Theoretical models and experimental evidence have suggested that connections from the dentate gyrus (DG) to CA3 play important roles in representing orthogonal information (i.e., pattern separation) in the hippocampus. However, the effects of eliminating the DG on neural firing patterns in the CA3 have rarely been tested in a goal-directed memory task that requires both the DG and CA3. In this study, selective lesions in the DG were made using colchicine in male Long–Evans rats, and single units from the CA3 were recorded as the rats performed visual scene memory tasks. The original scenes used in training were altered during testing by blurring to varying degrees or by using visual masks, resulting in maximal recruitment of the DG–CA3 circuits. Compared with controls, the performance of rats with DG lesions was particularly impaired when blurred scenes were used in the task. In addition, the firing rate modulation associated with visual scenes in these rats was significantly reduced in the single units recorded from the CA3 when ambiguous scenes were presented, largely because DG-deprived CA3 cells did not show stepwise, categorical rate changes across varying degrees of scene ambiguity compared with controls. These findings suggest that the DG plays key roles not only during the acquisition of scene memories but also during retrieval when modified visual scenes are processed in conjunction with the CA3 by making the CA3 network respond orthogonally to ambiguous scenes.

SIGNIFICANCE STATEMENT Despite the behavioral evidence supporting the role of the dentate gyrus in pattern separation in the hippocampus, the underlying neural mechanisms are largely unknown. By recording single units from the CA3 in DG-lesioned rats performing a visual scene memory task, we report that the scene-related modulation of neural firing was significantly reduced in the DG-lesion rats compared with controls, especially when the original scene stimuli were ambiguously altered. Our findings suggest that the dentate gyrus plays an essential role during memory retrieval and performs a critical computation to make categorical rate modulation occur in the CA3 between different scenes, especially when ambiguity is present in the environment.

Sensory systems integrate multiple stimulus features to generate coherent percepts. Spectral surround suppression, the phenomenon by which sound-evoked responses of auditory neurons are suppressed by stimuli outside their receptive field, is an example of this integration taking place in the auditory system. While this form of global integration is commonly observed in auditory cortical neurons, and potentially used by the nervous system to separate signals from noise, the mechanisms that underlie this suppression of activity are not well understood. We evaluated the contributions to spectral surround suppression of the two most common inhibitory cell types in the cortex, parvalbumin-expressing (PV+) and somatostatin-expressing (SOM⁺) interneurons, in mice of both sexes. We found that inactivating SOM⁺ cells, but not PV+ cells, significantly reduces sustained spectral surround suppression in excitatory cells, indicating a dominant causal role for SOM⁺ cells in the integration of information across multiple frequencies. The similarity of these results to those from other sensory cortices provides evidence of common mechanisms across the cerebral cortex for generating global percepts from separate features.

SIGNIFICANCE STATEMENT To generate coherent percepts, sensory systems integrate simultaneously occurring features of a stimulus, yet the mechanisms by which this integration occurs are not fully understood. Our results show that neurochemically distinct neuronal subtypes in the primary auditory cortex have different contributions to the integration of different frequency components of an acoustic stimulus. Together with findings from other sensory cortices, our results provide evidence of a common mechanism for cortical computations used for global integration of stimulus features.

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.

Dopaminergic neurons innervate extensive areas of the brain and release dopamine (DA) onto a wide range of target neurons. However, DA release is also precisely regulated. In Drosophila melanogaster brain explant preparations, DA is released specifically onto α3/α'3 compartments of mushroom body (MB) neurons that have been coincidentally activated by cholinergic and glutamatergic inputs. The mechanism for this precise release has been unclear. Here we found that coincidentally activated MB neurons generate carbon monoxide (CO), which functions as a retrograde signal evoking local DA release from presynaptic terminals. CO production depends on activity of heme oxygenase in postsynaptic MB neurons, and CO-evoked DA release requires Ca²⁺ efflux through ryanodine receptors in DA terminals. CO is only produced in MB areas receiving coincident activation, and removal of CO using scavengers blocks DA release. We propose that DA neurons use two distinct modes of transmission to produce global and local DA signaling.

