Neuregulins (NRGs) are protein ligands that impact neural development and circuit function. NRGs signal through the ErbB receptor tyrosine kinase family. NRG1/ErbB4 signaling in ...parvalbumin‐expressing (PV) inhibitory interneurons is critical for visual cortical plasticity. There are multiple types of NRGs and ErbBs that can potentially contribute to visual cortical plasticity at different developmental stages. Thus, it is important to understand the normal developmental expression profiles of NRGs and ErbBs in specific neuron types in the visual cortex, and to study whether and how their expression changes in PV inhibitory neurons and excitatory neurons track with sensory perturbation. Cell type‐specific translating ribosome affinity purification and qPCR was used to compare mRNA expression of nrg1,2,3,4 and erbB1,2,3,4 in PV and excitatory neurons in mouse visual cortex. We show that the expression of nrg1 and nrg3 decreases in PV neurons at the critical period peak, postnatal day 28 (P28) after monocular deprivation and dark rearing, and in the adult cortex (at P104) after 2‐week long dark exposure. In contrast, nrg1 expression by excitatory neurons is unchanged at P28 and P104 following sensory deprivation, whereas nrg3 expression by excitatory neurons shows changes depending on the age and the mode of sensory deprivation. ErbB4 expression in PV neurons remains consistently high and does not appear to change in response to sensory deprivation. These data provide new important details of cell type‐specific NRG/ErbB expression in the visual cortex and support that NRG1/ErbB4 signaling is implicated in both critical period and adult visual cortical plasticity.
There are several neuregulins and ErbBs that may contribute to visual cortical plasticity during the “critical period” or during adulthood. Herein, Grieco et al. report that that sensory deprivation results in downregulation of nrg1 expression in PV cells and results in changes in nrg3 expression in way that depends on the type of deprivation.
Alzheimer's disease (AD) causes progressive age-related defects in memory and cognitive function and has emerged as a major health and socio-economic concern in the US and worldwide. To develop ...effective therapeutic treatments for AD, we need to better understand the neural mechanisms by which AD causes memory loss and cognitive deficits. Here we examine large-scale hippocampal neural population calcium activities imaged at single cell resolution in a triple-transgenic Alzheimer's disease mouse model (3xTg-AD) that presents both amyloid plaque and neurofibrillary pathological features along with age-related behavioral defects. To measure encoding of environmental location in hippocampal neural ensembles in the 3xTg-AD mice in vivo, we performed GCaMP6-based calcium imaging using head-mounted, miniature fluorescent microscopes (“miniscopes”) on freely moving animals. We compared hippocampal CA1 excitatory neural ensemble activities during open-field exploration and track-based route-running behaviors in age-matched AD and control mice at young (3–6.5 months old) and old (18–21 months old) ages. During open-field exploration, 3xTg-AD CA1 excitatory cells display significantly higher calcium activity rates compared with Non-Tg controls for both the young and old age groups, suggesting that in vivo enhanced neuronal calcium ensemble activity is a disease feature. CA1 neuronal populations of 3xTg-AD mice show lower spatial information scores compared with control mice. The spatial firing of CA1 neurons of old 3xTg-AD mice also displays higher sparsity and spatial coherence, indicating less place specificity for spatial representation. We find locomotor speed significantly modulates the amplitude of hippocampal neural calcium ensemble activities to a greater extent in 3xTg-AD mice during open field exploration. Our data offer new and comprehensive information about age-dependent neural circuit activity changes in this important AD mouse model and provide strong evidence that spatial coding defects in the neuronal population activities are associated with AD pathology and AD-related memory behavioral deficits.
•Our study is the first to apply miniscope-based calcium imaging in freely behaving AD model mice.•Spatial coding defects are found in hippocampal neural calcium ensembles in AD mice.•AD mice show enhanced neuronal calcium activities in CA1 compared with controls.•CA1 neuronal populations of AD mice show lower spatial information score.•Locomotion modulates CA1 calcium activity amplitudes in AD mice.
