Functional recovery after cortical injury, such as stroke, is associated with neural circuit reorganization, but the underlying mechanisms and efficacy of therapeutic interventions promoting neural plasticity in primates are not well understood. Bone marrow mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), which mediate cell-to-cell inflammatory and trophic signaling, are thought be viable therapeutic targets. We recently showed, in aged female rhesus monkeys, that systemic administration of MSC-EVs enhances recovery of function after injury of the primary motor cortex, likely through enhancing plasticity in perilesional motor and premotor cortices. Here, using in vitro whole-cell patch-clamp recording and intracellular filling in acute slices of ventral premotor cortex (vPMC) from rhesus monkeys (Macaca mulatta) of either sex, we demonstrate that MSC-EVs reduce injury-related physiological and morphologic changes in perilesional layer 3 pyramidal neurons. At 14-16 weeks after injury, vPMC neurons from both vehicle- and EV-treated lesioned monkeys exhibited significant hyperexcitability and predominance of inhibitory synaptic currents, compared with neurons from nonlesioned control brains. However, compared with vehicle-treated monkeys, neurons from EV-treated monkeys showed lower firing rates, greater spike frequency adaptation, and excitatory:inhibitory ratio. Further, EV treatment was associated with greater apical dendritic branching complexity, spine density, and inhibition, indicative of enhanced dendritic plasticity and filtering of signals integrated at the soma. Importantly, the degree of EV-mediated reduction of injury-related pathology in vPMC was significantly correlated with measures of behavioral recovery. These data show that EV treatment dampens injury-related hyperexcitability and restores excitatory:inhibitory balance in vPMC, thereby normalizing activity within cortical networks for motor function.

SIGNIFICANCE STATEMENT Neuronal plasticity can facilitate recovery of function after cortical injury, but the underlying mechanisms and efficacy of therapeutic interventions promoting this plasticity in primates are not well understood. Our recent work has shown that intravenous infusions of mesenchymal-derived extracellular vesicles (EVs) that are involved in cell-to-cell inflammatory and trophic signaling can enhance recovery of motor function after injury in monkey primary motor cortex. This study shows that this EV-mediated enhancement of recovery is associated with amelioration of injury-related hyperexcitability and restoration of excitatory-inhibitory balance in perilesional ventral premotor cortex. These findings demonstrate the efficacy of mesenchymal EVs as a therapeutic to reduce injury-related pathologic changes in the physiology and structure of premotor pyramidal neurons and support recovery of function.

Nitric oxide (NO) is an important signaling molecule that fulfills diverse functional roles as a neurotransmitter or diffusible second messenger in the developing and adult CNS. Although the impact of NO on different behaviors such as movement, sleep, learning, and memory has been well documented, the identity of its molecular and cellular targets is still an area of ongoing investigation. Here, we identify a novel role for NO in strengthening inhibitory GABA_A receptor-mediated transmission in molecular layer interneurons of the mouse cerebellum. NO levels are elevated by the activity of neuronal NO synthase (nNOS) following Ca²⁺ entry through extrasynaptic NMDA-type ionotropic glutamate receptors (NMDARs). NO activates protein kinase G with the subsequent production of cGMP, which prompts the stimulation of NADPH oxidase and protein kinase C (PKC). The activation of PKC promotes the selective strengthening of α3-containing GABA_ARs synapses through a GABA receptor-associated protein-dependent mechanism. Given the widespread but cell type-specific expression of the NMDAR/nNOS complex in the mammalian brain, our data suggest that NMDARs may uniquely strengthen inhibitory GABAergic transmission in these cells through a novel NO-mediated pathway.

SIGNIFICANCE STATEMENT Long-term changes in the efficacy of GABAergic transmission is mediated by multiple presynaptic and postsynaptic mechanisms. A prominent pathway involves crosstalk between excitatory and inhibitory synapses whereby Ca²⁺-entering through postsynaptic NMDARs promotes the recruitment and strengthening of GABA_A receptor synapses via Ca²⁺/calmodulin-dependent protein kinase II. Although Ca²⁺ transport by NMDARs is also tightly coupled to nNOS activity and NO production, it has yet to be determined whether this pathway affects inhibitory synapses. Here, we show that activation of NMDARs trigger a NO-dependent pathway that strengthens inhibitory GABAergic synapses of cerebellar molecular layer interneurons. Given the widespread expression of NMDARs and nNOS in the mammalian brain, we speculate that NO control of GABAergic synapse efficacy may be more widespread than has been appreciated.

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing l-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with l-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of l-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in l-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of l-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.

