Jared VanderZwaag

Anxiety disorders are associated with dysfunction of amygdala circuits and altered mitochondrial homeostasis. Resveratrol (RSV), a naturally occurring polyphenol with antioxidant properties, produces anxiolytic-like effects in preclinical models. However, most studies have examined trans -RSV, whereas the neurobehavioural effects of its cis isomer remain poorly characterized. RSV can activate mechanistic/mammalian target of rapamycin complex 1 (mTORC1), which regulates cap-dependent mRNA translation through eukaryotic initiation factor 4E-binding proteins (4E-BPs), but it is unknown whether this pathway mediates its behavioural effects. Here, we investigated the behavioural and structural effects of chronic cis -RSV treatment in wild-type mice and mice lacking 4E-BP1 and 4E-BP2, Eif4ebp1 and Eif4ebp2 double-knockout mice ( Eif4ebp1/2 ^−/− ). Anxiety-like and stress-coping behaviours were assessed using the open-field test, elevated plus maze, light–dark box, and forced swim test. We evaluated fear learning and extinction using auditory fear-conditioning and extinction paradigms and examined basolateral amygdala (BLA) ultrastructure by focused ion beam-scanning electron microscopy. In males, cis -RSV reduced anxiety-like behaviour and enhanced fear-extinction retention in wild-type mice, but not in Eif4ebp1/2 ^−/− mice, indicating that these effects require 4E-BP-regulated mRNA translation. In females, cis -RSV produced no anxiolytic-like effects and modestly increased anxiety-like behaviour in some measures. Cis -RSV did not affect forced swim behaviour in either sex. In males, cis -RSV reduced BLA dendritic spine density independently of genotype but produced only modest changes in mitochondrial ultrastructure. Together, these findings identify sex-dependent effects of cis -RSV on anxiety-like behaviour and fear extinction and demonstrate that its behavioural, but not synaptic structural, effects require 4E-BP-regulated mRNA translation.

Background: Exposure to environmental agents, including viral infections, may increase Parkinson's disease (PD) susceptibility, especially in males, but the neurodegenerative risk extent of COVID‐19 remains uncertain. Objectives: We investigated the plausible link between severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and PD susceptibility across sexes. Methods: Mice overexpressing the human angiotensin‐converting enzyme 2 receptor (K18‐hACE2) were exposed to SARS‐CoV‐2 or 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) doses. This was followed by a two‐hit experiment in which mice received a moderate MPTP dose and SARS‐CoV‐2 11 days post‐MPTP. Striatal viral titer was measured 4 days postinfection (dpi). After 14 dpi, striatal dopamine and its metabolites (3,4‐dihydroxyphenylacetic acid, 3‐methoxytyramine, homovanillic acid), nigrostriatal degeneration, and glial responses in males and females were compared. Results: Only in males, SARS‐CoV‐2 resulted in progressive dopamine metabolic dysregulation by day 21. Coexposed females showed less weight loss than males. Coexposed males showed significant nigrostriatal degeneration, together with robust nigral astrocytic and microglial reactivity exceeding individual effects. In females, MPTP and/or SARS‐CoV‐2 had minimal effects on dopamine and its metabolism, degeneration, and microglial reactivity, whereas coexposure was associated with significant nigral astrocytic reactivity. In coexposed males, striatal microglia showed enhanced territorial spacing, whereas in females, they became more clustered, possibly because of an enrichment of cells with larger soma and retracted processes. In males, single or dual exposure stressed degenerating dopamine neurons to shrink and dilate their Golgi bodies, more prominently in the coexposed group. Conclusions: This study reports the sex‐dependent COVID‐19 effects on mice prodromal PD with a differential glial contribution, supporting glial‐ and sex‐based medical approaches. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Lipids are essential for neuron development and physiology^1,2,3. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear⁴. Here we show the presence and functional significance of neuronal lipid droplets (nLDs) in vivo using invertebrate and vertebrate models. We validate⁵ the presence of nLDs in vivo and demonstrate that triglyceride metabolism enzymes and LD-associated proteins control nLD formation through both canonical and recently discovered pathways⁶. Modulation of nLDs has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically in neurons that couple environmental cues with energy homeostasis. Mechanistically, nLD-derived lipids support neuron function by providing fatty acids and phospholipids to sustain mitochondrial and endoplasmic reticulum function and homeostasis. This identifies a conserved role for nLDs in coordinating lipid supply and demand in neurons, which has implications for maintenance of neuronal lipid homeostasis and function in health and disease.