Syngap1 haploinsufficiency is a common cause of sporadic intellectual disability. Syngap1 mutations disrupt developing pyramidal neurons, although it remains unclear if this process contributes to ...cognitive abnormalities. Here, we found that haploinsufficiency restricted to forebrain glutamatergic neurons was sufficient to disrupt cognition and removing mutations from this population prevented cognitive abnormalities. In contrast, manipulating Syngap1 function in GABAergic neurons had no effect on cognition, excitability, or neurotransmission, highlighting the specificity of Syngap1 mutations within forebrain excitatory neurons. Interestingly, cognitive abnormalities were reliably predicted by the emergence of enhanced excitatory synaptic function in mature superficial cortical pyramidal cells, which was a neurophysiological disruption caused by Syngap1 dysfunction in developing, but not adult, forebrain neurons. We conclude that reduced cognition in Syngap1 mutants is caused by isolated damage to developing forebrain glutamatergic neurons. This damage triggers secondary disruptions to synaptic homeostasis in mature cortical pyramidal cells, which perpetuates brain dysfunction into adulthood.
•Adult Syngap1 mutants have altered cortical rhythms and network hyperexcitability•Early glutamatergic neuron dysfunction is necessary and sufficient to cause phenotype•Early glutamatergic neuron dysfunction causes synaptic dyshomeostasis in adulthood•Excitatory synaptic dyshomeostasis predicts cognitive dysfunction
Syngap1 haploinsufficiency is a common cause of intellectual disability. It remains unclear how these genetic mutations cause cognitive impairments. Ozkan et al. found that reduced cognition in Syngap1 mutants is caused by isolated damage to developing, but not mature, forebrain glutamatergic neurons.
Maturation of the forebrain involves transitions from higher to lower levels of synaptic plasticity. The timecourse of these changes likely differs between regions, with the stabilization of some ...networks scaffolding the development of others. To gain better insight into neuroplasticity changes associated with maturation to adulthood, we examined the distribution of two molecular markers for developmental plasticity. We conducted the examination on male and female degus (
), a rodent species with a relatively long developmental timecourse that offers a promising model for studying both development and age-related neuropathology. Immunofluorescent staining was used to measure perineuronal nets (PNNs), an extracellular matrix structure that emerges during the closure of critical plasticity periods, as well as microglia, resident immune cells that play a crucial role in synapse remodeling during development. PNNs (putatively restricting plasticity) were found to be higher in non-juvenile (>3 month) degus, while levels of microglia (putatively mediating plasticity) decreased across ages more gradually, and with varying timecourses between regions. Degus also showed notable variation in PNN levels between cortical layers and hippocampal subdivisions that have not been previously reported in other species. These results offer a glimpse into neuroplasticity changes occurring during degu maturation and highlight adolescence as a unique phase of neuroplasticity, in which PNNs have been established but microglia remain relatively high.
Cerebral microhemorrhages (CMH) are associated with stroke, cognitive decline, and normal aging. Our previous study shows that the interaction between oxidatively stressed red blood cells (RBC) and ...cerebral endothelium may underlie CMH development. However, the real-time examination of altered RBC-brain endothelial interactions in vivo, and their relationship with clearance of stalled RBC, microglial responses, and CMH development, has not been reported.
RBC were oxidatively stressed using tert-butylhydroperoxide (t-BHP), fluorescently labeled and injected into adult Tie2-GFP mice. In vivo two-photon imaging and ex vivo confocal microscopy were used to evaluate the temporal profile of RBC-brain endothelial interactions associated with oxidatively stressed RBC. Their relationship with microglial activation and CMH was examined with post-mortem histology.
Oxidatively stressed RBC stall significantly and rapidly in cerebral vessels in mice, accompanied by decreased blood flow velocity which recovers at 5 days. Post-mortem histology confirms significantly greater RBC-cerebral endothelial interactions and microglial activation at 24 h after t-BHP-treated RBC injection, which persist at 7 days. Furthermore, significant CMH develop in the absence of blood-brain barrier leakage after t-BHP-RBC injection.
Our in vivo and ex vivo findings show the stalling and clearance of oxidatively stressed RBC in cerebral capillaries, highlighting the significance of microglial responses and altered RBC-brain endothelial interactions in CMH development. Our study provides novel mechanistic insight into CMH associated with pathological conditions with increased RBC-brain endothelial interactions.
