One of the first signs of viral infection is body-wide aches and pain. Although this type of pain usually subsides, at the extreme, viral infections can induce painful neuropathies that can last for decades. Neither of these types of pain sensitization is well understood. A key part of the response to viral infection is production of interferons (IFNs), which then activate their specific receptors (IFNRs) resulting in downstream activation of cellular signaling and a variety of physiological responses. We sought to understand how type I IFNs (IFN-α and IFN-β) might act directly on nociceptors in the dorsal root ganglion (DRG) to cause pain sensitization. We demonstrate that type I IFNRs are expressed in small/medium DRG neurons and that their activation produces neuronal hyper-excitability and mechanical pain in mice. Type I IFNs stimulate JAK/STAT signaling in DRG neurons but this does not apparently result in PKR-eIF2α activation that normally induces an anti-viral response by limiting mRNA translation. Rather, type I IFNs stimulate MNK-mediated eIF4E phosphorylation in DRG neurons to promote pain hypersensitivity. Endogenous release of type I IFNs with the double-stranded RNA mimetic poly(I:C) likewise produces pain hypersensitivity that is blunted in mice lacking MNK-eIF4E signaling. Our findings reveal mechanisms through which type I IFNs cause nociceptor sensitization with implications for understanding how viral infections promote pain and can lead to neuropathies.

SIGNIFICANCE STATEMENT It is increasingly understood that pathogens interact with nociceptors to alert organisms to infection as well as to mount early host defenses. Although specific mechanisms have been discovered for diverse bacterial and fungal pathogens, mechanisms engaged by viruses have remained elusive. Here we show that type I interferons, one of the first mediators produced by viral infection, act directly on nociceptors to produce pain sensitization. Type I interferons act via a specific signaling pathway (MNK-eIF4E signaling), which is known to produce nociceptor sensitization in inflammatory and neuropathic pain conditions. Our work reveals a mechanism through which viral infections cause heightened pain sensitivity

Hydrocephalus is a pathologic condition associated with various brain diseases, including Alzheimer's disease (AD). Dysfunctional ependymal cells (EpCs) are believed to contribute to the development of hydrocephalus. It is thus of interest to investigate EpCs' development and function. Here, we report that vacuolar protein sorting-associated protein 35 (VPS35) is critical for EpC differentiation, ciliogenesis, and survival, and thus preventing neonatal hydrocephalus. VPS35 is abundantly expressed in EpCs. Mice with conditional knock-out (cKO) of Vps35 in embryonic (Vps35^GFAP-Cre and Vps35^Emx1-Cre) or postnatal (Vps35^Foxj1-CreER) EpC progenitors exhibit enlarged lateral ventricles (LVs) and hydrocephalus-like pathology. Further studies reveal marked reductions in EpCs and their cilia in both Vps35^GFAP-Cre and Vps35^Foxj1-CreER mutant mice. The reduced EpCs appear to be due to impairments in EpC differentiation and survival. Additionally, both Vps35^GFAP-Cre and Vps35^Foxj1-CreER neonatal pups exhibit increased cell proliferation and death largely in a region close to LV-EpCs. Many microglia close to the mutant LV-EpC region become activated. Depletion of the microglia by PLX3397, an antagonist of colony-stimulating factor 1 receptor (CSF1R), restores LV-EpCs and diminishes the pathology of neonatal hydrocephalus in Vps35^Foxj1-CreER mice. Taken together, these observations suggest unrecognized functions of Vps35 in EpC differentiation, ciliogenesis, and survival in neonatal LV, and reveal pathologic roles of locally activated microglia in EpC homeostasis and hydrocephalus development.

SIGNIFICANCE STATEMENT This study reports critical functions of vacuolar protein sorting-associated protein 35 (VPS35) not only in promoting ependymal cell (EpC) differentiation, ciliogenesis, and survival, but also in preventing local microglial activation. The dysfunctional EpCs and activated microglia are likely to induce hydrocephalus.

Neonatal stroke is as frequent as stroke in the elderly, but many pathophysiological injury aspects are distinct in neonates, including immune signaling. While myeloid cells can traffic into the brain via multiple routes, the choroid plexus (CP) has been identified as a uniquely educated gate for immune cell traffic during health and disease. To understand the mechanisms of myeloid cell trafficking via the CP and their influence on neonatal stroke, we characterized the phenotypes of CP-infiltrating myeloid cells after transient middle cerebral artery occlusion (tMCAO) in neonatal mice of both sexes in relation to blood-brain barrier permeability, injury, microglial activation, and CX3CR1-CCR2 signaling, focusing on the dynamics early after reperfusion. We demonstrate rapid recruitment of multiple myeloid phenotypes in the CP ipsilateral to the injury, including inflammatory CD45⁺CD11b⁺Ly6c^highCD86⁺, beneficial CD45⁺CD11b⁺Ly6c^lowCD206⁺, and CD45⁺CD11b⁺Ly6c^lowLy6g^high cells, but only minor leukocyte infiltration into acutely ischemic-reperfused cortex and negligible vascular albumin leakage. We report that CX3CR1-CCR2-mediated myeloid cell recruitment contributes to stroke injury. Considering the complexity of inflammatory cascades triggered by stroke and a role for TLR2 in injury, we also used direct TLR2 stimulation as an independent injury model. TLR2 agonist rapidly recruited myeloid cells to the CP, increased leukocytosis in the CSF and blood, but infiltration into the cortex remained low over time. While the magnitude and the phenotypes of myeloid cells diverged between tMCAO and TLR2 stimulation, in both models, disruption of CX3CR1-CCR2 signaling attenuated both monocyte and neutrophil trafficking to the CP and cortex.

