Journal of Neuroscience最新文献

Learning occurs across multiple timescales, with fast learning crucial for adapting to sudden environmental changes, and slow learning beneficial for extracting robust knowledge from multiple events. Here we asked if miscalibrated fast vs slow learn-ing can lead to maladaptive decision-making in individuals with problem gambling. We recruited participants with problem gambling (PG; N=20; 9 female and 11 male) and a recreational gambling control group without any symptoms associated with problem gambling (N=20; 10 female and 10 male) from the community in Los Ange-les, CA. Participants performed a decision-making task involving reward-learning and loss-avoidance while being scanned with fMRI. Using computational model fitting, we found that individuals in the PG group showed evidence for an excessive dependence on slow timescales and a reduced reliance on fast timescales during learning. fMRI data implicated the putamen, an area associated with habit, and medial prefrontal cortex (PFC) in slow loss-value encoding, with significantly more robust encoding in medial PFC in the PG group compared to controls. The PG group also exhibited stronger loss prediction error encoding in the insular cortex. These findings suggest that individuals with PG have an impaired ability to adjust their predictions following losses, manifested by a stronger influence of slow value learning. This impairment could contribute to the behavioral inflexibility of problem gamblers, particularly the persistence in gambling behavior typically observed in those individuals after incur-ring loss outcomes.Significance Statement Over five million American adults are considered to experience problem gambling, leading to financial and social devastation. Yet the neural basis of problem gambling remains elusive, impeding the development of effective treatments. We apply computational modeling and neuroimaging to understand the mechanisms underlying problem gambling. In a decision-making task involving reward-learning and loss-avoidance, individuals with problem gambling show an impaired behavioral adjustment following losses. Computational model-driven analyses suggest that, while all participants relied on learning over both fast and slow timescales, individuals with problem gambling showed increased reliance on slow-learning from losses. Neuroimaging identified the putamen, medial prefrontal cortex, and insula as key brain regions in this learning disparity. This research offers new insights into the altered neural computations underlying problem gambling.

A key challenge in understanding the functional organisation of visual cortex stems from the fact that only a small proportion of the objects experienced during natural viewing can be presented in a typical experiment. This constraint often leads to experimental designs that compare responses to objects from experimenter-defined stimulus conditions, potentially limiting the interpretation of the data. To overcome this issue, we used images from the THINGS initiative, which provides a systematic sampling of natural objects. A data-driven analysis was then applied to reveal the functional organisation of the visual brain, incorporating both perceptual and neural responses to these objects. Perceptual properties of the objects were taken from an analysis of similarity judgements, and neural properties were taken from whole brain fMRI responses to the same objects. Partial least squares regression (PLSR) was then used to predict neural responses across the brain from the perceptual properties while simultaneously applying dimensionality reduction. The PLSR model accurately predicted neural responses across visual cortex using only a small number of components. These components revealed smooth, graded neural topographies, which were similar in both hemispheres, and captured a variety of object properties including animacy, real-world size, and object category. However, they did not accord in any simple way with previous theoretical perspectives on object perception. Instead, our findings suggest that visual cortex encodes information in a statistically efficient manner, reflecting natural variability among objects.Significance statement The ability to recognise objects is fundamental to how we interact with our environment, yet the organising principles underlying neural representations of visual objects remain contentious. In this study, we sought to address this question by analysing perceptual and neural responses to a large, unbiased sample of objects. Using a data-driven approach, we leveraged perceptual properties of objects to predict neural responses using a small number of components. This model predicted neural responses with a high degree of accuracy across visual cortex. The components did not directly align with previous explanations of object perception. Instead, our findings suggest the organisation of the visual brain is based on the statistical properties of objects in the natural world.

