Adaptive coding of stimuli is well documented in perception, where it supports efficient encoding over a broad range of possible percepts. Recently, a similar neural mechanism has been reported also in value-based decision, where it allows optimal encoding of vast ranges of values in PFC: neuronal response to value depends on the choice context (relative coding), rather than being invariant across contexts (absolute coding). Additionally, value learning is sensitive to the amount of feedback information: providing complete feedback (both obtained and forgone outcomes) instead of partial feedback (only obtained outcome) improves learning. However, it is unclear whether relative coding occurs in all PFC regions and how it is affected by feedback information. We systematically investigated univariate and multivariate feedback encoding in various mPFC regions and compared three modes of neural coding: absolute, partially-adaptive and fully-adaptive.

Twenty-eight human participants (both sexes) performed a learning task while undergoing fMRI scanning. On each trial, they chose between two symbols associated with a certain outcome. Then, the decision outcome was revealed. Notably, in one-half of the trials participants received partial feedback, whereas in the other half they got complete feedback. We used univariate and multivariate analysis to explore value encoding in different feedback conditions.

We found that both obtained and forgone outcomes were encoded in mPFC, but with opposite sign in its ventral and dorsal subdivisions. Moreover, we showed that increasing feedback information induced a switch from absolute to relative coding. Our results suggest that complete feedback information enhances context-dependent outcome encoding.

SIGNIFICANCE STATEMENT This study offers a systematic investigation of the effect of the amount of feedback information (partial vs complete) on univariate and multivariate outcome value encoding, within multiple regions in mPFC and cingulate cortex that are critical for value-based decisions and behavioral adaptation. Moreover, we provide the first comparison of three possible models of neural coding (i.e., absolute, partially-adaptive, and fully-adaptive coding) of value signal in these regions, by using commensurable measures of prediction accuracy. Taken together, our results help build a more comprehensive picture of how the human brain encodes and processes outcome value. In particular, our results suggest that simultaneous presentation of obtained and foregone outcomes promotes relative value representation.

Neurons and circuits each with a distinct balance of intrinsic and synaptic conductances can generate similar behavior but sometimes respond very differently to perturbation. Examining a large family of circuit models with non-identical neurons and synapses underlying rhythmic behavior, we analyzed the circuits' response to modifications in single and multiple intrinsic conductances in the individual neurons. To summarize these changes over the entire range of perturbed parameters, we quantified circuit output by defining a global stability measure. Using this measure, we identified specific subsets of conductances that when perturbed generate similar behavior in diverse individuals of the population. Our unbiased clustering analysis enabled us to quantify circuit stability when simultaneously perturbing multiple conductances as a nonlinear combination of single conductance perturbations. This revealed surprising conductance combinations that can predict the response to specific perturbations, even when the remaining intrinsic and synaptic conductances are unknown. Therefore, our approach can expose hidden variability in the balance of intrinsic and synaptic conductances of the same neurons across different versions of the same circuit solely from the circuit response to perturbations. Developed for a specific family of model circuits, our quantitative approach to characterizing high-dimensional degenerate systems provides a conceptual and analytic framework to guide future theoretical and experimental studies on degeneracy and robustness.

SIGNIFICANCE STATEMENT Neural circuits can generate nearly identical behavior despite neuronal and synaptic parameters varying several-fold between individual instantiations. Yet, when these parameters are perturbed through channel deletions and mutations or environmental disturbances, seemingly identical circuits can respond very differently. What distinguishes inconsequential perturbations that barely alter circuit behavior from disruptive perturbations that drastically disturb circuit output remains unclear. Focusing on a family of rhythmic circuits, we propose a computational approach to reveal hidden variability in the intrinsic and synaptic conductances in seemingly identical circuits based solely on circuit output to different perturbations. We uncover specific conductance combinations that work similarly to maintain stability and predict the effect of changing multiple conductances simultaneously, which often results from neuromodulation or injury.

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.