SIGNIFICANCE STATEMENT The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play critical roles in neuronal development and nervous system function. Here, we developed a model to study NMDARs in early development in zebrafish, by generating CRISPR-mediated lesions in the NMDAR genes, grin1a and grin1b, which encode the obligatory GluN1 subunits. While receptors containing grin1a or grin1b show high Ca²⁺ permeability, like their mammalian counterpart, grin1a is expressed earlier and more broadly in development than grin1b. Both grin1a^–/– and grin1b^–/– zebrafish are viable. Unlike in rodents, where the grin1 knockout is embryonic lethal, grin1 double-mutant fish (grin1a^–/–; grin1b^–/–), which lack all NMDAR-mediated synaptic transmission, survive until ~10 d dpf (days post fertilization), providing a unique opportunity to explore NMDAR function during development and in generating behaviors. Many behavioral defects in the grin1 double-mutant larvae, including abnormal evoked responses to light and acoustic stimuli, prey-capture deficits, and a failure to habituate to acoustic stimuli, are replicated by short-term treatment with the NMDAR antagonist MK-801, suggesting that they arise from acute effects of compromised NMDAR-mediated transmission. Other defects, however, such as periods of hyperactivity and alterations in place preference, are not phenocopied by MK-801, suggesting a developmental origin. Together, we have developed a unique model to study NMDARs in the developing vertebrate nervous system.

SIGNIFICANCE STATEMENT Rapid communication between cells in the nervous system depends on ion channels that are directly activated by chemical neurotransmitters. One such ligand-gated ion channel, the NMDAR, impacts nearly all forms of nervous system function. It has been challenging, however, to study the prolonged absence of NMDARs in vertebrates, and hence their role in nervous system development, due to experimental limitations. Here, we demonstrate that zebrafish lacking all NMDAR transmission are viable through early development and are capable of a wide range of stereotypic behaviors. As such, this zebrafish model provides a unique opportunity to study the role of NMDAR in the development of the early vertebrate nervous system.

For visually guided navigation, the use of environmental cues is essential. Particularly, detecting local boundaries that impose limits to locomotion and estimating their location is crucial. In a series of three fMRI experiments, we investigated whether there is a neural coding of navigational distance in the human visual cortex (both female and male). We used virtual reality software to systematically manipulate the distance from a viewer perspective to different types of a boundary. Using a multivoxel pattern classification employing a linear support vector machine, we found that the occipital place area (OPA) is sensitive to the navigational distance restricted by the transparent glass wall. Further, the OPA was sensitive to a non-crossable boundary only, suggesting an importance of the functional constraint of a boundary. Together, we propose the OPA as a perceptual source of external environmental features relevant for navigation.

SIGNIFICANCE STATEMENT One of major goals in cognitive neuroscience has been to understand the nature of visual scene representation in human ventral visual cortex. An aspect of scene perception that has been overlooked despite its ecological importance is the analysis of space for navigation. One of critical computation necessary for navigation is coding of distance to environmental boundaries that impose limit on navigator's movements. This paper reports the first empirical evidence for coding of navigational distance in the human visual cortex and its striking sensitivity to functional constraint of environmental boundaries. Such finding links the paper to previous neurological and behavioral works that emphasized the distance to boundaries as a crucial geometric property for reorientation behavior of children and other animal species.

Reward has a remarkable ability to invigorate motor behavior, enabling individuals to select and execute actions with greater precision and speed. However, if reward is to be exploited in applied settings, such as rehabilitation, a thorough understanding of its underlying mechanisms is required. In a series of experiments, we first demonstrate that reward simultaneously improves the selection and execution components of a reaching movement. Specifically, reward promoted the selection of the correct action in the presence of distractors, while also improving execution through increased speed and maintenance of accuracy. These results led to a shift in the speed-accuracy functions for both selection and execution. In addition, punishment had a similar impact on action selection and execution, although it enhanced execution performance across all trials within a block, that is, its impact was noncontingent to trial value. Although the reward-driven enhancement of movement execution has been proposed to occur through enhanced feedback control, an untested possibility is that it is also driven by increased arm stiffness, an energy-consuming process that enhances limb stability. Computational analysis revealed that reward led to both an increase in feedback correction in the middle of the movement and a reduction in motor noise near the target. In line with our hypothesis, we provide novel evidence that this noise reduction is driven by a reward-dependent increase in arm stiffness. Therefore, reward drives multiple error-reduction mechanisms which enable individuals to invigorate motor performance without compromising accuracy.