SIGNIFICANCE STATEMENT Dopamine (DA) is needed for various higher brain functions, including memory formation. However, DA neurons form extensive synaptic connections, while memory formation requires highly specific and localized DA release. Here we identify a mechanism through which DA release from presynaptic terminals is controlled by postsynaptic activity. Postsynaptic neurons activated by cholinergic and glutamatergic inputs generate carbon monoxide, which acts as a retrograde messenger inducing presynaptic DA release. Released DA is required for memory-associated plasticity. Our work identifies a novel mechanism that restricts DA release to the specific postsynaptic sites that require DA during memory formation.

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

The action potential (AP) waveform controls the opening of voltage-gated calcium channels and contributes to the driving force for calcium ion flux that triggers neurotransmission at presynaptic nerve terminals. Although the frog neuromuscular junction (NMJ) has long been a model synapse for the study of neurotransmission, its presynaptic AP waveform has never been directly studied, and thus the AP waveform shape and propagation through this long presynaptic nerve terminal are unknown. Using a fast voltage-sensitive dye, we have imaged the AP waveform from the presynaptic terminal of male and female frog NMJs and shown that the AP is very brief in duration and actively propagated along the entire length of the terminal. Furthermore, based on measured AP waveforms at different regions along the length of the nerve terminal, we show that the terminal is divided into three distinct electrical regions: A beginning region immediately after the last node of Ranvier where the AP is broadest, a middle region with a relatively consistent AP duration, and an end region near the tip of nerve terminal branches where the AP is briefer. We hypothesize that these measured changes in the AP waveform along the length of the motor nerve terminal may explain the proximal-distal gradient in transmitter release previously reported at the frog NMJ.

SIGNIFICANCE STATEMENT The AP waveform plays an essential role in determining the behavior of neurotransmission at the presynaptic terminal. Although the frog NMJ is a model synapse for the study of synaptic transmission, there are many unknowns centered around the shape and propagation of its presynaptic AP waveform. Here, we demonstrate that the presynaptic terminal of the frog NMJ has a very brief AP waveform and that the motor nerve terminal contains three distinct electrical regions. We propose that the changes in the AP waveform as it propagates along the terminal can explain the proximal-distal gradient in transmitter release seen in electrophysiological studies.

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.

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.

Awareness for surprising sensory events is shaped by prior belief inferred from past experience. Here, we combined hierarchical Bayesian modeling with fMRI on an associative learning task in 28 male human participants to characterize the effect of the prior belief of tactile events on connections mediating the outcome of perceptual decisions. Activity in anterior insular cortex (AIC), premotor cortex (PMd), and inferior parietal lobule (IPL) were modulated by prior belief on unexpected targets compared with expected targets. On expected targets, prior belief decreased the connection strength from AIC to IPL, whereas it increased the connection strength from AIC to PMd when targets were unexpected. Individual differences in the modulatory strength of prior belief on insular projections correlated with the precision that increases the influence of prediction errors on belief updating. These results suggest complementary effects of prior belief on insular-frontoparietal projections mediating the precision of prediction during probabilistic tactile learning.

SIGNIFICANCE STATEMENT In a probabilistic environment, the prior belief of sensory events can be inferred from past experiences. How this prior belief modulates effective brain connectivity for updating expectations for future decision-making remains unexplored. Combining hierarchical Bayesian modeling with fMRI, we show that during tactile associative learning, prior expectations modulate connections originating in the anterior insula cortex and targeting salience-related and attention-related frontoparietal areas (i.e., parietal and premotor cortex). These connections seem to be involved in updating evidence based on the precision of ascending inputs to guide future decision-making.

