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.

Prohibitin (PHB) is a critical protein involved in many cellular activities. In brain, PHB resides in mitochondria, where it forms a large protein complex with PHB2 in the inner TFmembrane, which serves as a scaffolding platform for proteins involved in mitochondrial structural and functional integrity. PHB overexpression at moderate levels provides neuroprotection in experimental brain injury models. In addition, PHB expression is involved in ischemic preconditioning, as its expression is enhanced in preconditioning paradigms. However, the mechanisms of PHB functional regulation are still unknown. Observations that nitric oxide (NO) plays a key role in ischemia preconditioning compelled us to postulate that the neuroprotective effect of PHB could be regulated by NO. Here, we test this hypothesis in a neuronal model of ischemia–reperfusion injury and show that NO and PHB are mutually required for neuronal resilience against oxygen and glucose deprivation stress. Further, we demonstrate that NO post-translationally modifies PHB through protein S-nitrosylation and regulates PHB neuroprotective function, in a nitric oxide synthase-dependent manner. These results uncover the mechanisms of a previously unrecognized form of molecular regulation of PHB that underlies its neuroprotective function.

SIGNIFICANCE STATEMENT Prohibitin (PHB) is a critical mitochondrial protein that exerts a potent neuroprotective effect when mildly upregulated in mice. However, how the neuroprotective function of PHB is regulated is still unknown. Here, we demonstrate a novel regulatory mechanism for PHB that involves nitric oxide (NO) and shows that PHB and NO interact directly, resulting in protein S-nitrosylation on residue Cys⁶⁹ of PHB. We further show that nitrosylation of PHB may be essential for its ability to preserve neuronal viability under hypoxic stress. Thus, our study reveals a previously unknown mechanism of functional regulation of PHB that has potential therapeutic implications for neurologic disorders.

We consider the question of how sensory networks enable the detection of sensory stimuli in a combinatorial coding space. We are specifically interested in the olfactory system, wherein recent experimental studies have reported the existence of rich, enigmatic response patterns associated with stimulus onset and offset. This study aims to identify the functional relevance of such response patterns (i.e., what benefits does such neural activity provide in the context of detecting stimuli in a natural environment). We study this problem through the lens of normative, optimization-based modeling. Here, we define the notion of a low-dimensional latent representation of stimulus identity, which is generated through action of the sensory network. The objective of our optimization framework is to ensure high-fidelity tracking of a nominal representation in this latent space in an energy-efficient manner. It turns out that the optimal motifs emerging from this framework possess morphologic similarity with prototypical onset and offset responses observed in vivo in locusts (Schistocerca americana) of either sex. Furthermore, this objective can be exactly achieved by a network with reciprocal excitatory–inhibitory competitive dynamics, similar to interactions between projection neurons and local neurons in the early olfactory system of insects. The derived model also makes several predictions regarding maintenance of robust latent representations in the presence of confounding background information and trade-offs between the energy of sensory activity and resultant behavioral measures such as speed and accuracy of stimulus detection.

SIGNIFICANCE STATEMENT A key area of study in olfactory coding involves understanding the transformation from high-dimensional sensory stimulus to low-dimensional decoded representation. Here, we examine not only the dimensionality reduction of this mapping but also its temporal dynamics, with specific focus on stimuli that are temporally continuous. Through optimization-based synthesis, we examine how sensory networks can track representations without prior assumption of discrete trial structure. We show that such tracking can be achieved by canonical network architectures and dynamics, and that the resulting responses resemble observations from neurons in the insect olfactory system. Thus, our results provide hypotheses regarding the functional role of olfactory circuit activity at both single neuronal and population scales.

The tuberal hypothalamus is comprised of the dorsomedial, ventromedial, and arcuate nuclei, as well as parts of the lateral hypothalamic area, and it governs a wide range of physiologies. During neurogenesis, tuberal hypothalamic neurons are thought to be born in a dorsal-to-ventral and outside-in pattern, although the accuracy of this description has been questioned over the years. Moreover, the intrinsic factors that control the timing of neurogenesis in this region are poorly characterized. Proneural genes, including Achate-scute-like 1 (Ascl1) and Neurogenin 3 (Neurog3) are widely expressed in hypothalamic progenitors and contribute to lineage commitment and subtype-specific neuronal identifies, but the potential role of Neurogenin 2 (Neurog2) remains unexplored. Birthdating in male and female mice showed that tuberal hypothalamic neurogenesis begins as early as E9.5 in the lateral hypothalamic and arcuate and rapidly expands to dorsomedial and ventromedial neurons by E10.5, peaking throughout the region by E11.5. We confirmed an outside-in trend, except for neurons born at E9.5, and uncovered a rostrocaudal progression but did not confirm a dorsal-ventral patterning to tuberal hypothalamic neuronal birth. In the absence of Neurog2, neurogenesis stalls, with a significant reduction in early-born BrdU⁺ cells but no change at later time points. Further, the loss of Ascl1 yielded a similar delay in neuronal birth, suggesting that Ascl1 cannot rescue the loss of Neurog2 and that these proneural genes act independently in the tuberal hypothalamus. Together, our findings show that Neurog2 functions as a classical proneural gene to regulate the temporal progression of tuberal hypothalamic neurogenesis.

