of FA exposure on Aβ and tau pathologies in human neural cell 3D culture systems remain unexplored. To investigate FA's role in AD initiation, we differentiated 3D-cultured immortalized human neural progenitor ReN cells (ReNcell VM) into neurons and glial cells, followed by FA treatment. FA exposure for 12 weeks resulted in a dose-dependent increase in Aβ40, Aβ42, and phosphorylated tau levels. To further examine FA's role in AD progression, we established a 3D human neural cell culture AD model by transfecting ReN cells with AD-related mutant genes, including mutant APP and PSEN1, which recapitulate key AD pathological events. Our findings demonstrate that FA exposure significantly elevated Aβ40, Aβ42, and phosphorylated tau levels in this 3D-cultured AD model. These results suggest that FA exposure contributes to the initiation and progression of AD pathology in 3D-cultured human neural cells.

INTRODUCTION/BACKGROUND:Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer's disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes. METHODS:We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo magnetic resonance imaging, to investigate early capillary dysfunction in C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax (Tg-SwDI) mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances. RESULTS:Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and amyloid beta (Aβ) load in 9- to 10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load. DISCUSSION/CONCLUSIONS:These findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD. HIGHLIGHTS/CONCLUSIONS:Uncovered early capillary dysfunction in a presymptomatic Alzheimer's disease (AD) mouse model. Evidence linking capillary stalls and capillary dysfunction with oxygen delivery issues in AD. Novel use of carbonic anhydrase inhibitors to prevent early capillary flow disturbances in AD.

Numerous studies support the role of dopamine in modulating aggression^1,2, but the exact neural mechanisms remain elusive. Here we show that dopaminergic cells in the ventral tegmental area (VTA) can bidirectionally modulate aggression in male mice in an experience-dependent manner. Although VTA dopaminergic cells strongly influence aggression in novice aggressors, they become ineffective in expert aggressors. Furthermore, eliminating dopamine synthesis in the VTA prevents the emergence of aggression in naive mice but leaves aggression intact in expert aggressors. VTA dopamine modulates aggression through the dorsal lateral septum (dLS), a region known for aggression control. Dopamine enables the flow of information from the hippocampus to the dLS by weakening local inhibition in novice aggressors. In expert aggressors, dLS local inhibition naturally weakens, and the ability of dopamine to modulate dLS cells diminishes. Overall, these results reveal a sophisticated role of dopamine in the rise of aggression in adult male mice.

The relative ease of generation and proliferation of omics datasets has moved considerably faster than the effective dissemination of these data to the scientific community. Despite advancements in making raw data publicly available, many researchers struggle with data analysis and integration. We propose sharing analyzed data through user-friendly platforms to enhance accessibility. Here, we present a free, online tool, for sharing basic omics data in a searchable and user-friendly format. Importantly, it requires no coding or prior computational knowledge to build-only a data spreadsheet. Overall, this tool facilitates the exploration of transcriptomic, proteomic, and metabolomics data, which is crucial for understanding glial diversity and function. This initiative underscores the importance of accessible molecular data in advancing neuroscience research.

Brain excitability is dysfunctional in epilepsy and overlapping neuropsychiatric conditions including autism spectrum disorder (ASD). Epilepsy and ASD are often attributed to malfunctioning coordination between synaptic excitation and inhibition. Dravet syndrome (DS) is a severe form of epilepsy arising from haploinsufficiency of the SCN1A gene that encodes the voltage-gated sodium channel Nav1.1. A DS mouse model (Scn1a^+/-) recapitulated essential features of DS and revealed that sodium current density was profoundly reduced in GABAergic inhibitory interneurons while pyramidal cells were spared, suggesting that DS is an "interneuronopathy." Further studies from the Catterall group and others have expanded this picture: DS symptoms, which include recurrent seizures, ataxia, cognitive impairment, ASD, and premature death, could be assigned in part to brain region-specific effects; the Nav1.1 mutations cause dysfunction in some subtypes of interneurons, not others, and are temporally restricted; DS-causing sodium channel mutations were found throughout SCN1A as well as in SCN1B, encoding the β1 subunit. Interest in therapeutic approaches was sparked by preclinical studies of cannabidiol (CBD) that led to the 2018 US Food and Drug Administration approval for treatment of seizures in patients with DS. Independent evidence showed that CBD antagonized GPR55, a G protein-coupled receptor activated by the lipid signaling molecule lysophosphatidylinositol (LPI). We summarized evidence from our group and others that CBD has a dual mechanism of action, targeting both ion channels and GPR55. CBD quells an epileptogenic vicious cycle: seizures strengthen LPI-GPR55 signaling while LPI-GPR55 signaling elevates the synaptic excitatory-inhibitory ratio, thereby promoting further seizures. SIGNIFICANCE STATEMENT: Modern medicine relies on ion channels and G protein-coupled receptors (GPCRs) as key targets. In studies of Dravet syndrome, a devastating genetic disorder with features of epilepsy and autism, William Catterall connected NaV1.1 mutations to deficient excitability of inhibitory neurons. He and his colleagues explored preclinical interventions using cannabidiol (CBD) and clobazam, opening the way to a current understanding of CBD's therapeutic mechanism. CBD affects both ion channels and GPR55, a GPCR activated by lysophosphatidylinositol, an activity-dependent lipid messenger, readjusting the synaptic excitatory-inhibitory ratio.