SIGNIFICANCE STATEMENT While reward is well-known for enhancing motor performance, how the nervous system generates these improvements is unclear. Despite recent work indicating that reward leads to enhanced feedback control, an untested possibility is that it also increases arm stiffness. We demonstrate that reward simultaneously improves the selection and execution components of a reaching movement. Furthermore, we show that punishment has a similar positive impact on performance. Importantly, by combining computational and biomechanical approaches, we show that reward leads to both improved feedback correction and an increase in stiffness. Therefore, reward drives multiple error-reduction mechanisms which enable individuals to invigorate performance without compromising accuracy. This work suggests that stiffness control plays a vital, and underappreciated, role in the reward-based imporvemenets in motor control.

The septo-hippocampal cholinergic system is critical for hippocampal learning and memory. However, a quantitative description of the in vivo firing patterns and physiological function of medial septal (MS) cholinergic neurons is still missing. In this study, we combined optogenetics with multichannel in vivo recording and recorded MS cholinergic neuron firings in freely behaving male mice for 5.5–72 h. We found that their firing activities were highly correlated with hippocampal theta states. MS cholinergic neurons were highly active during theta-dominant epochs, such as active exploration and rapid eye movement sleep, but almost silent during non-theta epochs, such as slow-wave sleep (SWS). Interestingly, optogenetic activation of these MS cholinergic neurons during SWS suppressed CA1 ripple oscillations. This suppression could be rescued by muscarinic M₂ or M₄ receptor antagonists. These results suggest the following important physiological function of MS cholinergic neurons: maintaining high hippocampal acetylcholine level by persistent firing during theta epochs, consequently suppressing ripples and allowing theta oscillations to dominate.

SIGNIFICANCE STATEMENT The major source of acetylcholine in the hippocampus comes from the medial septum. Early experiments found that lesions to the MS result in the disappearance of hippocampal theta oscillation, which leads to speculation that the septo-hippocampal cholinergic projection contributing to theta oscillation. In this article, by long-term recording of MS cholinergic neurons, we found that they show a theta state-related firing pattern. However, optogenetically activating these neurons shows little effect on theta rhythm in the hippocampus. Instead, we found that activating MS cholinergic neurons during slow-wave sleep could suppress hippocampal ripple oscillations. This suppression is mediated by muscarinic M₂ and M₄ receptors.

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.

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.

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.

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.

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.

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. [...]

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 [...]

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 [...]

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 [...]

‘‘—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 [...]

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 [...]

In its simplest form, a kitchen garden produces fresh fruits, vegetables and herbs for delicious, healthy meals. Research suggests that kitchen gardens can supply up to half of all non-staple food needs, as well as a significant number of vitamins and minerals. This makes them an invaluable tool for food security in vulnerable communities. ‘Imagine one day you lost everything you owned.  [...]

The United Nations launched the 2014 International Year of Family Farming to stress the vast potential family farmers have to eradicate hunger and preserve natural resources. In both developed and developing countries, more than 500 million, or nine out of ten, farms are managed by families, making family farms the predominant form of agriculture. They not only produce about 80% [...]

Join us virtually on the Dr Fridtjof Nansen, a marine research vessel, as it embarks on a month-long cruise departing from Cape Town, South Africa, to conduct scientific research in the deep seas of the Southeast Atlantic Fisheries Organization (SEAFO) convention area before arriving at Walvis Bay, Namibia.  Since 1975, FAO and the Norwegian Agency for Development Cooperation have collaborated with [...]

All over the world local varieties of fruit, vegetables and grain are grown. Many are seemingly forgotten or are underutilized despite having outstanding nutritional or taste qualities. Some have good commercial potential and could be an excellent cash crop for a smallscale or family farmers, aimed at the local, regional or international market. Here are six traditional crops and six facts [...]

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 [...]

We took a look around and put together a list of  Twitter accounts to keep you informed about what is happening in the world of soils.  Here are, in alphabetical order, ten voices on twitter you should follow for the latest on soils: @agriculturesnet The AgriCultures Network shares knowledge on small-scale family farming and agroecology. With agroecology we can build soils for life! http://t.co/pN62odtLt9 [...]

Ripe, juicy, and practically begging to be eaten, berries are a spring and summer treat that make your mouth water. To celebrate the pinnacle of berry season, we gathered some facts and figures and are challenging you to see how far your berry knowledge really goes. 

Feeding the world’s growing population, which is expected to go beyond 9 billion by 2050, is one of the world’s biggest challenges. Some of the highest rates of population growth are predicted to occur in areas that are highly dependent on the agriculture sector (i.e. crops, livestock, forests and fisheries). Sustainable agricultural growth is one of the most effective means [...]

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

In 2015 we celebrated the “International Year of Soils” and with good reason. Soil sustains all our agricultural and livestock food production, wood for fuel production, filters water so that we can drink it and fish can live in it. We also use it for construction - therefore it sustains our homes and infrastructure. As we approach the end of #IYS [...]

