Faculty Bibliography

A new study has identified the periaqueductal gray as an important brain region for play and tickle behavior in rats.

UNLABELLED:Interictal spikes (IIS) and seizures are well-documented in Alzheimer's disease (AD). IIS typically outnumber seizures, supporting their role as a prominent EEG biomarker in AD. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) also occur, but it is currently unknown how HFOs compare to IIS. Therefore, we asked whether the incidence of HFOs and IIS differed and if they are differentially affected by behavioral state. We used three mouse lines that simulate aspects of AD: Tg2576, presenilin 2 knockout, and Ts65Dn mice. We recorded and quantified HFOs and IIS in the hippocampus during wakefulness, slow-wave sleep, and rapid eye movement sleep. In all three mouse lines, HFOs were more frequent than IIS. High numbers of HFOs correlated with fewer IIS, suggesting for the first time possible competing dynamics among them in AD. Notably, HFOs occurred in more behavioral states than IIS. In summary, HFOs were the most abundant EEG abnormality when compared to IIS, and occurred in all behavioral states, suggesting they are a better biomarker than IIS. These findings pertained to three mouse lines, which is important because they simulate different aspects of AD. We also show that HFOs may inhibit IIS. SHORT SUMMARY/OBJECTIVE:Interictal spikes (IIS) and seizures are common in Alzheimer's disease (AD). IIS are more frequent than seizures and occur during earlier disease stages. In preclinical models, we showed that high frequency oscillations (HFOs>250Hz) occur, but a comparison between IIS and HFOs is lacking. Here we used 3 mouse lines with AD features and local field potential recordings to quantify IIS and HFOs. We found that HFOs outnumbered IIS and that their total numbers were inversely correlated with IIS. HFOs occurred during more behavioral states than IIS. Therefore, HFOs were the most abundant EEG abnormality, and this was generalizable across 3 types of preclinical AD.

Reciprocal interactions between non-myocytes and cardiomyocytes regulate cardiac growth and differentiation. Here, we report that the transcription factor Ebf1 is highly expressed in non-myocytes and potently regulates heart development. Ebf1-deficient hearts display myocardial hypercellularity and reduced cardiomyocyte size, ventricular conduction system hypoplasia, and conduction system disease. Growth abnormalities in Ebf1 knockout hearts are observed as early as embryonic day 13.5. Transcriptional profiling of Ebf1-deficient embryonic cardiac non-myocytes demonstrates dysregulation of Polycomb repressive complex 2 targets, and ATAC-Seq reveals altered chromatin accessibility near many of these same genes. Gene set enrichment analysis of differentially expressed genes in cardiomyocytes isolated from E13.5 hearts of wild-type and mutant mice reveals significant enrichment of MYC targets and, consistent with this finding, we observe increased abundance of MYC in mutant hearts. EBF1-deficient non-myocytes, but not wild-type non-myocytes, are sufficient to induce excessive accumulation of MYC in co-cultured wild-type cardiomyocytes. Finally, we demonstrate that BMP signaling induces Ebf1 expression in embryonic heart cultures and controls a gene program enriched in EBF1 targets. These data reveal a previously unreported non-cell-autonomous pathway controlling cardiac growth and differentiation.

Gastrointestinal fungal dysbiosis is a hallmark of several diseases marked by systemic immune activation. Whether persistent pathobiont colonization during immune alterations and impaired gut barrier function has a durable impact on host immunity is unknown. We found that elevated levels of Candida albicans immunoglobulin G (IgG) antibodies marked patients with severe COVID-19 (sCOVID-19) who had intestinal Candida overgrowth, mycobiota dysbiosis and systemic neutrophilia. Analysis of hematopoietic stem cell progenitors in sCOVID-19 revealed transcriptional changes in antifungal immunity pathways and reprogramming of granulocyte myeloid progenitors (GMPs) for up to a year. Mice colonized with C. albicans patient isolates experienced increased lung neutrophilia and pulmonary NETosis during severe acute respiratory syndrome coronavirus-2 infection, which were partially resolved with antifungal treatment or by interleukin-6 receptor blockade. sCOVID-19 patients treated with tocilizumab experienced sustained reductions in C. albicans IgG antibodies titers and GMP transcriptional changes. These findings suggest that gut fungal pathobionts may contribute to immune activation during inflammatory diseases, offering potential mycobiota-immune therapeutic strategies for sCOVID-19 with prolonged symptoms.

