Journal of Neuroscience最新文献

Mathematical learning disabilities (MLD) affect up to 14% of school-age children, yet the underlying neurocognitive mechanisms remain elusive. We developed Drift Diffusion Model with Dynamic Performance Monitoring (DDM-DPM), an innovative cognitive model that captures both external and internal sources of structural variability in task performance. Combining DDM-DPM with functional brain imaging, we examined symbolic and non-symbolic quantity discrimination in female and male children with MLD and typically developing children matched on age, gender, and IQ. Children with MLD showed format-dependent alterations in response caution and post-error adjustment, despite similar observed performance measures between groups. The latent cognitive processes during symbolic quantity discrimination predicted broader mathematical abilities better than those during non-symbolic quantity discrimination. Neuroimaging results revealed that reduced activity in middle frontal gyrus mediated deficits in response caution in symbolic format, while reduced activity in the anterior cingulate cortex mediated deficits in post-error adjustment in symbolic format in children with MLD. These findings provide novel support for a multidimensional deficit view of MLD that extends beyond basic number processing to include metacognitive processes. Our findings also provide novel support for and extend the access deficit model, which posits that individuals with MLD may have relatively intact quantity representations but struggle with numerical representations in symbolic formats. Our study highlights the value of integrating latent cognitive modeling with neuroimaging to reveal subtle mechanisms underlying learning disabilities and identify potential targets for intervention.Significance Statement Considerable debate exists regarding the nature of deficits in mathematical learning disabilities (MLD). By developing an innovative computational model that captures subtle aspects of decision-making processes, we reveal that children with MLD show specific difficulties in adapting their problem-solving strategies when working with numerical symbols. Using brain imaging, we found that these difficulties are linked to reduced activity in brain regions involved in monitoring and adjusting behavior. Importantly, these deficits were specific to symbolic number processing and predicted children's broader mathematical abilities. Our findings suggest that MLD involves not only difficulties with basic number processing, but also problems in regulating cognitive strategies when working with numerical symbols. This insight could lead to more effective interventions for children struggling with mathematics.

Our ability to retrieve the names of objects in our environment is a fundamental aspect of everyday life. This process requires a complex, dynamic network of cortical and subcortical interactions. While the cortical constituents of this network have been extensively studied with intracranial recordings, the subcortical nodes of the naming network are unclear. We probed the role of the left medial pulvinar nucleus in naming with direct intracranial recordings and stimulation in eight humans (3 male, 5 female) as they named objects using pictures, and auditory and written descriptions. We found a spectrotemporal signature of naming in the left medial pulvinar nucleus, characterized by a low frequency (8-20Hz) suppression, consistent across sensory modalities during naming, and absent during other non-naming language tasks. Within this frequency band, Granger causal interactions showed that the pulvinar nucleus received strong inputs from early visual, ventral temporal, and parahippocampal cortices. Direct thalamic stimulation reliably induced anomia, confirming that the left medial pulvinar nucleus is a critical node in the distributed naming network.Significance Statement for most people, the ability to retrieve the names of objects is a rapid, effortless process. However, damage to the brain's naming network can disrupt this ability. While the cortical hubs of the naming network have been extensively documented, the contributions of subcortical regions to naming are unclear. We used the rare opportunity to record directly from one such subcortical region, the medial pulvinar nucleus, in patients who were having electrodes placed for the treatment of epilepsy, to characterise its role in naming. Based on its neural activation, functional connectivity with cortical naming hubs, and causal role in behaviour when disrupted, this work provides direct evidence of the critical role of pulvinar in naming.

Parkinson's disease is a late onset neurodegenerative disease characterized by preferential degeneration of midbrain dopaminergic neurons and α-synuclein containing Lewy bodies that are found in both familial and sporadic forms. Genome wide association studies (GWAS) have identified many loci associated with risk of sporadic PD, but their role in PD pathogenesis remains largely unknown. We screened a subset of GWAS genes in Caenorhabditis elegans (C.elegans) as potential modulators of α-synuclein-mediated degeneration of dopaminergic neurons. Loss of ari-2 (human ARIH2), an E3 ubiquitin ligase was identified as the strongest suppressor of dopaminergic neurodegeneration in C.elegans. Unbiased proteomics analysis in human iPSC-derived dopaminergic neurons revealed novel substrates of ARIH2 including TPPP3, a regulator of microtubule dynamics. Importantly, TPPP3 was required for ARIH2's effects on α-synuclein induced dopaminergic neurodegeneration. Our studies reveal an unexpected genetic interaction between two PD-linked genes α-synuclein and ARIH2, and suggest that inhibition of ARIH2's enzymatic activity may serve as a potential therapeutic approach in PD.Significance Statement Parkinson's disease (PD) is a devastating neurodegenerative disorder marked by α-synuclein accumulation. Genome wide association studies (GWAS) have identified multiple risk genes linked to PD but their functional roles and crosstalk with α-synuclein are not completely understood. Here, we screened multiple GWAS-linked genes using an in vivo α-synuclein model of PD. We discovered that loss of αri-2 (human ARIH2), an E3 ubiquitin ligase was the strongest suppressor of dopaminergic neuron loss, and identified substrates of ARIH2 in human dopaminergic neurons which mediate this pathway. This work reveals a genetic interaction between two PD linked genes, ARIH2 and α-synuclein and provides important insights into neurodegeneration in PD.