Investment of cognitive effort is required in everyday life and has received ample attention in recent neurocognitive frameworks. The neural mechanism of effort investment is thought to be structured hierarchically, with dorsal anterior cingulate cortex (dACC) at the highest level, recruiting task-specific upstream areas. In the current fMRI study, we tested whether dACC is generally active when effort demand is high across tasks with different stimuli, and whether connectivity between dACC and task-specific areas is increased depending on the task requirements and effort level at hand. For that purpose, a perceptual detection task was administered that required male and female human participants to detect either a face or a house in a noisy image. Effort demand was manipulated by adding little (low effort) or much (high effort) noise to the images. Results showed a network of dACC, anterior insula (AI), and intraparietal sulcus (IPS) to be more active when effort demand was high, independent of the performed task (face or house detection). Importantly, effort demand modulated functional connectivity between dACC and face-responsive or house-responsive perceptual areas, depending on the task at hand. This shows that dACC, AI, and IPS constitute a general effort-responsive network and suggests that the neural implementation of cognitive effort involves dACC-initiated sensitization of task-relevant areas.

SIGNIFICANCE STATEMENT Although cognitive effort is generally perceived as aversive, its investment is inevitable when navigating an increasingly complex society. In this study, we demonstrate how the human brain tailors the implementation of effort to the requirements of the task at hand. We show increased effort-related activity in a network of brain areas consisting of dorsal anterior cingulate cortex (dACC), anterior insula, and intraparietal sulcus, independent of task specifics. Crucially, we also show that effort-induced functional connectivity between dACC and task-relevant areas tracks specific task demands. These results demonstrate how brain regions specialized to solve a task may be energized by dACC when effort demand is high.

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.

In the face of changing weather driven by climate change and the increasing demand for food, Conservation Agriculture (CA) aims to achieve sustainable and profitable agriculture and improve farmers’ livelihoods. Here are five things you need to know. 1. CA observes three main principles that you should remember Direct seeding involves growing crops without mechanical seedbed preparation and with minimal soil disturbance [...]

Youth around the world are increasingly turning away from agriculture. Traditionally requiring tough manual labour and offering low wages, agriculture does not often appeal to new generations who generally prefer to try their luck finding jobs in cities.  

FAO will attend the fourth Annual Strategic Consultation with the Government of Japan on Tuesday 21 January 2020, in Tokyo, Japan. The objective is to review the progress of [...]

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

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

The Spanish Surrealist painted a series of 100 watercolors inspired by Dante's "Divine Comedy"

A collection of 14 restored wooden statues, including a two-ton William IV, will be shown at the Box Museum in England

The pint-sized institution, which opened last year, is filled with 1,000 feline-themed knickknacks that journeyed with their owners from Ukraine

As monarchs leave their winter hideaways, conservationists are seeking assistance in studying their migration routes

Thieves pilfered "The Parsonage Garden at Nuenen in Spring 1884" from the Singer Laren in the early hours of Monday morning

Architects and designers restored royal ruins across Europe to their former glory

Traces of lead pollution frozen in a glacier confirm that British lead production waned just before the death of Thomas Becket

Pompeii Archaeological Park Director Massimo Osanna narrates stunning drone footage of preserved daily life in the ancient city

This eruption is the longest since 2018 when the volcano caused a deadly tsunami

A star 100-times more massive than the sun exploded with 10-times more energy than a normal-sized supernova

The "lost" apples will help restore genetic, culinary diversity to a crop North America once produced in astonishing variety

The purplish-blue pigment, derived from a Portuguese fruit, fell out of use by the 19th century

Over the past three years, the disease has claimed the lives of seven of the famously resilient ponies

The Catholic Church's actions during World War II have long been a matter of historical debate

Learn hip-hop dance or do citizen science without leaving home this week, thanks to the internet's many intrepid artists and educators

Engineers around the world are tweaking drones, robots and smart tools to help prevent the spread of the virus

A conversation about the challenges facing—and the resilience of—the largest reservation in the country, which has become a COVID-19 hotspot

Antelope Canyon is a slot canyon in the Southwestern United States, one of the most visited and photographed in the world. The geological formation has been pierced due to the passage of water currents through an epigenetic process for thousands of years, and its walls reach 40 meters high at some points.

