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年终盘点：2019年大脑学习和记忆的十大研究突破
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2019年大脑学习和记忆的十大研究突破
1.Nature—科学家揭示了运动皮层短期记忆引导未来运动的吸引子动力学原理
英文摘要：
Short-termmemories link events separated in time, such as past sensation and futureactions. Short-term memories are correlated with slow neural dynamics,including selective persistent activity, which can be maintained over seconds.In a delayed response task that requires short-term memory, neurons in themouse anterior lateral motor cortex (ALM) show persistent activity thatinstructs future actions. To determine the principles that underlie thispersistent activity, here we combined intracellular and extracellular electrophysiology with optogenetic perturbations andnetwork modelling. We show that during the delay epoch, the activity of ALMneurons moved towards discrete end points that correspond to specific movementdirections. These end points were robust to transient shifts in ALM activitycaused by optogenetic perturbations. Perturbations occasionally switched thepopulation dynamics to the other end point, followed by incorrect actions. Ourresults show that discrete attractor dynamics underlie short-term memoryrelated to motor planning.
参考文献：
Inagakiet al (2019). Discrete attractor dynamics underlies persistent activity in thefrontal cortex. Nature. 2019 Feb;566(7743):212-217.
2. Nature—物体向量细胞被定义：诺奖得主揭示了内嗅皮层编码物体向量的机制
英文摘要：
Thehippocampus and the medial entorhinal cortex are part of a brain system thatmaps self-location during navigation in the proximal environment1,2.In this system, correlations between neural firing and an animal'sposition or orientation are so evident that cell types have been givensimple descriptive names, such as place cells3, grid cells4,border cells5,6 and head-direction cells7. While thenumber of identified functional cell types is growing at a steadyrate, insights remain limited by an almost-exclusive reliance on recordingsfrom rodents foraging in empty enclosures that are different from the richlypopulated, geometrically irregular environments of the natural world. Inenvironments that contain discrete objects, animals are known to storeinformation about distance and direction to those objects and to use thisvector information to guide navigation8-10. Theoretical studies haveproposed that such vector operations are supported by neurons that use distanceand direction from discrete objects11,12 or boundaries13,14to determine the animal's location, but-although some cells with vector-codingproperties may be present in the hippocampus15 and subiculum16,17-itremains to be determined whether and how vectorial operations are implementedin the wider neural representation of space. Here we show that a large fractionof medial entorhinal cortex neurons fire specifically when mice are at givendistances and directions from spatially confined objects. These 'object-vectorcells' are tuned equally to a spectrum of discrete objects, irrespective oftheir location in the test arena, as well as to a broad range of dimensions andshapes, from point-like objects to extended surfaces. Our findings point tovector coding as a predominant form of position coding in the medial entorhinalcortex.
参考文献：
Høydalet al (2019). Object-vector coding in the medial entorhinal cortex. Nature.2019 Apr;568(7752):400-404.
3. Science—脑干不定核调控恐惧记忆的获得
英文摘要：
Hippocampalpyramidal cells encode memory engrams, which guide adaptive behavior. Selectionof engram-forming cells is regulated by somatostatin-positivedendrite-targeting interneurons, which inhibit pyramidal cells that are notrequired for memory formation. Here, we found that γ-aminobutyric acid(GABA)-releasing neurons of the mouse nucleus incertus (NI) selectively inhibitsomatostatin-positive interneurons in the hippocampus, both monosynapticallyand indirectly through the inhibition of their subcortical excitatory inputs.We demonstrated that NI GABAergic neurons receive monosynaptic inputs frombrain areas processing important environmental information, and theirhippocampal projections are strongly activated by salient environmental inputsin vivo. Optogenetic manipulations of NI GABAergic neurons can shifthippocampal network state and bidirectionally modify the strength of contextualfear memory formation. Our results indicate that brainstem NI GABAergic cellsare essential for controlling contextual memories.
参考文献：
Szőnyi et al (2019). Brainstem nucleus incertus controlscontextual memory formation. Science. 2019 May 24;364(6442).
