Endocannabinoid protection of the brain vasculature leads to stress resilience
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Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood–brain barrier alterations
Blood–brain barrier (BBB) alterations contribute to stress vulnerability and the development of depressive behaviors. In contrast, neurovascular adaptations underlying stress resilience remain unclear. Here we report that high expression of astrocytic cannabinoid receptor 1 (CB1) in the nucleus accumbens (NAc) shell, particularly in the end-feet ensheathing blood vessels, is associated with resilience during chronic social stress in adult male mice. Viral-mediated overexpression of Cnr1 in astrocytes of the NAc shell results in baseline anxiolytic effects and dampens stress-induced anxiety- and depression-like behaviors in male mice. It promotes the expression of vascular-related genes and reduces astrocyte inflammatory response and morphological changes following an immune challenge with the cytokine interleukin-6, linked to stress susceptibility and mood disorders. Physical exercise and antidepressant treatment increase the expression of astrocytic Cnr1 in the perivascular region in male mice. In human tissue from male donors with major depressive disorder, we observe loss of CNR1 in the NAc astrocytes. Our findings suggest a role for the astrocytic endocannabinoid system in stress responses via modulation of the BBB.
Coastal wetland resilience through local, regional and global conservation
Coastal wetlands, including tidal marshes, mangrove forests and tidal flats, support the livelihoods of millions of people. Understanding the resilience of coastal wetlands to the increasing number and intensity of anthropogenic threats (such as habitat conversion, pollution, fishing and climate change) can inform what conservation actions will be effective. In this Review, we synthesize anthropogenic threats to coastal wetlands and their resilience through the lens of scale. Over decades and centuries, anthropogenic threats have unfolded across local, regional and global scales, reducing both the extent and quality of coastal wetlands. The resilience of existing coastal wetlands is driven by their quality, which is modulated by both physical conditions (such as sediment supply) and ecological conditions (such as species interactions operating from local through to global scales). Protection and restoration efforts, however, are often localized and focus on the extent of coastal wetlands. The future of coastal wetlands will depend on an improved understanding of their resilience, and on society’s actions to enhance both their extent and quality across different scales.
Dopaminergic modulation and dosage effects on brain state dynamics and working memory component processes in Parkinson’s disease
Parkinson’s disease (PD) is primarily diagnosed through its characteristic motor deficits, yet it also encompasses progressive cognitive impairments that profoundly affect quality of life. While dopaminergic medications are routinely prescribed to manage motor symptoms in PD, their influence extends to cognitive functions as well. Here we investigate how dopaminergic medication influences aberrant brain circuit dynamics associated with encoding, maintenance and retrieval working memory (WM) task-phases processes. PD participants, both on and off dopaminergic medication, and healthy controls, performed a Sternberg WM task during fMRI scanning. We employ a Bayesian state-space computational model to delineate brain state dynamics related to different task phases. Importantly, a within-subject design allows us to examine individual differences in the effects of dopaminergic medication on brain circuit dynamics and task performance. We find that dopaminergic medication alters connectivity within prefrontal-basal ganglia-thalamic circuits, with changes correlating with enhanced task performance. Dopaminergic medication also restores engagement of task-phase-specific brain states, enhancing task performance. Critically, we identify an “inverted-U-shaped” relationship between medication dosage, brain state dynamics, and task performance. Our study provides valuable insights into the dynamic neural mechanisms underlying individual differences in dopamine treatment response in PD, paving the way for more personalized therapeutic strategies.
Resting-state fMRI reveals altered functional connectivity associated with resilience and susceptibility to chronic social defeat stress in mouse brain
Chronic stress is a causal antecedent condition for major depressive disorder and associates with altered patterns of neural connectivity. There are nevertheless important individual differences in susceptibility to chronic stress. How functional connectivity (FC) amongst interconnected, depression-related brain regions associates with resilience and susceptibility to chronic stress is largely unknown. We used resting-state functional magnetic resonance imaging (rs-fMRI) to examine FC between established depression-related regions in susceptible (SUS) and resilient (RES) adult mice following chronic social defeat stress (CSDS). Seed-seed FC analysis revealed that the ventral dentate gyrus (vDG) exhibited the greatest number of FC group differences with other stress-related limbic brain regions. SUS mice showed greater FC between the vDG and subcortical regions compared to both control (CON) or RES groups. Whole brain vDG seed-voxel analysis supported seed-seed findings in SUS mice but also indicated significantly decreased FC between the vDG and anterior cingulate area compared to CON mice. Interestingly, RES mice exhibited enhanced FC between the vDG and anterior cingulate area compared to SUS mice. Moreover, RES mice showed greater FC between the infralimbic prefrontal cortex and the nucleus accumbens shell compared to CON mice. These findings indicate unique differences in FC patterns in phenotypically distinct SUS and RES mice that could represent a neurobiological basis for depression, anxiety, and negative-coping behaviors that are associated with exposure to chronic stress.
Systemic HER3 ligand-mimicking nanobioparticles enter the brain and reduce intracranial tumour growth
Crossing the blood–brain barrier (BBB) and reaching intracranial tumours is a clinical challenge for current targeted interventions including antibody-based therapies, contributing to poor patient outcomes. Increased cell surface density of human epidermal growth factor receptor 3 (HER3) is associated with a growing number of metastatic tumour types and is observed on tumour cells that acquire resistance to a growing number of clinical targeted therapies. Here we describe the evaluation of HER3-homing nanobiological particles (nanobioparticles (NBPs)) on such tumours in preclinical models and our discovery that systemic NBPs could be found in the brain even in the absence of such tumours. Our subsequent studies described here show that HER3 is prominently associated with both mouse and human brain endothelium and with extravasation of systemic NBPs in mice and in human-derived BBB chips in contrast to non-targeted agents. In mice, systemically delivered NBPs carrying tumoricidal agents reduced the growth of intracranial triple-negative breast cancer cells, which also express HER3, with improved therapeutic profile compared to current therapies and compared to agents using traditional BBB transport routes. As HER3 associates with a growing number of metastatic tumours, the NBPs described here may offer targeted efficacy especially when such tumours localize to the brain.
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