Center for Excellence in Brain Science and Intelligence Technology

The top-down influence of working memory (WM) can manifest as both attentional capture and small systematic biases in perceptual judgement (i.e., “tinted lens” effect). Yet it remains unclear whether these influences arise from a single mechanism or reflect functionally distinct processes operating over different timescales. Across two experiments, we embedded a perceptual estimation task during the delay interval of a WM task and tracked continuous mouse trajectories during both perceptual matching and subsequent WM tests. Hierarchical Bayesian mixture modeling revealed robust bidirectional attraction between memory and perception. Time-resolved analyses of mouse trajectories further revealed two distinct components: an early, endpoint-inconsistent deviation that varied with movement onset latency, whereas a slower, endpoint-consistent drift that closely tracked biases in the final report. This pattern is consistent with a fast, capture-like influence of the WM template, and a sustained bias in the evolving decision, respectively. Notably, the prospective influence of WM on perception expressed both early deviation and sustained drift, whereas the retrospective influence of perception on WM primarily involved the sustained component. These findings indicate that WM shapes perceptual decisions through at least two temporally distinct contributions, and illustrate how continuous trajectories can reveal the dynamic structure of top-down influences within single trials.Our minds do not simply record the external world as it is, but reconstruct it actively through the lens of past experience and internal goals. Using continuous mouse-tracking, this study shows that working memory (WM) influences what we attend to and what we see, yet these effects unfold over different timescales. WM can momentarily capture attention toward memory-matching information while also producing a slower, sustained shift that changes how things appear. These findings suggest that WM serves as an active and flexible prior that continuously integrates past and present in shaping perceptual experience.

The existence of human hippocampal neurogenesis has long been disputed1–12 and its relevance in cognition remains unknown. Recent studies have established the presence of proliferating progenitors and immature neurons and a reduction in the latter in Alzheimer’s disease (AD)11,13. However, their origin and the molecular networks that regulate neurogenesis and function are poorly understood. Here we studied human post-mortem hippocampi obtained from different cohorts: young adults with intact memory, aged adults with no cognitive impairments, aged adults with extraordinary memory capacity (SuperAgers)14,15, adults with preclinical intermediate pathology or adults with AD. Using multiomic single-cell sequencing (single-nucleus RNA sequencing and single-nuclei assay for transposase-accessible chromatin with sequencing), we analysed the profiles of 355,997 nuclei isolated from the hippocampus samples and identified neural stem cells, neuroblasts and immature granule neurons. Dysregulated neurogenesis was largely associated with changes in chromatin accessibility. Analyses of transcription factors and target gene signatures that distinguished each of the groups revealed early alterations in chromatin accessibility of neurogenic cells from individuals with preclinical AD, and such changes were even more evident in samples from individuals with AD. We identified a distinct profile of neurogenesis in SuperAgers that may reflect a ‘resilience signature’. Finally, alterations in the profile of astrocytes and CA1 neurons govern cognitive function in the ageing hippocampus. Together, our study points to a multiomic molecular signature of the hippocampus that distinguishes cognitive resilience and deterioration with ageing.

Tinnitus affects 10-15% of adults globally, yet there are still no effective treatments for this major health condition. Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuromodulation technique, allows modulation of pathologically altered functional activities to promote symptom remission. However, its efficacy critically depends on the selection of stimulation targets, and substantial interindividual variability has been observed in clinical trials. Here, we aimed to identify potential target regions that are causally involved in alleviating distinct functional abnormalities using the digital twin brain (DTB). A cohort of 89 participants was used to characterize whole-brain neural activity patterns. Multimodal neuroimaging data were used to develop the tinnitus-specific DTB and to generate causal response maps based on more than 1.64 million virtual stimulations. Whole-brain gene expression data were further integrated to examine the neurobiological plausibility of the DTB-derived causal response maps. Finally, we validated the predictive capacity of such response maps using an independent rTMS dataset. We identified two aberrant brain states that emerged sequentially with disease progression, predominantly overlapping with the somatomotor and default mode networks, respectively. DTB-derived causal response maps revealed that the modulation of sensory and cognitive states requires stimulation of distinct, functionally specialized regions. Specifically, parieto-occipital regions play a crucial role in sensory modulation, while the dorsolateral prefrontal cortex exerts a causal influence on cognitive modulation. Moreover, these causal response maps correlate with the expression of tinnitus risk genes. By incorporating individual connectivity profiles of target regions, DTB-derived causal response maps accurately predicted rTMS effects on both sensory state (r > 0.85, Ppermutation < 0.01) and cognitive state (r > 0.78, Ppermutation < 0.05). Particularly, the predictive capacity exhibited a state-specific nature. This work suggests that brain functional alterations in tinnitus evolve with disease progression, and DTB has the potential to predict rTMS effects on distinct brain states, thereby informing more precise and targeted noninvasive brain stimulation interventions for tinnitus. Trial registered with https://www.chictr.org.cn/indexEN.html , Explore the mechanism of repetitive transcranial magnetic stimulation intervention in tinnitus based on multi-modal functional magnetic resonance imaging (ChiCTR2100047989), Submitted June 2021, First Patient Enrolled July 2021.

Abstract One ubiquitous feature of human intelligence is the ability to flexibly switch between multiple tasks. Abstract task representations provide a basis for task learning, switching, and generalization, yet how the brain coordinates multiple task representations to support multitasking and task-switching remains poorly understood. We recorded functional MRI activity in human participants while they concurrently held multiple task rules in working memory and prioritized different rules for stimulus processing across trials. Our results reveal two distinct coding schemes for task prioritization. First, an active coding scheme supports the spatial separation of prioritized and unprioritized task rules: prioritized rules are represented across a distributed cortical network, whereas unprioritized rules are only found in the posterior cortex. Second, besides this active scheme, subregions of the default mode network, including the medial prefrontal cortex and hippocampus, contribute to offloading task representations into an unprioritized state and subsequently maintain sustained representations of these rules across trials via latent neural codes. Behavioral predictions using on-task, trial-wise and sustained, block-wise representations further support the neural dissociation. These findings unveil a dual neural system with distinct coding schemes that jointly enable cognitive flexibility for task implementation and switching.

The number and diversity of inhibitory neurons (INs) increased substantially during mammalian brain evolution. However, the generative mechanisms of the vast repertoire of human INs remain elusive. We performed spatial and single-cell transcriptomics of human medial ganglionic eminence (hMGE), a pivotal source of cortical and subpallial INs, and built the trajectories of hMGE-derived cells during brain development. We identified spatiotemporally and molecularly segregated progenitor cell populations fated to produce distinct IN types. We uncovered an evolutionarily distinct progenitor cell type in the hMGE subventricular zone that maintained the production of INs and glial cells throughout human brain development. Our findings reveal evolutionarily distinct features of IN generation and shed light on the distinct mechanisms underlying human brain development.