查看更多>>摘要：Differing from other subtypes of inhibitory interneuron,chandelier or axo-axonic cells form depolar-izing GABAergic synapses exclusively onto the axon initial segment(AIS)of targeted pyramidal cells(PCs).However,the debate whether these AIS-GABAergic inputs produce excitation or inhibition in neuronal processing is not resolved.Using realistic NEURON modeling and electrophysiological recording of cortical layer-5 PCs,we quantitatively demonstrate that the onset-timing of AIS-GABAergic input,relative to dendritic excitatory gluta-matergic inputs,determines its bi-directional regulation of the efficacy of synaptic integration and spike generation in a PC.More specifically,AIS-GABAergic inputs promote the boosting effect of voltage-activated Na?channels on summed synaptic excitation when they precede gluta-matergic inputs by[15 ms,while for nearly concurrent excitatory inputs,they primarily produce a shunting inhibition at the AIS.Thus,our findings offer an integrative mechanism by which AIS-targeting interneurons exert sophisticated regulation of the input-output function in targeted PCs.
查看更多>>摘要：Recent work in decision neuroscience suggests that visual saliency can interact with reward-based choice,and the lateral intraparietal cortex(LIP)is implicated in this process.In this study,we recorded from LIP neurons while monkeys performed a two alternative choice task in which the reward and luminance associated with each offer were varied independently.We discovered that the animal's choice was dictated by the reward amount while the luminance had a marginal effect.In the LIP,neuronal activity corresponded well with the animal's choice pattern,in that a majority of reward-modulated neurons encoded the reward amount in the neuron's preferred hemifield with a positive slope.In contrast,compared to their responses to low luminance,an approximately equal proportion of luminance-sensitive neurons responded to high luminance with increased or decreased activity,leading to a much weaker population-level response.Meanwhile,in the non-preferred hemifield,the strength of encoding for reward amount and luminance was positively correlated,suggesting the integration of these two factors in the LIP.Moreover,neurons encoding reward and luminance were homogeneously distributed along the anterior-posterior axis of the LIP.Overall,our study pro-vides further evidence supporting the neural instantiation of a priority map in the LIP in reward-based decisions.
查看更多>>摘要：Fear memory contextualization is critical for selecting adaptive behavior to survive.Contextual fear con-ditioning(CFC)is a classical model for elucidating related underlying neuronal circuits.The primary visual cortex(V1)is the primary cortical region for contextual visual inputs,but its role in CFC is poorly understood.Here,our experi-ments demonstrated that bilateral inactivation of V1 in mice impaired CFC retrieval,and both CFC learning and extinc-tion increased the turnover rate of axonal boutons in V1.The frequency of neuronal Ca2+activity decreased after CFC learning,while CFC extinction reversed the decrease and raised it to the naïve level.Contrary to control mice,the frequency of neuronal Ca2+activity increased after CFC learning in microglia-depleted mice and was maintained after CFC extinction,indicating that microglial depletion alters CFC learning and the frequency response pattern of extinction-induced Ca2+activity.These findings reveal a critical role of microglia in neocortical information pro-cessing in V1,and suggest potential approaches for cellular-based manipulation of acquired fear memory.
查看更多>>摘要：Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adult-hood,one of which is sleep disturbance.As the cortico-tropin-releasing hormone(CRH)-corticotropin-releasing hormone receptor 1(CRHR1)system and nucleus accum-bens(NAc)play important roles in both stress responses and sleep-wake regulation,in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice.Using the limited nesting and bedding material para-digm from postnatal days 2 to 9,we found that early-life stress disrupted sleep-wake behaviors during adulthood,including increased wakefulness and decreased non-rapid eye movement(NREM)sleep time during the dark period and increased rapid eye movement(REM)sleep time dur-ing the light period.The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure.Importantly,Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology,whereas NAc Crhr1 knockdown reversed these effects(including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy).Together,our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc,and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.
查看更多>>摘要：PiT2 is an inorganic phosphate(Pi)transporter whose mutations are linked to primary familial brain calcification(PFBC).PiT2 mainly consists of two ProDom(PD)domains and a large intracellular loop region(loop7).The PD domains are crucial for the Pi transport,but the role of PiT2-loop7 remains unclear.In PFBC patients,mutations in PiT2-loop7 are mainly nonsense or frame shift mutations that probably cause PFBC due to C-PD1131 deletion.To date,six missense mutations have been identified in PiT2-loop7;however,the mechanisms by which these mutations cause PFBC are poorly understood.Here,we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2.Furthermore,we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase(AMPK)-or protein kinase B(AKT)-mediated PiT2 phosphorylation.In contrast,the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities.These results sug-gested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2.This study helps under-stand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phos-phorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
查看更多>>摘要：The optimal protocol for neuromodulation by transcranial direct current stimulation(tDCS)remains unclear.Using the rotarod paradigm,we found that mouse motor learning was enhanced by anodal tDCS(3.2 mA/cm2)during but not before or after the performance of a task.Dual-task experiments showed that motor learning enhance-ment was specific to the task accompanied by anodal tDCS.Studies using a mouse model of stroke induced by middle cerebral artery occlusion showed that concurrent anodal tDCS restored motor learning capability in a task-specific manner.Transcranial in vivo Ca2+imaging further showed that anodal tDCS elevated and cathodal tDCS suppressed neuronal activity in the primary motor cortex(M1).Anodal tDCS specifically promoted the activity of task-related M1 neurons during task performance,suggesting that elevated Hebbian synaptic potentiation in task-activated circuits accounts for the motor learning enhancement.Thus,appli-cation of tDCS concurrent with the targeted behavioral dysfunction could be an effective approach to treating brain disorders.
查看更多>>摘要：Neurodegenerative diseases(NDs)have become a significant threat to an aging human society.Numerous studies have been conducted in the past decades to clarify their pathologic mechanisms and search for reliable bio-markers.Magnetic resonance imaging(MRI)is a powerful tool for investigating structural and functional brain altera-tions in NDs.With the advantages of being non-invasive and non-radioactive,it has been frequently used in both animal research and large-scale clinical investigations.MRI may serve as a bridge connecting micro-and macro-level analysis and promoting bench-to-bed translational research.Nevertheless,due to the abundance and complexity of MRI techniques,exploiting their potential is not always straight-forward.This review aims to briefly introduce research pro-gress in clinical imaging studies and discuss possible strate-gies for applying MRI in translational ND research.
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