Autism spectrum disorder (ASD) is characterized partly by atypical attentional engagement, reflected in exaggerated and variable responses to sensory stimuli. Attentional engagement is known to be regulated by the locus ceruleus (LC). Moderate baseline LC activity globally dampens neural responsivity and is associated with adaptive deployment and narrowing of attention to task-relevant stimuli. In contrast, increased baseline LC activity enhances neural responsivity across cortex and widening of attention to environmental stimuli regardless of their task relevance. Given attentional atypicalities in ASD, this study is the first to evaluate whether, under different attentional task demands, individuals with ASD exhibit a different profile of LC activity compared with typically developing controls. Males and females with ASD and age- and gender-matched controls participated in a one-back letter detection test while task-evoked pupillary responses, an established correlate for LC activity, were recorded. Participants completed this task in two conditions, either in the absence or presence of distractor auditory tones. Compared with controls, individuals with ASD evinced atypical pupillary responses in the presence versus absence of distractors. Notably, this atypical pupillary profile was evident despite the fact that both groups exhibited equivalent task performance. Moreover, between-group differences in pupillary responses were observed specifically in response to task-relevant events, providing confirmation that the group differences most likely were specifically associated with distinctions in LC activity. These findings suggest that individuals with ASD show atypical modulation of LC activity with changes in attentional demands, offering a possible mechanistic and neurobiological account for attentional atypicalities in ASD.

SIGNIFICANCE STATEMENT Individuals with autism spectrum disorder (ASD) exhibit atypical attentional behaviors, including altered sensory responses and atypical fixedness, but the neural mechanism underlying these behaviors remains elusive. One candidate mechanism is atypical locus ceruleus (LC) activity, as the LC plays a critical role in attentional modulation. Specifically, LC activity is involved in regulating the trade-off between environmental exploration and focused attention. This study shows that, under tightly controlled conditions, task-evoked pupil responses, an LC activity proxy, are lower in individuals with ASD than in controls, but only in the presence of task-irrelevant stimuli. This suggests that individuals with ASD evince atypical modulation of LC activity in accordance with changes in attentional demands, offering a mechanistic account for attentional atypicalities in ASD.

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.

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.

Behavior can be guided by neuronal activity in visual, auditory, or somatosensory cerebral cortex, depending on task requirements. In contrast to this flexible access of cortical signals, several observations suggest that behaviors depend more on neurons in later areas of visual cortex than those in earlier areas, although neurons in earlier areas would provide more reliable signals for many tasks. We recorded from neurons in different levels of visual cortex of 2 male rhesus monkeys while the animals did a visual discrimination task and examined trial-to-trial correlations between neuronal and behavioral responses. These correlations became stronger in primary visual cortex as neuronal signals in that area became more reliable relative to the other areas. The results suggest that the mechanisms that read signals from cortex might access any cortical area depending on the relative value of those signals for the task at hand.

SIGNIFICANCE STATEMENT Information is encoded by the action potentials of neurons in various cortical areas in a hierarchical manner such that increasingly complex stimulus features are encoded in successive stages. The brain must extract information from the response of appropriate neurons to drive optimal behavior. A widely held view of this decoding process is that the brain relies on the output of later cortical areas to make decisions, although neurons in earlier areas can provide more reliable signals. We examined correlations between perceptual decisions and the responses of neurons in different levels of monkey visual cortex. The results suggest that the brain may access signals in any cortical area depending on the relative value of those signals for the task at hand.

Structural plasticity of dendritic spines is a key component of the refinement of synaptic connections during learning. Recent studies highlight a novel role for the NMDA receptor (NMDAR), independent of ion flow, in driving spine shrinkage and LTD. Yet little is known about the molecular mechanisms that link conformational changes in the NMDAR to changes in spine size and synaptic strength. Here, using two-photon glutamate uncaging to induce plasticity at individual dendritic spines on hippocampal CA1 neurons from mice and rats of both sexes, we demonstrate that p38 MAPK is generally required downstream of non-ionotropic NMDAR signaling to drive both spine shrinkage and LTD. In a series of pharmacological and molecular genetic experiments, we identify key components of the non-ionotropic NMDAR signaling pathway driving dendritic spine shrinkage, including the interaction between NOS1AP (nitric oxide synthase 1 adaptor protein) and neuronal nitric oxide synthase (nNOS), nNOS enzymatic activity, activation of MK2 (MAPK-activated protein kinase 2) and cofilin, and signaling through CaMKII. Our results represent a large step forward in delineating the molecular mechanisms of non-ionotropic NMDAR signaling that can drive shrinkage and elimination of dendritic spines during synaptic plasticity.