Protocadherins, a family of adhesion molecules with crucial role in cell-cell interactions, have emerged as key players in neurodevelopmental and psychiatric disorders. In particular, growing evidence links genetic alterations in Protocadherin 9 (PCDH9) gene with Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD). Furthermore, Pcdh9 deletion induces neuronal defects in the mouse somatosensory cortex, accompanied by sensorimotor and memory impairment. However, the synaptic and molecular mechanisms of PCDH9 in the brain remain largely unknown, particularly concerning its impact on brain pathology. To address this question, we conducted a comprehensive investigation of PCDH9 role in the male mouse hippocampus at the ultrastructural, biochemical, transcriptomic, electrophysiological and network level. We show that PCDH9 mainly localizes at glutamatergic synapses and its expression peaks in the first week after birth, a crucial time window for synaptogenesis. Strikingly, Pcdh9 KO neurons exhibit oversized presynaptic terminal and postsynaptic density (PSD) in the CA1. Synapse overgrowth is sustained by the widespread up-regulation of synaptic genes, as revealed by single-nucleus RNA-seq (snRNA-seq), and the dysregulation of key drivers of synapse morphogenesis, including the SHANK2/CORTACTIN pathway. At the functional level, these structural and transcriptional abnormalities result into increased excitatory postsynaptic currents (mEPSC) and reduced network activity in the CA1 of Pcdh9 KO mice. In conclusion, our work uncovers Pcdh9 pivotal role in shaping the morphology and function of CA1 excitatory synapses, thereby modulating glutamatergic transmission within hippocampal circuits.Significance statement Converging evidence indicates that genetic alterations in Protocadherin 9 (PCDH9) gene are associated with Autism Spectrum Disorder (ASD) and Major Depressive Disorder (MDD). However, our understanding of PCDH9 physiological role and molecular mechanisms in the brain, as well as its connection to synaptic dysfunction and brain pathology, remains limited. Here we demonstrate that Pcdh9 regulates the transcriptional profile, morphology and function of glutamatergic synapses in the CA1, thereby tuning hippocampal network activity. Our results elucidate the molecular and synaptic mechanisms of a gene implicated in neurodevelopmental and psychiatric disorders, and suggest potential hippocampal alterations contributing to the cognitive deficits associated with these conditions.

Neuronal hyperexcitability is a hallmark of epilepsy. It has been recently shown in rodent models of seizures that microglia, the brain's resident immune cells, can respond to and modulate neuronal excitability. However, how human microglia interact with human neurons to regulate hyperexcitability mediated by an epilepsy-causing genetic mutation found in patients is unknown. The SCN2A gene is responsible for encoding the voltage-gated sodium channel Nav1.2, one of the leading contributors to monogenic epilepsies. Previously, we demonstrated that the recurring Nav1.2-L1342P mutation leads to hyperexcitability in a male donor (KOLF2.1) hiPSC-derived cortical neuron model. Microglia originate from a different lineage (yolk sac) and are not naturally present in hiPSCs-derived neuronal cultures. To study how microglia respond to neurons carrying a disease-causing mutation and influence neuronal excitability, we established a co-culture model comprising hiPSC-derived neurons and microglia. We found that microglia display increased branch length and enhanced process-specific calcium signal when co-cultured with Nav1.2-L1342P neurons. Moreover, the presence of microglia significantly lowered the repetitive action potential firing and current density of sodium channels in neurons carrying the mutation. Additionally, we showed that co-culturing with microglia led to a reduction in sodium channel expression within the axon initial segment of Nav1.2-L1342P neurons. Furthermore, we demonstrated that Nav1.2-L1342P neurons release a higher amount of glutamate compared to control neurons. Our work thus reveals a critical role of human iPSCs-derived microglia in sensing and dampening hyperexcitability mediated by an epilepsy-causing mutation.Significance Statement Seizure studies in mouse models have highlighted the role of microglia in modulating neuronal activity, particularly in the promotion or suppression of seizures. However, a gap persists in comprehending the influence of human microglia on intrinsically hyperexcitable neurons carrying epilepsy-associated pathogenic mutations. This research addresses this gap by investigating human microglia and their impact on neuronal functions. Our findings demonstrate that microglia exhibit dynamic morphological alterations and calcium fluctuations in the presence of neurons carrying an epilepsy-associated SCN2A mutation. Furthermore, microglia suppressed the excitability of hyperexcitable neurons, suggesting a potential beneficial role. This study underscores the role of microglia in the regulation of abnormal neuronal activity, providing insights into therapeutic strategies for neurological conditions associated with hyperexcitability.