SIGNIFICANCE STATEMENT Here, we investigated the general timing and pattern of neurogenesis within the tuberal hypothalamus. Our results confirmed an outside-in trend of neurogenesis and uncovered a rostrocaudal progression. We also showed that Neurog2 acts as a classical proneural gene and is responsible for regulating the birth of early-born neurons within the ventromedial hypothalamus, acting independently of Ascl1. In addition, we revealed a role for Neurog2 in cell fate specification and differentiation of ventromedial -specific neurons. Last, Neurog2 does not have cross-inhibitory effects on Neurog1, Neurog3, and Ascl1. These findings are the first to reveal a role for Neurog2 in hypothalamic development.

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.

MECP2 gain-of-function and loss-of-function in genetically engineered monkeys recapitulates typical phenotypes in patients with autism, yet where MECP2 mutation affects the monkey brain and whether/how it relates to autism pathology remain unknown. Here we report a combination of gene–circuit–behavior analyses including MECP2 coexpression network, locomotive and cognitive behaviors, and EEG and fMRI findings in 5 MECP2 overexpressed monkeys (Macaca fascicularis; 3 females) and 20 wild-type monkeys (Macaca fascicularis; 11 females). Whole-genome expression analysis revealed MECP2 coexpressed genes significantly enriched in GABA-related signaling pathways, whereby reduced β-synchronization within fronto-parieto-occipital networks was associated with abnormal locomotive behaviors. Meanwhile, MECP2-induced hyperconnectivity in prefrontal and cingulate networks accounted for regressive deficits in reversal learning tasks. Furthermore, we stratified a cohort of 49 patients with autism and 72 healthy controls of 1112 subjects using functional connectivity patterns, and identified dysconnectivity profiles similar to those in monkeys. By establishing a circuit-based construct link between genetically defined models and stratified patients, these results pave new avenues to deconstruct clinical heterogeneity and advance accurate diagnosis in psychiatric disorders.

SIGNIFICANCE STATEMENT Autism spectrum disorder (ASD) is a complex disorder with co-occurring symptoms caused by multiple genetic variations and brain circuit abnormalities. To dissect the gene–circuit–behavior causal chain underlying ASD, animal models are established by manipulating causative genes such as MECP2. However, it is unknown whether such models have captured any circuit-level pathology in ASD patients, as demonstrated by human brain imaging studies. Here, we use transgenic macaques to examine the causal effect of MECP2 overexpression on gene coexpression, brain circuits, and behaviors. For the first time, we demonstrate that the circuit abnormalities linked to MECP2 and autism-like traits in the monkeys can be mapped to a homogeneous ASD subgroup, thereby offering a new strategy to deconstruct clinical heterogeneity in ASD.

FAO is working to help typhoon-affected farmers to ensure the next harvests in 2014 – You can help as well. Philippine farmers need urgent assistance  to avoid a double tragedy befalling rural survivors of Typhoon Haiyan. The typhoon hit just as farmers were beginning a new planting season, and FAO estimates that over one million farmers have been affected and hundreds of [...]

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 [...]

They are delicious, they are nutritious and they make your mouth water.  If you know your apples from your oranges, then pit your wits against our fruit quiz. You will need to guess where different fruits come from, where they are most popular and how good they are for you. Let’s get started. 1. Which country is the biggest producer of dates? A.    [...]

As the clock ticks on the Millennium Development Goals (MDGs), the world community is deep in discussion over the successor global framework. Many current practices are damaging the planet’s ecosystems and the biodiversity essential for healthy food production. By 2050 an estimated additional 2 billion people will be living on Earth.  This means food production must rise by 60%. From 8 MDGs [...]

It’s been around for thousands of years; the UN General Assembly named an international year for it in 2013; and now it has been sent into space. Quinoa is a superfood in more ways than one. It is a good source of protein, the highest of all the whole grains; and its edible seeds provide all of the essential amino acids the body [...]

Bees pollinate a third of what we eat and play a vital role in sustaining the planet’s ecosystems. Some 84% of the crops grown for human consumption need bees or other insects to pollinate them to increase their yields and quality. Bee pollination not only results in a higher number of fruits, berries or seeds, it may also give a [...]

As we celebrate our 70-year anniversary, find out how much you know about the work that FAO is doing around the world. Answer these 7 questions and help us fight hunger by becoming an ambassador of FAO!