While cannabis use during pregnancy is often perceived as harmless, little is known about its consequences on offspring neurodevelopment. There is an urgent need to map the effects of prenatal cannabis exposure on the brain through the course of the lifespan. We used magnetic resonance imaging spanning nine timepoints, behavioral assays, and electron microscopy to build a trajectory from gestation to adulthood in mice exposed prenatally to delta-9-tetrahydrocannabinol (THC). Our results demonstrate a spatio-temporal patterning, with ventriculomegaly in THC-exposed embryos followed by a deceleration of brain growth in neonates that is sustained until adulthood, especially in females. We observed consistently impacted regions in both the cortex and subcortex, aligned with sex-dependent changes to social behavior in neonates and increased anxiety-like behavior in adolescents. Our results suggest prenatal THC exposure has a sustained sex-dependent impact on neurodevelopment that may persist into early adulthood.

Alzheimer's disease (AD) involves cognitive decline, possibly via multiple concurrent pathologies associated with iron accumulation. To investigate if iron accumulation in AD is more likely due to pathological iron‐rich compartments, or a compensatory response of iron within oligodendrocytes to disease progression, we sought to quantify iron‐rich staining (via Perl's diaminobenzidine; DAB). Healthy wild‐type (WT) and APP^Swe‐PS1Δe9 (APP‐PS1; amyloid‐beta overexpressing) male mice were examined during middle age, at 14 months. The frontal cortex, a brain region affected over the course of dementia progression, was investigated. Iron‐rich compartments were found across genotypes, including oligodendrocytes and immune cells at the blood–brain barrier, and exclusively amyloid plaques in the APP‐PS1 genotype. A semi‐automated approach was employed to quantify the staining intensity of iron‐rich compartments with light microscopy. Mouse frontal cortex of each genotype was also assessed qualitatively and ultrastructurally with scanning electron microscopy, to novelly discern and confirm iron‐rich staining (via Perl's DAB). We found parenchymal iron staining corresponding to oligodendrocytes, pericytes, astrocytes, microglia and/or infiltrating macrophages, and amyloid plaques; increased iron deposition and clustering were detected in middle‐aged male APP‐PS1 versus WT frontal cortex, supporting that AD pathology may involve greater brain iron levels and local clustering. Unexpectedly, iron‐rich cells were enriched at the central nervous system (CNS) interface and perivascular space in control and APP‐PS1 mouse models, with ultrastructural examination revealing examples of these cells loaded with many secretory granules containing iron. Together, our results provide novel exploration and confirmation of iron‐rich cells/compartments in scanning electron microscopy and reinforce literature that iron deposition is relatively increased in AD over healthy cognitive aging and involves greater local clusters of iron burden. Increased iron burden along the aging trajectory, regardless of cognitive status, may also be attributed to novelly discovered iron‐rich cells secreting granules along the CNS border. image

Psychological stress is the major risk factor for major depressive disorder. Sustained stress causes changes in behaviour, brain connectivity and in its cells and organelles. Resilience to stress is understood as the ability to recover from stress in a positive way or the resistance to the negative effects of psychological stress. Microglia, the resident immune cells of the brain, are known players of stress susceptibility, but less is known about their role in stress resilience and the cellular changes involved. Ultrastructural analysis has been a useful tool in the study of microglia and their function across contexts of health and disease. Despite increased access to electron microscopy, the interpretation of electron micrographs remains much less accessible. In this review, we will first present microglia and the concepts of psychological stress susceptibility and resilience. Afterwards, we will describe ultrastructural analysis, notably of microglia, as a readout to study the mechanisms underlying psychological stress resilience. Lastly, we will cover nutritional ketosis as a therapeutic intervention that was shown to be effective in promoting psychological stress resilience as well as modifying microglial function and ultrastructure.