SIGNIFICANCE STATEMENT Signaling through the NMDA receptor (NMDAR) is vitally important for the synaptic plasticity that underlies learning. Recent studies highlight a novel role for the NMDAR, independent of ion flow, in driving synaptic weakening and dendritic spine shrinkage during synaptic plasticity. Here, we delineate several key components of the molecular pathway that links conformational signaling through the NMDAR to dendritic spine shrinkage during synaptic plasticity.

Nestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Last, we use cortical cultures derived from Dcx KO mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown.

SIGNIFICANCE STATEMENT Nestin, an intermediate filament protein highly expressed in neural progenitors, was recently identified in developing neurons where it regulates growth cone morphology and responsiveness to the guidance cue Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, but the roles of intermediate filaments in this process are poorly understood. We now report that nestin selectively facilitates phosphorylation of the lissencephaly-linked doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected. This substrate selectivity is based on preferential scaffolding of DCX, cdk5, and p35 by nestin. Additionally, we demonstrate a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating intracellular kinase signaling in developing neurons.

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.

Persistent alterations in neuronal activity elicit homeostatic plastic changes in synaptic transmission and/or intrinsic excitability. However, it is unknown whether these homeostatic processes operate in concert or at different temporal scales to maintain network activity around a set-point value. Here we show that chronic neuronal hyperactivity, induced by M-channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in cultured hippocampal pyramidal neurons from mice of either sex. Homeostatic changes of intrinsic excitability occurred at a fast timescale (1–4 h) and depended on ongoing spiking activity. This fast intrinsic adaptation included plastic changes in the threshold current and a distal relocation of FGF14, a protein physically bridging Na_v1.6 and K_v7.2 channels along the axon initial segment. In contrast, synaptic adaptations occurred at a slower timescale (~2 d) and involved decreases in miniature EPSC amplitude. To examine how these temporally distinct homeostatic responses influenced hippocampal network activity, we quantified the rate of spontaneous spiking measured by multielectrode arrays at extended timescales. M-Channel blockade triggered slow homeostatic renormalization of the mean firing rate (MFR), concomitantly accompanied by a slow synaptic adaptation. Thus, the fast intrinsic adaptation of excitatory neurons is not sufficient to account for the homeostatic normalization of the MFR. In striking contrast, homeostatic adaptations of intrinsic excitability and spontaneous MFR failed in hippocampal GABAergic inhibitory neurons, which remained hyperexcitable following chronic M-channel blockage. Our results indicate that a single perturbation such as M-channel inhibition triggers multiple homeostatic mechanisms that operate at different timescales to maintain network mean firing rate.

SIGNIFICANCE STATEMENT Persistent alterations in synaptic input elicit homeostatic plastic changes in neuronal activity. Here we show that chronic neuronal hyperexcitability, induced by M-type potassium channel inhibition, triggered intrinsic and synaptic homeostatic plasticity at different timescales in hippocampal excitatory neurons. The data indicate that the fast adaptation of intrinsic excitability depends on ongoing spiking activity but is not sufficient to provide homeostasis of the mean firing rate. Our results show that a single perturbation such as M-channel inhibition can trigger multiple homeostatic processes that operate at different timescales to maintain network mean firing rate.

Eradicating hunger must be accompanied by strenuous efforts to end malnutrition and its devastating effects. That was a pivotal message at the launch of FAO’s key publication The State of Food and Agriculture, which this year focuses on Food systems for better nutrition. “FAO’s message is that we must strive for nothing less than the eradication of hunger and malnutrition,” said Director-General [...]

FAO has begun field tests for a new approach to measuring hunger and food insecurity – part of a collaboration with polling specialists Gallup, Inc. The project – known as Voices of the Hungry – is based on a “food insecurity experience scale,” with annual data collected using eight interview questions about people’s experiences of food insecurity over the preceding [...]

