NEUROSCIENCE
How cannabinoid signaling regulates a recurrent excitatory circuit in the hippocampus
Dentate gyrus of the hippocampus.
The hippocampus contains a recurrent excitatory neural network implicated in pattern separation and epilepsy and formed by reciprocal connections between excitatory mossy cells (MCs) and dentate granule cells (GC). MC axons express high levels of type-1 cannabinoid receptors (CB1Rs) whose activation by exogenous and endogenous cannabinoids (eCBs) suppresses neurotransmitter release. However, the precise role of CB1Rs at MC-GC synapses is unclear. Using rodent hippocampal slices, Kyle Jensen, Coralie Berthoux, et al. found that MC CB1Rs were constitutively active even in the absence of eCB release from GCs, and this tonic activity was likely mediated by βγ subunits. Tonic CB1R activity inhibited MC-GC synaptic transmission, long-term potentiation (LTP), and GC output. In addition, eCBs released from GCs suppressed MC-GC synaptic transmission and dampened MC-GC LTP via two distinct mechanisms downstream of CB1Rs. Transient eCB release during LTP induction inhibited plasticity via βγ signaling, while more sustained eCB-mediated activation of CB1Rs before LTP induction triggered presynaptic metaplasticity that inhibited LTP generation via αi/o signaling. Furthermore, a single in vivo exposure to exogenous cannabinoids inhibited LTP induction by inducing this presynaptic metaplasticity. The authors conclude that CB1R activation can powerfully dampen MC-GC activity by selectively suppressing both MC-GC synaptic transmission and LTP induction, and suggest that cannabinoids may contribute to dentate gyrus-dependent forms of learning while protecting the hippocampus from runaway excitation. — S.R.
PNAS e2017590118 (2021)
APPLIED PHYSICAL SCIENCES
Noninvasive acoustic tweezers and efficiency of drug delivery
Tornado-inspired acoustic vortex tweezer trapping and manipulating microbubbles.
Blood flows with high velocity, making it hard to spatially concentrate and manipulate biotherapeutic agents within the circulatory system. To improve current drug delivery methods, Wei-Chen Lo et al. developed a tornado-inspired acoustic vortex tweezer (AVT) that employs destructive interference to produce net forces for noninvasive intravascular trapping and manipulation of lipid-shelled gaseous microbubbles (MBs). The authors showed that the AVT could be used to successfully trap MBs and increase their local concentration in both static and flow conditions. In addition, the AVT could selectively trap MBs without trapping or damaging red blood cells. The authors found that AVT trapping performance was influenced by several factors, including pressure, duty cycle, the number of transducer elements, and frequency. The authors also demonstrated the in vivo trapping capability of AVTs in mice and found that MB signals within mouse capillaries could be locally improved 1.7-fold, and the location of trapped MBs could be manipulated during the initiation of an AVT. The results demonstrate the effectiveness of AVTs for noninvasive trapping and manipulation of MBs, and the technique could be used to increase local drug concentrations and improve the efficiency of drug delivery. According to the authors, the AVT technique could enable the systemic administration of drugs at very low doses. — S.R.
PNAS e2023188118 (2021)
BIOPHYSICS AND COMPUTATIONAL BIOLOGY
Molecular structure of brain tissue-derived common amyloid-β fibril polymorph
In Alzheimer’s disease (AD), amyloid-β (Aβ) peptides form slender fibers, or fibrils, that aggregate into plaque-like deposits in the brain. A body of evidence suggests that structural variations in Aβ fibrils may correlate to specific clinical and pathological characteristics of the disease. In addition, recent studies suggest that Aβ fibrils grown in vitro for research purposes may differ structurally from those found in human brain tissue. Ujjayini Ghosh et al. used cryogenic electron microscopy, mass-per-length measurements, and solid state nuclear magnetic resonance to detail the molecular structure of a specific 40-residue Aβ fibril polymorph that was previously identified as the most common polymorph in typical AD. The fibril, prepared by seeded fibril growth from cortical tissue of an AD patient, exhibits a number of qualitative differences from all previously reported Aβ fibril structural models, including a fully extended peptide conformation, as opposed to U-shaped, S-shaped, or C-shaped. In addition, the analysis reveals a surprising two-fold screw symmetry about the fibril growth axis, despite a mass-per-length value consistent with three molecules per β-sheet repeat distance. According to the authors, the identification of these unique features may suggest structure-specific strategies for inhibiting Aβ aggregation or provide targets for antibodies in this common AD polymorph. — T.J.