Alzheimer’s disease (AD) involves cognitive decline, possibly via multiple concurrent pathologies associated with iron accumulation. To investigate if iron accumulation in AD is more likely due to pathological iron-rich compartments, or a compensatory response of iron within oligodendrocytes to disease progression, we sought to quantify iron-rich staining (via Perl’s diaminobenzidine; DAB). Healthy wild-type (WT) and APP^Swe-PS1Δe9 (APP-PS1; amyloid-beta overexpressing) male mice were examined during midde-age, at 14 months. The prefrontal cortex, a brain region affected over the course of dementia progression, was investigated. Iron-rich compartments were found across genotypes, including oligodendrocytes, and immune cells at the blood-brain barrier, and exclusively amyloid plaques in the APP-PS1 genotype. A semi-automated approach was employed to quantify staining intensity of iron-rich compartments with light microscopy. Mouse prefrontal cortex of each genotype was also assessed qualitatively and ultrastructurally with scanning electron microscopy, to novelly discern and confirm iron-rich staining (via Perl’s DAB). We found parenchymal iron staining corresponding to oligodendrocytes, pericytes, astrocytes, microglia and/or infiltrating macrophages, and amyloid plaques; increased iron deposition and clustering were detected in middle-aged male APP-PS1 vs WT prefrontal cortex, supporting that AD pathology may involve greater brain iron levels and local clustering. Unexpectedly, iron-rich cells were enriched at the central nervous system (CNS) interface and perivascular space in control and APP-PS1 mouse models, with ultrastructural examination revealing examples of these cells loaded with many secretory granules containing iron. Together, our results provide novel exploration and confirmation of iron-rich cells/compartments in scanning electron microscopy and reinforce literature that iron deposition is relatively increased in AD over healthy cognitive aging and involves greater local clusters of iron burden. Increased iron burden along the aging trajectory, regardless of cognitive status, may also be attributed to novelly-discovered iron-rich cells secreting granules along the CNS border.

Microglia, the central nervous system resident immune cells, are now recognized to critically impact homeostasis maintenance and contribute to the outcomes of various pathological conditions including Parkinson’s disease (PD). Microglia are heterogenous, with a variety of states recently identified in aging and neurodegenerative disease models, including the ‘disease-associated microglia’ (DAM) which present a selective enrichment of CLEC7A encoding the CLEC7A or DECTIN1 protein, and the ‘dark microglia’ (DM) displaying markers of cellular stress at the ultrastructural level. However, the roles of CLEC7A-positive microglia and DM in the pathology of PD have remained largely elusive. By applying immunofluorescence and scanning electron microscopy, we aimed to characterize 1) the CLEC7A -positive cell population, and 2) their possible relationships to DM in a mouse model harboring a G2019S pathogenic mutation of the LRRK2 gene, the most common mutation linked to PD. We examined 18-month-old mice, comparing between LRRK2 G2019S knock-in mice and wild-type controls. In the dorsal striatum, a region affected by PD pathology, extensive ultrastructural features of cellular stress (e.g., endoplasmic reticulum and Golgi apparatus dilation), as well as reduced direct cellular contacts, were observed for microglia from LRRK2 G2019S mice versus controls. CLEC7A-positive microglia exhibited extensive phagocytic ultrastructural characteristics in the LRRK2 G2019S mice. Additionally, the LRRK2 G2019S mice presented a higher proportion of DM. Lastly, immunofluorescence and biochemical analysis revealed higher number of CLEC7A-positive cells in Lrrk2 G2019S genotype versus controls both in tissues and in primary microglia cells. Of note, CLEC7A-positive cells present a selective enrichment of ameboid morphology and tend to cluster in the pathogenic animal. In summary, we provide novel insights into the involvement of recently-defined microglial states, CLEC7A-positive cells and DM, in the context of LRRK2 G2019S PD pathology.