10: EtymologyThe word pulse originates directly from the Latin puls meaning "thick gruel, porridge, mush.” 9: Pulses vs legumes, what’s the difference?The term "legume" refers to the plants whose fruit is enclosed in a pod. Pulses are a subgroup of the legume family, but the term “pulse” refers only to the dried seed. Dried beans, lentils and peas are the most commonly known and consumed types [...]

Maize, rice and wheat are fundamental to world food security. We must safeguard production in the world’s grain belts and rice bowls, and increase yields in countries where production has to substantially improve as populations grow. Climate change adds new pressures on cereals, including rising temperatures and a higher incidence of pests, diseases, droughts and floods. FAO’s model of ecosystem-based agriculture, [...]

When thinking of this fruit we love so much what is the image that first pops to mind? Perhaps a green or a yellow with a greenish tint energy food? Or maybe a banana packaged in a perfect shade of yellow? If that’s the case, then it is time to broaden that perspective. Say hello to the Fe’i banana! This traditional [...]

E-learning was quite the buzzword a couple of decades ago – then when the internet started in earnest it became even more so. Today e-learning is mainstreamed in many organization, including FAO with more than 400 000 learners taking advantage of FAO’s offerings. FAO’s e-learning center offers free interactive courses – in English, French and Spanish - on topics ranging [...]

Radio culture is gaining more and more ground as millions of listeners take to audio podcasts as a convenient and accessible way to learn new information.  Which is why FAO is stepping up into the medium to bring you insights into some of the issues concerning food and agriculture worldwide. Here are the first seven audio offerings of FAO’s new podcast [...]

Illegal, Unreported and Unregulated fishing, also known as IUU, robs the world’s oceans of 26 million tonnes of seafood annually, bringing financial losses to a staggering US$ 23 billion a year. Illegal fishing severely affects the livelihoods of fishers and other fisher-sector stakeholders and exacerbates poverty and food insecurity. It undermines the accuracy of fisheries’ stock assessments and threatens the [...]

Every year, FAO publishes a number of major ‘State of the World’ reports containing balanced, science-based reviews of issues related to food, agriculture, forestry, fisheries and natural resources. The reports also cover vital areas such as food production and hunger alleviation, which are at the heart of FAO’s work. With close to 800 million people currently chronically undernourished and an extra [...]

In 2016 we celebrated the International Year of Pulses and it is obvious why. Pulses are good for you, beneficial to farmers' livelihoods and have a positive impact on the environment. It is clear that even though dried beans, lentils and peas have been around for centuries, they will play a fundamental role in our sustainable future. Even though #IYP2016 has [...]

Water is essential for agricultural production and food security.  It is the lifeblood of ecosystems, including forests, lakes and wetlands, on which the food and nutritional security of present and future generations depends on. Yet, our freshwater resources are dwindling at an alarming rate. Growing water scarcity is now one of the leading challenges for sustainable development.  This challenge will [...]

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

Some of the most innovative ways being used to improve agricultural practices involve nuclear technology. Nuclear applications in agriculture rely on the use of isotopes and radiation techniques to combat pests and diseases, increase crop production, protect land and water resources, ensure food safety and authenticity, and increase livestock production. FAO and the International Atomic Energy Agency (IAEA) have been expanding [...]

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

Paseano Gómez López is a farmer from Nuevo Sonora, Chiapas state, Mexico. He grows corn and chili peppers. But to cultivate fields, farmers need money to buy supplies. They are often forced to take loans at high interest rates (10-20 percent). Sometimes, the farm’s yields don’t even cover the costs and they fall into debt. Farmers in Mexico are also battling with poor [...]

Eradicating world hunger can only be achieved if food is safe, nutritious and of good quality. Eating unsafe food increases the chances of contracting diseases and can be, in some cases, deadly. Unsafe food can also lead to rejections causing food to be wasted, which then impacts on food security. One thing is certain: there can be no food security [...]

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

Ghost fishing. Sounds eerie, right? Unfortunately, it is indeed as eerie as it sounds. Ghost fishing occurs when lost or abandoned fishing gear stays in the ocean and traps fish or other marine life, indiscriminately killing whatever it catches. Abandoned, lost or otherwise discarded fishing gear (ALDFG), as it is known officially, is being recognized as a topic that we must [...]

Women and children, especially pregnant women and children 0-2 years of age, are among the groups most vulnerable to food insecurity and chronic malnutrition. This is no different in Mozambique where, according to the FAO Technical Secretariat for Food Security and Nutrition 35% of the population is food insecure and 43% of children under 5 are chronically malnourished. Chronic undernutrition levels [...]