A key challenge in developing diagnosis and treatments for Alzheimer's disease (AD) is to detect abnormal network activity at as early a stage as possible. To date, behavioral and neurophysiological ...investigations in AD model mice have yet to conduct a longitudinal assessment of cellular pathology, memory deficits, and neurophysiological correlates of neuronal activity. We therefore examined the temporal relationships between pathology, neuronal activities and spatial representation of environments, as well as object location memory deficits across multiple stages of development in the 5xFAD mice model and compared these results to those observed in wild-type mice. We performed longitudinal in vivo calcium imaging with miniscope on hippocampal CA1 neurons in behaving mice. We find that 5xFAD mice show amyloid plaque accumulation, depressed neuronal calcium activity during immobile states, and degenerate and unreliable hippocampal neuron spatial tuning to environmental location at early stages by 4 months of age while their object location memory (OLM) is comparable to WT mice. By 8 months of age, 5xFAD mice show deficits of OLM, which are accompanied by progressive degradation of spatial encoding and, eventually, impaired CA1 neural tuning to object-location pairings. Furthermore, depressed neuronal activity and unreliable spatial encoding at early stage are correlated with impaired performance in OLM at 8-month-old. Our results indicate the close connection between impaired hippocampal tuning to object-location and the presence of OLM deficits. The results also highlight that depressed baseline firing rates in hippocampal neurons during immobile states and unreliable spatial representation precede object memory deficits and predict memory deficits at older age, suggesting potential early opportunities for AD detecting.
•In vivo longitudinal miniscope calcium imaging was applied in freely behaving 5xFAD mice.•Depressed CA1 neuronal activity and spatial encoding deficits develop at early stage.•Impaired circuit function precedes object location memory deficit in 5xFAD mice.•Impaired circuit function at early stage predicts future memory deficits.
One of the major challenges of daily wearable electroencephalogram (EEG) monitoring is that there are rarely suitable EEG electrodes for hairy sites. Wet electrodes require conductive gels, which ...will dry over the acquisition time, making them unstable for long-term EEG monitoring. Additionally, the electrode-scalp impedances of most dry electrodes are not adequate for high quality EEG collection at hairy sites. In view of the above problems, a flexible multi-layer semi-dry electrode was proposed for EEG monitoring in this study. The semi-dry electrode contains a flexible electrode body layer, foam layer and reservoir layer. The probe structure of the electrode body layer enables the electrode to work effectively at hairy sites. During long-term EEG monitoring, electrolytes stored in the reservoir layer are continuously released through the foam layer to the electrode-scalp interface, ensuring a lower electrode-scalp contact impedance. The experimental results showed that the average electrode-scalp impedance of the semi-dry electrode at a hairy site was only 23.89 ± 7.44 KΩ at 10 Hz, and it was lower than 40 KΩ over a long-term use of 5 h. The electrode performed well in both static and dynamic EEG monitoring, where the temporal correlation with wet electrode signals at the hairy site could reach 94.25% and 90.65%, respectively, and specific evoked EEG signals could be collected. The flexible multi-layer semi-dry electrode can be well applied to scalp EEG monitoring at hairy sites, providing a promising solution for daily long-term monitoring of wearable EEGs.
Disrupted operations of the reward circuit underlie major emotional disorders, including depression, which commonly arise following early life stress / adversity (ELA). However, how ELA enduringly ...impacts reward circuit functions remains unclear. We characterize a stress-sensitive projection connecting basolateral amygdala (BLA) and nucleus accumbens (NAc) that co-expresses GABA and the stress-reactive neuropeptide corticotropin-releasing hormone (CRH). We identify a crucial role for this projection in executing disrupted reward behaviors provoked by ELA: chemogenetic and optogenetic stimulation of the projection in control male mice suppresses several reward behaviors, recapitulating deficits resulting from ELA and demonstrating the pathway's contributions to normal reward behaviors. In adult ELA mice, inhibiting-but not stimulating-the projection, restores typical reward behaviors yet has little effect in controls, indicating ELA-induced maladaptive plasticity of this reward-circuit component. Thus, we discover a stress-sensitive, reward inhibiting BLA → NAc projection with unique molecular features, which may provide intervention targets for disabling mental illnesses.
Rank-based learning with the deep neural network has been widely used for image cropping. However, the performance of ranking-based methods is often poor and this is mainly due to two reasons: 1) ...image cropping is a listwise ranking task rather than a pairwise comparison and 2) the rescaling caused by pooling layer and the deformation in view generation damage the performance of composition learning. In this paper, we develop a novel model to overcome these problems. To address the first problem, we formulate the image cropping as a listwise ranking problem to find the best view composition. For the second problem, a refined view sampling (called RoIRefine) is proposed to extract refined feature maps for candidate view generation. Given a series of candidate views, the proposed model learns the Top-1 probability distribution of views and picks up the best one. By integrating refined sampling and listwise ranking, the proposed network called the listwise view ranking network (LVRN) achieves the state-of-the-art performance both in accuracy and speed.
PDF