4. Science—小鼠中缝区调控负面情绪和负面经历的获得
英文摘要：
Adverseevents need to be quickly evaluated and memorized, yet how these processes arecoordinated is poorly understood. We discovered a large population ofexcitatory neurons in mouse median raphe region (MRR) expressing vesicularglutamate transporter 2 (vGluT2) that received inputs from several negativeexperience-related brain centers, projected to the main aversion centers, andactivated the septohippocampal system pivotal for learningof adverse events. These neurons were selectively activated by aversive but notrewarding stimuli. Their stimulation induced place aversion, aggression,depression-related anhedonia, and suppression of reward-seeking behavior andmemory acquisition-promoting hippocampal theta oscillations. By contrast, theirsuppression impaired both contextual and cued fear memory formation. Theseresults suggest that MRR vGluT2 neurons are crucial for the acquisition ofnegative experiences and may play a central role in depression-related mooddisorders.
参考文献：
Szőnyi et al (2019). Median raphe controls acquisition ofnegative experience in the mouse. Science. 2019 Nov 29;366(6469).
5. Nature—肠道微生物调控神经元功能和恐惧记忆的消除
英文摘要：
Multicellularorganisms have co-evolved with complex consortia of viruses, bacteria, fungiand parasites, collectively referred to as the microbiota1. Inmammals, changes in the composition of the microbiota can influence manyphysiologic processes (including development, metabolism and immune cellfunction) and are associated with susceptibility to multiple diseases2.Alterations in the microbiota can also modulate host behaviours-such as socialactivity, stress, and anxiety-related responses-that are linked to diverseneuropsychiatric disorders3. However, the mechanisms by which themicrobiota influence neuronal activity and host behaviour remain poorlydefined. Here we show that manipulation of the microbiota in antibiotic-treatedor germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of themedial prefrontal cortex of the brain revealed significant alterations in geneexpression in excitatory neurons, glia and other cell types. Transcranialtwo-photon imaging showed that deficits in extinction learningafter manipulation of the microbiota in adult mice were associated with defectivelearning-related remodelling of postsynapticdendritic spines and reduced activity in cue-encoding neurons in the medialprefrontal cortex. In addition, selective re-establishment of the microbiotarevealed a limited neonatal developmental window in which microbiota-derivedsignals can restore normal extinction learning inadulthood. Finally, unbiased metabolomic analysis identified four metabolitesthat were significantly downregulated in germ-free mice and have been reportedto be related to neuropsychiatric disorders in humans and mouse models,suggesting that microbiota-derived compounds may directly affect brain functionand behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both duringearly postnatal neurodevelopment and in adult mice, with implications for ourunderstanding of how diet, infection, and lifestyle influence brain health andsubsequent susceptibility to neuropsychiatric disorders.
参考文献：
Chu et al (2019). The microbiota regulate neuronalfunction and fear extinction learning. Nature. 2019 Oct;574(7779):543-548.
6. Science—科学家首次在鸟类动物中实现语音学习记忆的插入
英文摘要：
Animalslearn many complex behaviors by emulating the behavior of more experiencedindividuals. This essential, yet still poorly understood, form of learning relies on the ability to encode lastingmemories of observed behaviors. We identified a vocal-motor pathway in thezebra finch where memories that guide learning ofsong-element durations can be implanted. Activation of synapses in this pathwayseeds memories that guide learning of song-elementduration and can override learning from socialinteractions with other individuals. Genetic lesions of this circuit aftermemory formation, however, do not disrupt subsequent song imitation, whichsuggests that these memories are stored at downstream synapses. Thus, activityat these sensorimotor synapses can bypass learningfrom auditory and social experience and embed memories that guide learning of song timing.
参考文献：
Zhao et al (2019). Inception of memories that guide vocallearning in the songbird. Science. 2019 Oct 4;366(6461):83-89.
7. Cell—研究首次揭示了睡眠中慢波振荡和Delta波在记忆和遗忘中的相反作用
英文摘要：
Sleephas been implicated in both memory consolidation and forgetting of experiences.However, it is unclear what governs the balance between consolidation andforgetting. Here, we tested how activity-dependent processing during sleepmight differentially regulate these two processes. We specifically examined howneural reactivations during non-rapid eye movement (NREM) sleep were causallylinked to consolidation versus weakening of the neural correlates ofneuroprosthetic skill. Strikingly, we found that slow oscillations (SOs) anddelta (δ) waves have dissociable and competing roles in consolidation versusforgetting. By modulating cortical spiking linked to SOs or δ waves usingclosed-loop optogenetic methods, we could, respectively, weaken or strengthenconsolidation and thereby bidirectionally modulate sleep-dependent performancegains. We further found that changes in the temporal coupling of spindles toSOs relative to δ waves could account for such effects. Thus, our resultsindicate that neural activity driven by SOs and δ waves have competing roles insleep-dependent memory consolidation.