Popular diets often influence dietary patterns, which have different implications for kidney stone risk. Despite the wide variety of popular diets, some general principles can be gleaned from investigating their potential impact on nephrolithiasis. Plant-based diets, including Dietary Approaches to Stop Hypertension, Mediterranean, flexitarian, and vegetarian diets, may protect against nephrolithiasis when they consist largely of unprocessed plant foods, while carbohydrate-restricted diets (including high-protein diets and the ketogenic diet) may raise kidney stone risk. Patients should be advised to consume a diet rich in whole plants, particularly fruits and vegetables, and minimize their consumption of animal proteins. Accompanying fruits and vegetables that are higher in oxalate content with more water and some dairy intake may also be useful. (We address the oxalate content of fruits and vegetables further below). Calcium consumption is an important component of decreasing the risk of kidney stones, as higher dietary calcium from dairy or nondairy sources is independently associated with lower kidney stone risk. Patients should also be advised to be conscious of fat intake, as fat in the intestinal lumen may complex with calcium and therefore increase urinary oxalate excretion. Finally, patients should avoid consumption of processed foods, which often contain added fructose and high sodium content, two factors that increase kidney stone risk.

Reinhart M, Puil L, Salzwedel DM, et al. First-line diuretics versus other classes of antihypertensive drugs for hypertension. Cochrane Database Syst Rev. 2023;7:CD008161. 37439548.

Kidney stones are rising in incidence and prevalence worldwide. Given the temperature dependence of kidney stone presentations, climate change is projected to further increase the burden of disease for individuals and society. PATIENT SUMMARY: This mini-review reports current knowledge on climate change in relation to kidney stone disease. Kidney stones are more common in patients living in parts of the world that are hotter and more humid. Kidney stone problems are also more common after periods of high heat, which have a greater impact on men than on women. As temperatures rise with climate change, it is likely that the occurrence of kidney stones and the costs associated with their diagnosis and treatment will increase as well.

Excitation-transcription coupling (E-TC) links synaptic and cellular activity to nuclear gene transcription. It is generally accepted that E-TC makes a crucial contribution to learning and memory through its role in underpinning long-lasting synaptic enhancement in late-phase long-term potentiation and has more recently been linked to late-phase long-term depression: both processes require de novo gene transcription, mRNA translation and protein synthesis. E-TC begins with the activation of glutamate-gated N-methyl-D-aspartate-type receptors and voltage-gated L-type Ca²⁺ channels at the membrane and culminates in the activation of transcription factors in the nucleus. These receptors and ion channels mediate E-TC through mechanisms that include long-range signalling from the synapse to the nucleus and local interactions within dendritic spines, among other possibilities. Growing experimental evidence links these E-TC mechanisms to late-phase long-term potentiation and learning and memory. These advances in our understanding of the molecular mechanisms of E-TC mean that future efforts can focus on understanding its mesoscale functions and how it regulates neuronal network activity and behaviour in physiological and pathological conditions.

INTRODUCTION/BACKGROUND:Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies. METHODS:Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration-approved against glaucoma and high-altitude sickness. RESULTS:Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro-clearance pathways, resulting in the reduction of Aβ deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase-VB (CA-VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aβ treatment. Strikingly, CA-VB silencing specifically reduces Aβ-mediated endothelial apoptosis. DISCUSSION/CONCLUSIONS:This work substantiates the potential application of CAIs in clinical trials for AD and CAA.

Down syndrome (DS) is a genetic disorder caused by triplication of human chromosome 21. In addition to intellectual disability, DS is defined by a premature aging phenotype and Alzheimer's disease (AD) neuropathology, including septohippocampal circuit vulnerability and degeneration of basal forebrain cholinergic neurons (BFCNs). The Ts65Dn mouse model recapitulates key aspects of DS/AD pathology, namely age-associated atrophy of BFCNs and cognitive decline in septohippocampal-dependent behavioral tasks. We investigated whether maternal choline supplementation (MCS), a well-tolerated treatment modality, protects vulnerable BFCNs from age- and genotype-associated degeneration in trisomic offspring. We also examined the effect of trisomy, and MCS, on GABAergic basal forebrain parvalbumin neurons (BFPNs), an unexplored neuronal population in this DS model. Unbiased stereological analyses of choline acetyltransferase (ChAT)-immunoreactive BFCNs and parvalbumin-immunoreactive BFPNs were conducted using confocal z-stacks of the medial septal nucleus and the vertical limb of the diagonal band (MSN/VDB) in Ts65Dn mice and disomic (2N) littermates at 3-4 and 10-12 months of age. MCS trisomic offspring displayed significant increases in ChAT-immunoreactive neuron number and density compared to unsupplemented counterparts, as well as increases in the area of the MSN/VDB occupied by ChAT-immunoreactive neuropil. MCS also rescued BFPN number and density in Ts65Dn offspring, a novel rescue of a non-cholinergic cell population. Furthermore, MCS prevented age-associated loss of BFCNs and MSN/VDB regional area in 2N offspring, indicating genotype-independent neuroprotective benefits. These findings demonstrate MCS provides neuroprotection of vulnerable BFCNs and non-cholinergic septohippocampal BFPNs, indicating this modality has translational value as an early life therapy for DS, as well as extending benefits to the aging population at large.