I imagine the year to be 1957, when Havana was the world's 4th-most-expensive city at the time. Many vintage buildings remain in Havana today, and many of my friends still play and live in such buildings. Today, as the Castro era wanes, Cuba's youth have their doubts, dreams and stories... It is time to make new memories and new histories, while revisiting and reevaluating old ones...1957 is a collection of portraits and stories of my friends in Cuba...This one is called Havana Queen Story, a portrait for the drag Queen Salma. Drag Queens, together with many of the LGBT community are all issues that haven’t been tolerated well at all until recently. In recent years, they are playing to sell-out crowds again every night.

Monuments in winter

This photo was taken from the Tunnel View at Yosemite National Park. The photo is of Bridalveil Fall consumed by smoke due to controlled burning on the Yosemite Valley floor.

Magenta skies over Monument Valley at sunset.

In the hours after disaster struck Anchorage, an unexpected figure named Genie Chance came to the rescue

The Beatles guitarist visited his sister in southern Illinois just months before he'd become world famous

The medieval English longbow first came to prominence during the Hundred Years War. In 1346, English forces used it to devastating effect to cut down a superior French army.

A contemporary weapons expert is about to test a medieval war hammer on a steel breastplate from that era. The aim is to find out how much damage this fearsome instrument of death could deal.

From bikes to vinyl records to a remote controlled airplane, Yellowknifers looking to get rid of or find second-hand treasures have a new place to look.

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Crombie REIT, which owns the Avalon Mall, is awaiting details before applying for government's commercial rent relief.

Arrival Day brought teens, Service Team members, coaches and thunderstorms. As another incredible TeenStreet began, teens shared what they are most looking forward to in the week ahead.

In a new twist on oral history, University of Alberta paleontologists have discovered that an Argentinian reptile from 95 million years ago developed a type of tooth enamel that is common in humans and other mammals but rare among reptiles.

Every year Washingtonians are treated to a feast for the eyes as ornamental cherry trees bloom across the city, most prominently by the Tidal Basin. As cherry blossom season approaches, we would like to share information about two related resources that we hope will offer some inspiration for those near and far: a selected set […]

Recent literature has highlighted that international trade is mostly priced in a few key vehicle currencies, and is increasingly dominated by intermediate goods and global value chains (GVCs). Taking these features into account, this paper reexamines the business cycle dynamics of international trade and its relationship with monetary policy and exchange rates.

Our ongoing celebration of the Library of Congress National Book Festival continues with Poets Laureate Tracy K. Smith and Robert Hass discussing the making of poetry, the position of Poet Laureate and their new books, "American Journal: Fifty Poems for Our Time" (edited by Smith) and "A Little Book on Form: An Exploration into the Formal Imagination of Poetry" (Hass), on the Poetry & Prose stage at the 2018 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with presidential scholar Annette Gordon-Reed discussing "The Hemingses of Monticello: An American Family" on the Special Programs stage at the 2015 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with crime writer Patricia Cornwell discussing "Red Mist,” her 19th Kay Scarpetta novel, on the Fiction & Mystery stage at the 2012 Festival.

Our ongoing celebration of the Library of Congress National Book Festival continues with young adult and fantasy author Leigh Bardugo discussing "Crooked Kingdom" on the Genre Fiction stage at the 2018 Festival. This post includes prompts for writing and thinking that young readers, families and teachers can use to explore the author and the author’s work—recommended for ages 13+.

Our ongoing celebration of the Library of Congress National Book Festival continues with former Secretary of State Condoleezza Rice discussing "Democracy: Stories from the Long Road to Freedom" on the Main Stage at the 2017 Festival.