Production of rapid movement sequences relies on preparation before (pre-planning) and during (online planning) movement. Here, we compared these processes and asked whether they recruit different cortical areas. Human participants performed three single-finger and three multi-finger sequences in a delayed movement paradigm while undergoing 7T functional MRI. During preparation, primary motor (M1) and somatosensory (S1) areas showed pre-activation of the first movement, even without increases in overall activation. During production, the temporal summation of activity patterns corresponding to constituent fingers explained activity in these areas (M1 and S1). In contrast, the dorsal premotor cortex (PMd) and anterior superior parietal lobule (aSPL) showed substantial activation during the preparation (pre-planning) of multi-finger compared to single-finger sequences. These regions (PMd and aSPL) were also more active during production of multi-finger sequences, suggesting that pre- and online planning may recruit the same regions. However, we observed small but robust differences between the two contrasts, suggesting distinct contributions to pre- and online planning. Multivariate analysis revealed sequence-specific representations in both PMd and aSPL, which remained stable across both preparation and production phases. Our analyses show that these areas maintain a sequence-specific representation before and during sequence production, likely guiding the execution-related areas in the production of rapid movement sequences.Significance Statement Understanding how the brain orchestrates complex behavior remains a core challenge in human neuroscience. Here, we combine high-resolution neuroimaging and a carefully crafted design to study the neural control of rapid sequential finger movements, like typing or playing the piano. Advancing prior research, we show that the brain areas involved in planning these movements maintain those representations throughout the execution of the sequence. This representational stability across planning and execution suggests an intricate connection between these processes. Our results shed light on the nuanced contributions of different cortical areas to different aspects of coordinating skilled movement. This work is well placed to inform future research in animal models and the development of targeted interventions against movement disorders.

Understanding how heterogeneous neural populations represent sensory input to give rise to behavior remains a central problem in systems neuroscience. Here we investigated how midbrain neurons within the electrosensory system of Apteronotus leptorhynchus code for object location in space. In vivo simultaneous recordings were achieved via Neuropixels probes, high-density electrode arrays, with the stimulus positioned at different locations relative to the animal. Midbrain neurons exhibited heterogeneous response profiles, with a significant proportion (65%) seemingly non-responsive to moving stimuli. Remarkably, we found that non-responsive neurons increased population coding of object location through synergistic interactions with responsive neurons by effectively reducing noise. Mathematical modeling demonstrated that increased response heterogeneity together with the experimentally observed correlations was sufficient to give rise to independent encoding by responsive neurons. Further, addition of non-responsive neurons in the model gave rise to synergistic population coding. Taken together, our findings reveal that non-responsive neurons, which are frequently excluded from analysis, can significantly improve population coding of object location through synergistic interactions with responsive neurons. Combinations of responsive and non-responsive neurons have been observed in sensory systems across taxa; it is likely that similar synergistic interactions improve population coding across modalities and behavioral tasks.Significance Statement Here we show that including the activities of non-responsive neurons with those of responsive neurons increases Fisher information about stimulus location. Further analysis revealed that this is because including non-responsive neurons led to reduced noise levels for responsive neurons. A combination of multi-unit recordings from neural populations and mathematical modeling reveals that response heterogeneity and spatially decaying correlations are necessary to observe this effect. It is likely that synergistic population coding by responsive and non-responsive neurons will be observed in other systems.

Cognitive models of reading assume that speech production occurs after visual and phonological processing of written words. This traditional view is at odds with more recent magnetoencephalography studies showing that the left posterior inferior frontal cortex (pIFC) classically associated with spoken production responds to print at 100-150 ms after word-onset, almost simultaneously with posterior brain regions for visual and phonological processing. Yet the theoretical significance of this fast neural response remains open to date. We used transcranial magnetic stimulation (TMS) to investigate how the left pIFC contributes to the early stage of reading. In Experiment 1, 23 adult participants (14 females) performed three different tasks about written words (oral reading, semantic judgment and perceptual judgment) while single-pulse TMS was delivered to the left pIFC, fusiform gyrus or supramarginal gyrus at different time points (50 to 200 ms after word-onset). A robust double dissociation was found between tasks and stimulation sites - oral reading, but not other control tasks, was disrupted only when TMS was delivered to pIFC at 100 ms. This task-specific impact of pIFC stimulation was further corroborated in Experiment 2, which revealed another double dissociation between oral reading and picture naming. These results demonstrate that the left pIFC specifically and causally mediates rapid computation of speech motor codes at the earliest stage of reading and suggest that this fast sublexical neural pathway for pronunciation, although seemingly dormant, is fully functioning in literate adults. Our results further suggest that these left-hemisphere systems for reading overall act faster than known previously.Significance Statement Recent neuroimaging data suggest that left posterior inferior frontal cortex, classically associated with spoken production, responds to print simultaneously with left fusiform and supramarginal gyri, each responsible for visual and phonological processing, contrary to traditional serial cascade models of reading. While the region is now known to mediate different aspects of cognitive processing, the functional significance of this fast neural response remains unclear. Using transcranial magnetic stimulation, we show that early inferior frontal activation plays a specific and causal role in speeded oral reading at 100 ms after word-onset. This fast sublexical neural pathway for pronunciation, although seemingly dormant, is fully functioning in literate adults. We also propose that the left-hemisphere reading systems act differently and faster than known previously.