Pulses have been consumed for at least 10 000 years and are among the most extensively used foods in the world. They provide protein and fibre, and are a great source of vitamins and minerals, such as iron, zinc and magnesium. You probably already eat more pulses than you realize but can you put your finger on these facts on pulses? [...]

Mountains provide freshwater and biodiversity, and are a major source of food. By definition, they dominate their surroundings with towering height and protect valleys and their inhabitants. They play a critical part in moving the world towards sustainable economic growth and have a leading role as indicators of climate change. As we celebrate the International Mountain Day, see how much you [...]

Banana split, banana muffins, banana bread, banana pudding, banana pancakes – whether plain, cooked, baked or fried, bananas are among the most widely consumed fruits on the planet. However, how much do we really know about this most produced and exported fruit? Here are 11 interesting facts you should know about bananas: Based on written references discovered in Sanskrit around the year [...]

For the first time in history, more than 50 percent of the world’s population now lives in towns and cities. By 2050, this number is expected to increase to 66 percent. The shift from rural to urban areas, mainly in Africa and Asia, is due to poverty and related socio-economic factors.   For the most part, the rapid expansion of cities [...]

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 [...]

Pizza and pasta are pretty obviously out, but what are the other no-nos?

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

After the Napoleonic Wars caused a shortage of British Oak, frigate builders looked all over the empire for an alternative. They found one in India

But the scientists still aren’t sure what the birds are saying

The missionary who lived in the house during the mid-1800s delivered vaccinations to locals during a smallpox epidemic

New research suggests the civilization used huge enclosures to trap and stockpile live fish to support its complex society

The story of two bored art lovers who found a way to "a-mouse" themselves

Researchers found that almost half of the mountain lions they tested showed signs of plague infection

Ceramics artist Eny Lee Parker hosted a contest that asked quarantined creators to imagine their ideal rooms

Closed due to COVID-19, the Museum Hotel Antakya looks forward to welcoming guests with its blend of luxury and history once restrictions are lifted

"Occupy White Walls" allows players to design their own art galleries—and explore others' out-of-the-box creations

The 20th-century architect defined a uniquely American style that used nature-inspired motifs and horizontal lines

The event was part of the company's week of #LetsBuildTogether challenges

By building a new broch, the project aims to better understand how and why the original structures were constructed

The specimen may be the earliest known example of a squid-like creature on the attack

Items recovered include fossils, paintings, ancient coins, ceramics and jewelry

Man working on a new building

A flock of Whooper Swans enjoying a peaceful, calm morning at Lake Kussharo, Hokkaido Island

I was wandering in a foggy morning, suddenly I saw a group of village children were going for tuition and they have to cross the rail line every day. I was amazed to see this. But it was natural for them. To me it was so dangerous and too risky. Oh God, please save them.

A newly discovered pyramid yields a baffling mystery: A royal tomb, usually reserved for kings, is found to contain a mystery woman. Who was she and why was she given such a great honor?

A 19-year-old man was flown back to Ontario after he pleaded guilty to violating New Brunswick’s emergency measures order prohibiting visitors from entering the province.

An industrial building in Thunder Bay was slightly damaged in a fire late Thursday afternoon.

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Independent MHA Eddie Joyce is suing four people, including the premier, for defamation over the handling of a harassment complaint that saw him turfed from the Liberal cabinet and caucus in 2018.

Equip Day is a special time to encourage the Service Team at TeenStreet (TS) to be part of God's mission. Taking the time to prepare before the teens arrive is proving to be a valuable addition to the annual TS schedule.

The following is a guest post by Katherine Blood, Curator of Fine Prints, Prints & Photographs Division. As the Library of Congress marks its 220th year of serving the nation, the publication of a new guide tells two stories: how staff have for decades worked with art professionals to build the collections and how by […]

The following is a post by Kristi Finefield, Reference Specialist in the Prints & Photographs Division, and member of the Picture This blog team. As the Library of Congress marks its 220th year, we take the opportunity to explore one example of its efforts to sustain and celebrate the arts in its physical spaces. Above […]

The liquidity trap is synonymous with ineffective monetary policy. The common wisdom is that, as the short-term interest rate nears its effective lower bound, monetary policy cannot do much to stimulate the economy. However, central banks have resorted to alternative instruments, such as QE, credit easing and forward guidance.

The Covid-19 shock is placing enormous strains on corporates cash buffers. Corporate financial statements from 2019 suggest that 50% of firms do not have sufficient cash to cover total debt servicing costs over the coming year. Credit lines could provide firms with additional liquidity. On average undrawn credit stood around 120% of debt servicing costs at end 2019. However, access is uneven and banks may be reluctant to renew or extend them in the current environment. Sticky operating expenses result in many firms running operating losses, placing an additional burden on cash buffers. Estimates indicate that following a 10% drop in revenues, operating expenses only fall by 6% on average. Simulations suggest that if revenues fall by 25% in 2020, then closing the entire funding gap with debt would raise firm leverage by around 10 percentage points.