SIGNIFICANCE STATEMENT Stroke during the neonatal period leads to long-term disabilities. The mechanisms of ischemic injury and inflammatory response differ greatly between the immature and adult brain. We examined leukocyte trafficking via the choroid plexus (CP) following neonatal stroke in relation to blood-brain barrier integrity, injury, microglial activation, and signaling via CX3CR1 and CCR2 receptors, or following direct TLR2 stimulation. Ischemia-reperfusion triggered marked unilateral CX3CR1-CCR2 dependent accumulation of diverse leukocyte subpopulations in the CP without inducing extravascular albumin leakage or major leukocyte infiltration into the brain. Disrupted CX3CR1-CCR2 signaling was neuroprotective in part by attenuating monocyte and neutrophil trafficking. Understanding the migratory patterns of CP-infiltrating myeloid cells with intact and disrupted CX3CR1-CCR2 signaling could identify novel therapeutic targets to protect the neonatal brain.

Statistical regularities in natural sounds facilitate the perceptual segregation of auditory sources, or streams. Repetition is one cue that drives stream segregation in humans, but the neural basis of this perceptual phenomenon remains unknown. We demonstrated a similar perceptual ability in animals by training ferrets of both sexes to detect a stream of repeating noise samples (foreground) embedded in a stream of random samples (background). During passive listening, we recorded neural activity in primary auditory cortex (A1) and secondary auditory cortex (posterior ectosylvian gyrus, PEG). We used two context-dependent encoding models to test for evidence of streaming of the repeating stimulus. The first was based on average evoked activity per noise sample and the second on the spectro-temporal receptive field. Both approaches tested whether differences in neural responses to repeating versus random stimuli were better modeled by scaling the response to both streams equally (global gain) or by separately scaling the response to the foreground versus background stream (stream-specific gain). Consistent with previous observations of adaptation, we found an overall reduction in global gain when the stimulus began to repeat. However, when we measured stream-specific changes in gain, responses to the foreground were enhanced relative to the background. This enhancement was stronger in PEG than A1. In A1, enhancement was strongest in units with low sparseness (i.e., broad sensory tuning) and with tuning selective for the repeated sample. Enhancement of responses to the foreground relative to the background provides evidence for stream segregation that emerges in A1 and is refined in PEG.

SIGNIFICANCE STATEMENT To interact with the world successfully, the brain must parse behaviorally important information from a complex sensory environment. Complex mixtures of sounds often arrive at the ears simultaneously or in close succession, yet they are effortlessly segregated into distinct perceptual sources. This process breaks down in hearing-impaired individuals and speech recognition devices. By identifying the underlying neural mechanisms that facilitate perceptual segregation, we can develop strategies for ameliorating hearing loss and improving speech recognition technology in the presence of background noise. Here, we present evidence to support a hierarchical process, present in primary auditory cortex and refined in secondary auditory cortex, in which sound repetition facilitates segregation.

The superior colliculus (SC) is arguably the most important visual structure in the mouse brain and is well known for its involvement in innate responses to visual threats and prey items. In other species, the SC plays a central role in voluntary as well as innate visual functions, including crucial contributions to selective attention and perceptual decision-making. In the mouse, the possible role of the SC in voluntary visual choice behaviors has not been established. Here, we demonstrate that the mouse SC of both sexes plays a causal role in visual perceptual decision-making by transiently inhibiting SC activity during an orientation change detection task. First, unilateral SC inhibition-induced spatially specific deficits in detection. Hit rates were reduced, and reaction times increased for orientation changes in the contralateral but not ipsilateral visual field. Second, the deficits caused by SC inhibition were specific to a temporal epoch coincident with early visual burst responses in the SC. Inhibiting SC during this 100-ms period caused a contralateral detection deficit, whereas inhibition immediately before or after did not. Third, SC inhibition reduced visual detection sensitivity. Psychometric analysis revealed that inhibiting SC visual activity significantly increased detection thresholds for contralateral orientation changes. In addition, effects on detection thresholds and lapse rates caused by SC inhibition were larger in the presence of a competing visual stimulus, indicating a role for the mouse SC in visual target selection. Together, our results demonstrate that the mouse SC is necessary for the normal performance of voluntary visual choice behaviors.