FAO and its partners have launched an initiative aimed at cutting food waste across the Asia-Pacific region. Save Food Asia-Pacific Campaign targets losses both straight after harvest and between the market and people’s plates. FAO estimates that reducing global food waste by just one quarter would be sufficient to feed the 870 million people suffering from chronic hunger in the world. [...]

FAO Director-General José Graziano da Silva underlined his firm belief that a hunger-free world is possible "within our lifetimes," during high-level talks in New York. "The Zero Hunger Challenge calls for something new – something bold, but long overdue," he said. It was a "decisive global commitment to end hunger, eliminate childhood stunting, make all food systems sustainable, eradicate rural poverty, [...]

We will only achieve zero hunger if we speak on behalf of those unable to represent themselves. That was a key message during an event titled “Zero Hunger: are we ready?” at FAO headquarters in Rome, Italy, on Friday, 11 October. “Hungry people have no voice, they are different from all others,” said FAO Director-General José Graziano da Silva (pictured, left). “We [...]

FAO’s emergency programme to support farmers affected by severe flooding in northern Benin includes creating resilience among communities in order to avert further threats to their livelihoods and food security. Farming families in northern Benin lost crops, livestock and fishing grounds when the Niger River overran its banks in August, just as many villagers were trying to recover from previous floods [...]

Help raise the profile of the IYFF 2014 and its role in eradicating hunger Family farming is the predominant form of agriculture in the world with more than 500 million family farmers playing a key role in securing a future where more quality food is produced in a sustainable way.  For this reason, the 2014 International Year of Family Farming plays a [...]

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 [...]

Did you know that cash transfer (CT) programmes in countries of the sub-Saharan Africa actually have a significant impact? In Malawi, these programmes helped families invest in agricultural equipment and livestock to produce their own food and reduce levels of negative coping strategies, like begging and school drop-outs. In Kenya, secondary school attendance rose by 9 percent and access to [...]

Enjoy a low-cost, healthy diet from your very own vegetable garden and get the chance to make money by selling your own products. Start your own vegetable garden to grow, prepare and eat your own delicious fruits and vegetables with these tips: Do your research: When you begin your own vegetable garden you should understand the type of soil you work [...]

Have you ever wondered if you are getting adequate nutrients from the food you eat? It is a common misconception that malnutrition means not getting enough food. This is, however, incorrect! People who take in insufficient food can be malnourished, but also those who consume too much face the same risks. Malnutrition is defined as “An abnormal physiological condition caused by [...]

Global food security largely depends on smallholder family farms where in many regions of the world women play a crucial role as both producers and providers of food. Studies show that when women and other rural poor have better access to resources, the benefits are far-reaching. Families are healthier, more children attend school, agricultural productivity improves, incomes increase, and rural communities [...]

Forests and trees sustain and protect us, providing clean air and water, safeguarding biodiversity and acting as a buffer against climate change. For many people, they also offer food, shelter and employment. Here are ten facts about trees you might not be aware of: The  world’s forests store 289 gigatonnes (Gt) of carbon in their biomass alone. Deforestation accounts for up to 20% [...]

International Kungfu superstar and renowned Hollywood film actor Jackie Chan has joined FAO in the fight against hunger. In a recent visit to Ethiopia, Chan met with beneficiaries of the ‘Purchase from Africans for Africa’ (PAA) project as well as a South-South Cooperation Programme where he discussed with Chinese experts how they exchange technical knowledge with Ethiopian farmers to help them [...]

Today leading international experts on climate change, the IPCC, presented their latest report on the impacts of climate change on humanity, and what we can do about it. It’s a lengthy report, so we’ve shrunk it down to Oxfam's five key takeaways on climate change and hunger. 1. Climate change: the impacts on crops are worse than we thought Climate change has [...]

As FAO launches dedicated webpages on post-2015, here are seven things to know about the process and how FAO is playing its part. 7 - Post-2015 development agenda - The name refers to the process through which Member States agree on a new global development framework to succeed the Millennium Development Goals (MDGs), eight goals that followed the UN Millennium Declaration [...]

The mission for an end to hunger in the world’s most populous region has received a boost, with member countries responding positively to a call by FAO for a “massive effort” to end hunger in Asia and the Pacific. 1. Asia-Pacific is home to nearly two-thirds of the world’s chronically hungry people. |True|     Asia-Pacific, with over 4.2 billion people, is home [...]