The sudden appearance of a visual distractor shortly before saccade initiation can capture spatial attention and modulate the saccade trajectory in spite of the ongoing execution of the initial plan to shift gaze straight to the saccade target. To elucidate the neural correlates underlying these curved saccades, we recorded from single neurons in the frontal eye field of two male rhesus monkeys shifting gaze to a target while a distractor with the same eccentricity appeared either left or right of the target at various delays after target presentation. We found that the population level of presaccadic activity of neurons representing the distractor location encoded the direction of the saccade trajectory. Stronger activity occurred when saccades curved toward the distractor, and weaker when saccades curved away. This relationship held whether the distractor was ipsilateral or contralateral to the recorded neurons. Meanwhile, visually responsive neurons showed asymmetrical patterns of excitatory responses that varied with the location of the distractor and the duration of distractor processing relating to attentional capture and distractor inhibition. During earlier distractor processing, neurons encoded curvature toward the distractor. During later distractor processing, neurons encoded curvature away from the distractor. This was observed when saccades curved away from distractors contralateral to the recording site and when saccades curved toward distractors ipsilateral to the recording site. These findings indicate that saccadic motor planning involves dynamic push-pull hemispheric interactions producing attraction or repulsion for potential but unselected saccade targets.

Endogenous reprogramming of glia into neurogenic progenitors holds great promise for neuron restoration therapies. Using lessons from regenerative species, we have developed strategies to stimulate mammalian Müller glia to regenerate neurons in vivo in the adult retina. We have demonstrated that the transcription factor Ascl1 can stimulate Müller glia neurogenesis. However, Ascl1 is only able to reprogram a subset of Müller glia into neurons. We have reported that neuroinflammation from microglia inhibits neurogenesis from Müller glia. Here we found that the peripheral immune response is a barrier to CNS regeneration. We show that monocytes from the peripheral immune system infiltrate the injured retina and negatively influence neurogenesis from Müller glia. Using CCR2 knock-out mice of both sexes, we found that preventing monocyte infiltration improves the neurogenic and proliferative capacity of Müller glia stimulated by Ascl1. Using scRNA-seq analysis, we identified a signaling axis wherein Osteopontin, a cytokine highly expressed by infiltrating immune cells is sufficient to suppress mammalian neurogenesis. This work implicates the response of the peripheral immune system as a barrier to regenerative strategies of the retina.

Basolateral amygdala (BLA) neurons are engaged by emotionally salient stimuli. An area of increasing interest is how BLA dynamics relate to evolving reward-seeking behavior, especially under situations of uncertainty or ambiguity. Here, we recorded the activity of individual BLA neurons in male rats across the acquisition and extinction of conditioned reward seeking. We assessed ongoing neural dynamics in a task where long reward cue presentations preceded an unpredictable, variably time reward delivery. We found that, with training, BLA neurons discriminated the CS+ and CS- cues with sustained cue-evoked activity that correlated with behavior and terminated only after reward receipt. BLA neurons were bidirectionally modulated, with a majority showing prolonged inhibition during cued reward seeking. Strikingly, population-level analyses revealed that neurons showing cue-evoked inhibitions and those showing excitations similarly represented the CS+ and behavioral state. This sustained population code rapidly extinguished in parallel with conditioned behavior. We next assessed the contribution of the orbitofrontal cortex (OFC), a major reciprocal partner to the BLA. Inactivation of the OFC while simultaneously recording in the BLA revealed a blunting of sustained cue-evoked activity in the BLA that accompanied reduced reward seeking. Optogenetic disruption of BLA activity and OFC terminals in the BLA also reduced reward seeking. Our data indicate that the BLA represents reward-seeking states via sustained, bidirectional cue-driven neural encoding. This code is regulated by cortical input and is important for the maintenance of vigilant reward-seeking behavior.