Identifying directed spectral information flow between multivariate time series is important for many applications in finance, climate, geophysics and neuroscience. Spectral Granger causality (SGC) is a prediction-based measure characterizing directed information flow at specific oscillatory frequencies. However, traditional vector autoregressive (VAR) approaches are insufficient to assess SGC when time series have mixed frequencies (MF) or are coupled by nonlinearity. Here we propose a time-frequency canonical correlation analysis approach ("MF-TFCCA") to assess the strength and driving frequency of spectral information flow. We validate the approach with extensive computer simulations on MF time series under various interaction conditions and further assess statistical significance of the estimate with surrogate data. In various benchmark comparisons, MF-TFCCA consistently outperforms the traditional parametric MF-VAR model in both computational efficiency and detection accuracy, and recovers the dominant driving frequencies. We further apply MF-TFCCA to real-life finance, climate and neuroscience data. Our analysis framework provides an exploratory and computationally efficient nonparametric approach to quantify directed information flow between MF time series in the presence of complex and nonlinear interactions.

Cortical GABAergic interneurons (INs) are comprised of distinct types that provide tailored inhibition to pyramidal cells (PCs) and other INs, thereby enabling precise control of cortical circuit activity. INs expressing the neuropeptide vasoactive-intestinal peptide (VIP) have attracted attention recently following the discovery that they predominantly function by inhibiting dendritic-targeting somatostatin (SST) expressing INs, thereby disinhibiting PCs. This VIP-SST disinhibitory circuit motif is observed throughout the neocortex from mice to humans, and serves as a key mechanism for top-down (feedback) and context-dependent information processing. Thus, VIP IN-mediated disinhibition has been found to play an important role in sensory processing, control of executive functions, attention, sensorimotor integration and other cortico-cortical and thalamocortical feedback interactions. Furthermore, VIP INs have been implicated in mediating the effects of reinforcement signals, both reward and aversive, via their responsiveness to neuromodulators such as acetylcholine (ACh), and in facilitating synaptic plasticity and learning. While it is evident from transcriptomic analyses that VIP INs are a molecularly heterogeneous group, the physiological significance of this diversity is unclear at present. Here, we have characterized the functional diversity of VIP INs in the primary somatosensory cortex by leveraging intersectional genetic approaches to study distinct VIP IN subtypes. We found that VIP INs can be divided into four different populations: a group that expresses the Ca²⁺-binding protein calretinin (CR), two distinct groups that express the neuropeptide cholecystokinin (CCK), and a group that does not express either CR or CCK (non-CCK non-CR; or nCCK nCR). VIP neurons in each group exhibit different laminar distributions, axonal and dendritic arbors, intrinsic electrophysiological properties, and efferent connectivity, VIP/CR INs target almost exclusively SST INs, VIP/nCCK nCR INs also mainly target SST INs but also have connections to parvalbumin (PV) expressing INs. These two groups have essentially no connectivity to pyramidal cells (PCs). On the other hand, the two types of VIP/CCK INs target PCs, but differ in the degree to which synaptic release from each type is modulated by endocannabinoids. We also found that long-range inputs differentially recruit distinct VIP IN groups. Intriguingly, we find that distinct VIP IN populations target distinct SST INs subtypes in turn, indicating the presence of specialized VIP-SST disinhibitory subcircuits. Activation of distinct VIP IN subpopulations in vivo results in differential effects on the cortical network, thus providing evidence for modularity in VIP IN-mediated actions during cortical information processing.

Preclinical diffusion MRI (dMRI) has proven value in methods development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages that facilitate high spatial resolution and high SNR images, cutting-edge diffusion contrasts, and direct comparison with histological data as a methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with many decisions that not only differ dramatically from in vivo imaging of small animals, but ultimately affect what questions can be answered using the data. This work concludes a three-part series of recommendations and considerations for preclinical dMRI. Herein, we describe best practices for dMRI of ex vivo tissue, with a focus on image pre-processing, data processing, and comparisons with microscopy. In each section, we attempt to provide guidelines and recommendations but also highlight areas for which no guidelines exist (and why), and where future work should lie. We end by providing guidelines on code sharing and data sharing and point toward open-source software and databases specific to small animal and ex vivo imaging.