PNAS e2023089118 (2021)
NEUROSCIENCE
How hydrogen sulfide protects against Alzheimer’s disease
Alzheimer’s disease (AD) is the most common cause of aging-related dementia. One potential therapeutic target is the gaseous signaling molecule hydrogen sulfide, which is depleted in patients with AD and protects neurons in rodent models of the disease, but the underlying molecular mechanisms have not been clear. Daniel Giovinazzo et al. provide evidence that hydrogen sulfide inhibits the activity of an enzyme called glycogen synthase kinase 3β (GSK3β), thereby decreasing the magnitude of tau hyperphosphorylation—a major neurotoxic hallmark of AD. The authors report that normal Tau, but not the mutant version of the protein, binds to cystathionine γ-lyase (CSE). This neuronal enzyme synthesizes hydrogen sulfide and signals through sulfhydration of target proteins. The results also reveal that CSE decreases Tau phosphorylation via GSK3β. Both CSE levels and sulfhydration are reduced in a mouse model of AD and in cerebral cortex brain tissue from patients with the disease. Treatment of the mouse model with a compound that releases hydrogen sulfide protects against deficits in locomotor activity and memory. According to the authors, the findings shed light on a potential therapeutic strategy for aging-related dementia, including the most prominent form, AD. — J.W.
PNAS e2017225118 (2021)
EVOLUTION
Bacteria-derived genes and the evolutionary success of diatoms
Horizontal gene transfer (HGT)—the movement of genetic material between organisms—plays an important role in evolution. However, relatively little is known about the exact timing and mechanisms of HGTs in ochrophytes—an ancient, diverse group of algae that dominate photosynthesis in the ocean. Richard Dorrell et al. harnessed an expanded set of ochrophyte sequence libraries and combined computational and experimental techniques to examine HGTs across ochrophytes, including diatoms. The authors used both targeted and holistic approaches: manually verifying all HGTs in the model diatom Phaeodactylum tricornutum, and automatically identifying all likely bacterial HGTs across ochrophytes. The results revealed that continuous HGTs from bacteria have been the main source of recently incorporated genes in P. tricornutum. By contrast, genes transferred from other algae predominated at earlier evolutionary time points. Moreover, the number of genes originating from bacteria likely increased at important points in the evolution of diatoms, after their divergence from other ochrophytes. Bacteria-derived genes are involved in diverse metabolic functions in P. tricornutum and have disproportionately encoded secreted proteins throughout the evolutionary history of ochrophytes. According to the authors, the findings suggest that genes transferred from bacteria may have contributed to the success of diatoms in exploiting diverse ecological niches in modern oceans. — J.W.
PNAS e2009974118 (2021)
SOCIAL SCIENCES
Experiences of underrepresented graduate students in STEM
STEM has diversified in the past five decades, but systemic inequities remain. Using 2013 survey data from the American Chemical Society, Jean Stockard et al. examined graduate school experiences and career plans of 1,375 students pursuing chemistry PhDs at top-ranked US universities. Compared with their colleagues, women—especially those from historically marginalized racial and ethnic groups in chemistry—had fewer positive interactions with advisors. Both men and women in these historically marginalized groups were less likely than their colleagues to have supportive peer relationships or report sufficient financial support for their studies; this difference in adequate funding was slightly smaller but still observable in the most resource-rich departments. Women were less likely than men—especially in the most prestigious departments—to express commitment to graduating, staying in chemistry, and pursuing a research-oriented professorship upon graduation. Despite a lack of peer or financial support, students from historically marginalized groups were more likely than their peers to express commitment to scholastic goals, especially when in departments with at least one faculty member who also identified as being part of an underrepresented group. The findings suggest that graduate school experiences can mirror inequities in other areas of society and potentially work against achieving the goal of diversifying STEM, according to the authors. — M.S.
PNAS e2020508118 (2021)
COMPUTER SCIENCES
Automated framework to detect online disinformation campaigns
Automated framework detects and characterizes influence operation (IO) campaigns.
The rapid, large-scale spread of disinformation on social media platforms is a growing problem, underscoring the immense challenge of identifying and countering hostile influence operations. Steven Smith, Edward Kao, Erika Mackin, Donald Rubin, et al. developed an automated approach to accurately detect and assess the impact of online influence operation campaigns. This approach combines natural language processing, machine learning, graph analytics, and network causal inference. The authors applied their framework to more than 28 million Twitter posts and nearly one million accounts potentially relevant to the 2017 French presidential election. The classifier detected influence operation accounts with 96% precision, outperforming two online bot detectors by 20%. Moreover, network causal inference quantified the impact of accounts in propagating specific narratives by influencing others’ tweets, discovering high-impact accounts that would not be captured by traditional statistical analysis of Twitter activity (e.g., tweet and retweet counts) and network centrality. The identity of several high-impact accounts was corroborated by Twitter’s election integrity dataset and reports from the US Congress and investigative journalists. According to the authors, this approach could be used to warn social media platform providers and the public about disinformation campaigns. — J.W.
PNAS e2011216118 (2021)
NEUROSCIENCE
Friends appear to share patterns of brain activity
Researchers asked whether MRI scans from Korean villagers correlated with social ties. Image credit: Shutterstock/Yeongsik Im.
Posted on January 15, 2021
Amber Dance
Great minds think alike, so goes the saying. Greatness notwithstanding, a study in PNAS finds that the minds of friends do appear to share patterns of activity. “A lot of us have the intuition that our friends are kind of similar to us,” says senior author Carolyn Parkinson, a social neuroscientist at the University of California, Los Angeles. The new work suggests that there’s some neurological basis behind that suspicion. Continue Reading⇒