参考文献：
Kim et al (2019). Competing Roles of Slow Oscillationsand Delta Waves in Memory Consolidation versus Forgetting. Cell. 2019 Oct3;179(2):514-526.e13.
8. Science—皮层动力学研究突破：Layer 2/3 和layer 5神经元的动力学涌现驱动感知行为
英文摘要：
Perceptualexperiences may arise from neuronal activity patterns in mammalian neocortex.We probed mouse neocortex during visual discrimination using a red-shiftedchannelrhodopsin (ChRmine, discovered through structure-guided genome mining)alongside multiplexed multiphoton-holography (MultiSLM), achieving control ofindividually specified neurons spanning large cortical volumes with millisecondprecision. Stimulating a critical number of stimulus-orientation-selectiveneurons drove widespread recruitment of functionally related neurons, a processenhanced by (but not requiring) orientation-discrimination task learning. Optogenetic targeting of orientation-selectiveensembles elicited correct behavioral discrimination. Cortical layer-specificdynamics were apparent, as emergent neuronal activity asymmetrically propagatedfrom layer 2/3 to layer 5, and smaller layer 5 ensembles were as effective aslarger layer 2/3 ensembles in eliciting orientation discrimination behavior.Population dynamics emerging after optogenetic stimulation both correctlypredicted behavior and resembled natural internal representations of visualstimuli at cellular resolution over volumes of cortex.
参考文献：
Marshel et al (2019). Cortical layer-specific criticaldynamics triggering perception. Science. 2019 Aug 9;365(6453).
9.Science—长时程海马尖波涟漪的功能被阐明：长时程海马尖波涟漪促进记忆
英文摘要：
Hippocampalsharp wave ripples (SPW-Rs) have been hypothesized as a mechanism for memoryconsolidation and action planning. The duration of ripples shows a skeweddistribution with a minority of long-duration events. We discovered thatlong-duration ripples are increased in situations demanding memory in rats.Prolongation of spontaneously occurring ripples by optogenetic stimulation, butnot randomly induced ripples, increased memory during maze learning. Theneuronal content of randomly induced ripples was similar to short-durationspontaneous ripples and contained little spatial information. The spike contentof the optogenetically prolonged ripples was biased by the ongoing, naturallyinitiated neuronal sequences. Prolonged ripples recruited new neurons thatrepresented either arm of the maze. Long-duration hippocampal SPW-Rs replayinglarge parts of planned routes are critical for memory.
参考文献：
Fernández-Ruizet al (2019). Long-duration hippocampal sharp wave ripples improve memory. Science.2019 Jun 14;364(6445):1082-1086.
10. Cell—人类记忆的“重演“自发的重组其行为经历
英文摘要：
Knowledgeabstracted from previous experiences can be transferred to aid new learning. Here, we asked whether such abstract knowledgeimmediately guides the replay of new experiences. We first trained participantson a rule defining an ordering of objects and then presented a novel set ofobjects in a scrambled order. Across two studies, we observed that representationsof these novel objects were reactivated during a subsequent rest. As inrodents, human "replay" events occurred in sequences accelerated intime, compared to actual experience, and reversed their direction after areward. Notably, replay did not simply recapitulate visual experience, butfollowed instead a sequence implied by learned abstract knowledge. Furthermore,each replay contained more than sensory representations of the relevantobjects. A sensory code of object representations was preceded 50 ms bya code factorized into sequence position and sequence identity. We arguethat this factorized representation facilitates the generalization of apreviously learned structure to new objects.
参考文献：
Liuet al (2019). Human Replay Spontaneously Reorganizes Experience. Cell. 2019 Jul25;178(3):640-652.e14.
2019年十大研究进展名录
6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）
11. 年终盘点：2019年医学和生物学领域深度学习和神经网络十大基础研究进展
15.年终盘点：2019年神经发育及成年神经再生十大研究突破
2018年十大研究进展名录
14. 2018年的十大睡眠研究突破
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