Basic facts The world contains an estimated 1 400 million cubic km of water. Only 0.003% of this vast amount, about 45 000 cubic km, are what is called “fresh water resources” - water that theoretically can be used for drinking, hygiene, agriculture and industry. But not all of this water is accessible. For example, seasonal flooding makes water extremely difficult [...]

‘‘—the first 1000 days are a critical window in a child’s development, but let’s not forget this child on day 1,001.’’ School nutrition programmes help to address the +1,001 day gap. Today, perceptions of school gardens are changing in response to increasingly urgent needs for greater food security, environmental protection, more secure livelihoods and better nutrition. School gardens have new multiple [...]

People have never consumed so much fish or depended so greatly on the sector for their well-being as they do today. Did you know?  Fish is one of the most-traded food commodities worldwide, worth almost US$130 billion in 2012 – a figure that will probably continue to increase. World per capita apparent fish consumption increased from an average of 9.9 kg in the [...]

The challenge is to maintain and develop the socioeconomic benefits from forests while safeguarding the resource. FAO’s State of the World’s Forests (SOFO) 2014 argues that if the focus of data collection and policy is shifted from trees to people, forests can be sustainably managed to meet society’s growing demands. Read the most important findings: The formal forestry sector employs some 13.2 [...]

Today’s fisheries sector hosts a multibillion dollar industry that is a vital source of food and nutrition, employment, trade, economic wellbeing and recreation. What is blue growth? The concept of a "blue economy" came out of the 2012 Rio+20 Conference and emphasizes conservation and sustainable management, based on the premise that healthy ocean ecosystems are more productive and a must for sustainable [...]

Malnutrition isn’t just a problem of hunger in developing countries—it exists in all regions and across socio-economic classes. The effects on human health Besides undernutrition, malnutrition also includes micronutrient-deficient diets and overweight and obesity. Chronic malnutrition can have serious, often life-threatening, health consequences, especially for children. Undernutrition can lead to physical and cognitive stunting, and makes children more susceptible to infectious diseases. Micronutrient deficiencies [...]

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 [...]

Hundreds of millions of people around the world continue to suffer from hunger and malnutrition. Governments are urged to make stronger commitments at November’s Second International Conference on Nutrition (ICN2) to ensure healthier diets for all. That's according to the Food and Agriculture Organization and the World Health Organization of the United Nations. Watch this video to find out the challenges that [...]

Farmer field schools (FFS) are essentially schools without walls that introduce new technological innovations while building on indigenous knowledge. In FFS, farmers are the experts. Key features and principles of the FFS approach – TRUE or FALSE? The FFS approach allows farmers to learn through testing changes in a controlled, group-based environment TRUE:  Discovery-based learning is an essential part of the FFS as [...]

Each year, 30 percent of global food production is lost after harvest or wasted in shops, households and catering services. This represents 750 billion USD in terms of producer or farmgate prices, going up to almost a trillion US dollars of trade value of food every year – half the GDP of Italy!If nature asked us to pay the total [...]

At the Rio+20 Conference on Sustainable Development in June 2012, UN Secretary-General Ban Ki-moon announced a new global challenge for world leaders and individuals from all sectors: create a world where no one is hungry. He emphasized that there is enough food in the world to feed our population, so the challenge comes from making sure that everyone has access [...]

Have you ever thought about producing a video on food, nutrition, sustainability or hunger? Whether you’re a food buff, a student, an activist, movie geek or professional filmmaker, we have just the thing for you.Short Food Movie is a global open call for videos inspired by the theme for Expo Milano 2015, “Feeding the Planet. Energy for Life.”  It includes [...]

Biodiversity for food and agriculture is among the earth’s most important resources. Biodiversity is indispensable: be it the insects that pollinate plants, the microscopic bacteria used for making cheese, the diverse livestock breeds used to make a living in harsh environments, the thousands species of fish, and other aquatic species in our lakes, rivers and oceans, or the thousands of [...]