SIGNIFICANCE STATEMENT The mouse superior colliculus (SC) has become a popular model for studying the circuit organization and development of the visual system. Although the SC is a fundamental component of the visual pathways in mice, its role in visual perceptual decision-making is not clear. By investigating how temporally precise SC inhibition influenced behavioral performance during a visually guided orientation change detection task, we identified a 100-ms temporal epoch of SC visual activity that is crucial for the ability of mice to detect behaviorally relevant visual changes. In addition, we found that SC inhibition also caused deficits in visual target selection. Thus, our findings highlight the importance of the SC for visual perceptual choice behavior in the mouse.

Calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, are widely used as standard immunosuppressants in organ transplantation recipients. However, these drugs can cause severe pain in patients, commonly referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Although calcineurin inhibition increases NMDAR activity in the spinal cord, the underlying mechanism remains enigmatic. Using an animal model of CIPS, we found that systemic administration of FK506 in male and female mice significantly increased the amount of α2-1–GluN1 complexes in the spinal cord and the level of α2-1–bound GluN1 proteins in spinal synaptosomes. Treatment with FK506 significantly increased the frequency of mEPSCs and the amplitudes of monosynaptic EPSCs evoked from the dorsal root and puff NMDAR currents in spinal dorsal horn neurons. Inhibiting α2-1 with gabapentin or disrupting the α2-1–NMDAR interaction with α2-1Tat peptide completely reversed the effects of FK506. In α2-1 gene KO mice, treatment with FK506 failed to increase the frequency of NMDAR-mediated mEPSCs and the amplitudes of evoked EPSCs and puff NMDAR currents in spinal dorsal horn neurons. Furthermore, systemic administration of gabapentin or intrathecal injection of α2-1Tat peptide reversed thermal and mechanical hypersensitivity in FK506-treated mice. In addition, genetically deleting GluN1 in dorsal root ganglion neurons or α2-1 genetic KO similarly attenuated FK506-induced thermal and mechanical hypersensitivity. Together, our findings indicate that α2-1–bound NMDARs mediate calcineurin inhibitor-induced tonic activation of presynaptic and postsynaptic NMDARs at the spinal cord level and that presynaptic NMDARs play a prominent role in the development of CIPS.

SIGNIFICANCE STATEMENT Calcineurin inhibitors are immunosuppressants used to prevent rejection of transplanted organs and tissues. However, these drugs can cause severe, unexplained pain. We showed that calcineurin inhibition enhances physical interaction between α2-1 and NMDARs and their synaptic trafficking in the spinal cord. α2-1 is essential for calcineurin inhibitor-induced aberrant activation of presynaptic and postsynaptic NMDARs in the spinal cord. Furthermore, inhibiting α2-1 or disrupting α2-1–NMDAR interaction reduces calcineurin inhibitor-induced pain hypersensitivity. Eliminating NMDARs in primary sensory neurons or α2-1 KO also attenuates calcineurin inhibitor-induced pain hypersensitivity. This new information extends our mechanistic understanding of the role of endogenous calcineurin in regulating synaptic plasticity and nociceptive transmission and suggests new strategies for treating this painful condition.

Once known as “the gold of the Incas,” quinoa has been one of the world’s neglected crops but is currently becoming more and more popular. For centuries, quinoa remained a hidden treasure grown almost exclusively by indigenous communities in the Andean heights. Lately, quinoa has been growing in popularity with foodies and health-conscious consumers around the world. It was even [...]

The photos below were entries in the XIV World Forestry Congress ‘Forests and People’ photo contest. Take a tour with us around the world and learn interesting facts on forests and the socioeconomic benefits they provide to people around the world. 

Fish plays an important role in fighting hunger and malnutrition and is the main source of animal protein in many developing countries. Seafood is not only a source of proteins and healthy long-chain omega-3 fats, but also an essential source of other nutrients like iodine, vitamin D and calcium, which are crucial to living a healthy life. Here are 10 interesting [...]

At the beginning of the year we took a tour of 6 incredible plants you might not have heard of. Diets worldwide – from forest roots and leaves such as the moringa in Africa and parts of Asia to cardoon, the close relative of the artichoke in Europe – are varied, suited to local environment and can counter malnutrition and [...]

Smallholders and people living in rural areas in Africa grow a huge variety of edible plants other than rice, wheat or maize. These crops, including the African yam bean, have long been neglected although they represent an excellent alternative food supplement to most diets. Grown in pockets of tropical Central, West and East Africa, the African yam bean (Sphenostylis stenocarpa) [...]

Constituting only 5 percent of the world population, indigenous peoples nevertheless are vital stewards of the environment. Traditional indigenous territories encompass 22 percent of the world’s land surface, but 80 percent of the planet’s biodiversity.  A third of global forests, crucial for curbing gas emissions, are primarily managed by indigenous peoples, families, smallholders and local communities. Indigenous foods are also particularly [...]

The terraced hills of the Andes, the rice paddies of southern China, the oasis systems of the Maghreb: agriculture molds landscapes and places. Agriculture also shapes livelihoods, lifestyles, food traditions and cultures. What kind of plants grow or can’t grow, how they are harvested and what people eat define people’s lives.  Because our natural resources are under great strain, we need [...]

Kalu, in the Amhara region of northern Ethiopia, is home to 28-year-old Yimam Ali. However, many young people from this region of Ethiopia move to the Middle East looking for work and a better life. The amount of job opportunities in the country has not matched its growth. 71 percent of Ethiopia’s population is under the age of 30 and many [...]

Last year, Ashmita Thapa’s husband left their hometown in southern Nepal to find work in Saudi Arabia. He had been working as a farmer and used to be able to grow enough food for the family. But now, Ashmita explains, the yields are poorer and poorer. “This is a part of climate change,” she adds. “There isn’t as much rain as [...]

Everything we do at FAO aims at ensuring a better future. Sure, we need to tackle the huge food and environmental challenges we face today. But we always keep an eye on what that means for tomorrow. More than just quick fixes, we look for sustainable solutions that will benefit generations to come. The future of our world depends on today’s [...]

Knocking on closed doors is something Renu Bala is very good at. First, it was the doors of her neighbours in Panjor Bhanga, her home village in northern Bangladesh. She had an idea for them: what if they formed a milk cooperative? They didn’t have much to lose. “The women of this village are very poor and raise only local Deshi cattle,” Renu explains. [...]

“The anniversary of my brother’s death is on the 26 of July. He was killed 27 years ago,” says Robinson Salas. Robinson is one of the millions of people who had been displaced from their homes and their lands by the armed conflict between the Government of Colombia and the FARC (Revolutionary Armed Forces of Colombia) rebel group. This 52-year [...]

If you are an avid reader, then you might know that today is World Book Day. You also probably know the word prolific and when it comes to books, FAO is nothing short of prolific. In fact, a library was at the origins of FAO. David Lubin, a Polish-born American citizen, saw the struggles that farmers face and helped to start the [...]

All over the world, holidays mean the return of certain specialties: Olivier salad for New Year’s in Russia, Red bean porridge for solstice in Korea, Haleem for Ramadan in India and the Middle East, Mince pies for Christmas in England, Pogača bread for Orthodox Easter, Banana cakes for Lunar New Year in Vietnam. Whatever the holiday is and wherever in [...]

27-year-old Amiat Ahmed and her two-year-old son live with Amiat’s parents in the South Wollo Zone of Amhara Region, Ethiopia. Like many other young people in her region, Amiat used to feel that there were limited opportunities to earn income in her village, which led to her decision to migrate to Saudi Arabia.  

What does William Shakespeare have in common with Mexican beekeeper Francisco Lenin Bartolo Reyes? Both men understand the importance of the honey bee, a small but invaluable ally of the human race.

Akuilina Ihurre used to think she was too old to join a farmers’ group but she knew she needed support to overcome years of hunger. Today, she is producing food with seeds, agricultural tools and techniques acquired through an FAO Farmer Field School in Torit, in South Sudan.  

Disasters, like an earthquake or a violent coup d’état, can strike suddenly, or like droughts and floods, develop slowly. Emergencies are devastating for people everywhere, but for those whose livelihoods or food needs depend entirely on agriculture and natural resources, these disasters can often be overwhelming. FAO addresses emergencies in a variety of ways from early warning and preparedness to [...]

The 2019 Report of the Technical Cooperation Programme (TCP) examines the role of the TCP to deliver FAO technical assistance for agriculture, food and nutrition in response to countries’ most [...]

An independent survey finds that although NPS's annual budget is around $3 billion, Americans are willing to pay much more

Here's what you need to know to preserve your copy of history

The National Cherry Blossom Festival has moved online due to the novel coronavirus pandemic

A new biography explores the remarkable feats of Virginia Hall, a disabled secret agent determined to play her part in the fight against the Nazis

In 2011, declassified CIA documents shed light on a covert government program dating back to WWII

The USS Silversides is patrolling the Pacific during WWII when it finds itself in a terrifying situation: one of its torpedoes has jammed

The 15th-century edition of Hafez's "Divan" will be sold at Sotheby's next month

Built nearly 4,700 years ago as a tomb for the pharaoh Djoser, the structure underwent more than a decade of on-and-off restorations

The snails are an invasive crop pest that are known to eat more than just coffee rust