Flexible prioritisation in working memory (WM) is supported by neural oscillations in frontal and sensory brain areas, but the roles of different oscillations remain poorly understood. Recordings in humans suggest an interplay between prefrontal slow frequency (2-8Hz) and posterior alpha-band (10Hz) oscillations regulating top-down control and retrieval of WM representations, respectively. Complementary work, primarily in non-human primates, suggests an additional role for beta (15-30Hz) oscillations in clearing or inhibiting stimuli from entering WM. Here we investigated the role of neural oscillations in prioritising WM content using electroencephalography (EEG) as participants (humans of any sex) performed a task requiring frequent priority switches between two memorized oriented bars. Behavioural performance revealed switch costs, which scaled with the angular distance between the two items, suggesting that priority shifts are modulated by shift magnitude. Time-frequency analyses revealed increased frontal theta (4-8Hz) and decreased central-parietal beta (15-25Hz) power during switches. Crucially, only beta power scaled with the magnitude of the priority shift and predicted the fidelity of neural decoding of the newly prioritized item during subsequent recall. Theta power, by contrast, was elevated on switch trials but did not vary with update magnitude or decoding strength, suggesting a more general role in signaling control demands. Our findings highlight a particular and previously overlooked role for beta-band oscillations in the flexible prioritisation of WM content.Significance Statement Working memory permits flexible switching between mental representations, so we can focus on what is most relevant at the moment. Different brain rhythms in frontal control and sensory memory storage areas orchestrate switches but their respective roles remain unclear. Here, using EEG, we show that power reductions of ∼20Hz oscillations over central-parietal regions, usually associated with the motor system, closely track the magnitude of the required switch and the fidelity of the prioritized memory. In contrast, slower 4-8Hz (theta-band) activity over frontal regions increases during priority switches but tracks neither magnitude nor fidelity. Our findings suggest a unique function for central-parietal beta oscillations in the flexible control of working memory.

Higher order (HO) thalamic nuclei are characterized by receiving driver input from layer 5 (L5) of cortex and serve as a transthalamic route of corticocortical communication. These HO nuclei are also innervated by subcortical sources. In the posterior medial nucleus (POm), a somatosensory HO thalamic nucleus, excitatory glutamatergic inputs arise from L5 of sensorimotor cortices and the spinal trigeminal nucleus (SpV), while inhibitory GABAergic sources are the anterior pretectal nucleus (APn) and zona incerta (ZI). Here, we tested a key postulate of transthalamic pathway function: that their disynaptic nature allows information traversing them from L5 to be modulated or gated by other inputs. We used optogenetics in acute slices from mice (both sexes) to test individual POm relays for convergent innervation. We found that modulatory inputs from SpV intersect with drivers from L5 of somatosensory cortex. Further, GABAergic inputs from the APn converge with both L5 and SpV inputs. In contrast, we found minimal convergence between ZI and L5 or SpV-a surprise considering previous evidence that ZI blocks whisker-dependent activation of POm relays. Therefore, we sought alternative explanations for this discrepancy. First, we detected robust convergence in POm between the ZI (and APn) and superior colliculus, which is whisker responsive. Second, we discovered that ZI innervates the thalamic reticular nucleus with glutamatergic synapses, comprising an alternative feedforward inhibitory circuit to POm. These results substantiate several mechanisms by which transthalamic information is modulated or gated while enhancing the resolution of our understanding of POm function.Significance Statement Environmental information arrives in cortex via pathways relayed through thalamus. It is then further processed by at least two circuits: direct corticocortical connections and recently appreciated cortico-thalamo-cortical (transthalamic) circuits. But why have transthalamic pathways that parallel direct ones? Here, we provide evidence for a potential reason-information traversing transthalamic circuits can be modified by inputs that converge onto transthalamic relay cells. Indeed, we show that both excitatory modification and inhibitory gating of transthalamic signals, as well as signals to thalamus relayed from certain subcortical sources, occur on relay cells in the somatosensory thalamus. These findings set the stage for understanding how individual thalamic relays integrate bottom-up and top-down (i.e., corticothalamic) information to dynamically regulate interregional cortical communication.

Knowledge of how vocal communication signals are represented in the auditory system is crucial for understanding the perceptual basis of vocal communication. Using male and female zebra finches, we identified a series of differentially expressed markers that helped define distinct (caudal, rostral, dorsal and ventral) domains within the caudomedial nidopallium (NCM), a high-order cortical auditory area known for its song-selective responses. Using expression analysis of the activity-inducible gene zenk, we found that the number of activated neurons is more stimulus dependent in NCM than in the auditory midbrain or the caudomedial mesopallium, and that information on the density and spatial distribution of responsive neurons in NCM is sufficient to discriminate responses to conspecific song from other stimuli. We observed stronger activation of dorsal NCM, higher selectivity of caudal NCM towards conspecific song, and strong activation of the inhibitory network of rostral NCM by non-conspecific song stimuli. Song auditory representation in NCM was dependent on acoustic features, with the spatial organization of responsive cells particularly sensitive to both spectral and temporal components. We also obtained evidence of broadly distributed song-selective neuronal ensembles and that individual NCM neurons participate in the representation of conspecific songs, implying independent activation and molecular induction responses. We conclude that some basic aspects of the cortical response to complex auditory stimuli are topographically organized, a finding that has been elusive in other systems. These findings advance our knowledge of the functional organization of a key song-processing cortical area, providing novel insights into the auditory representation of conspecific vocal communication signals.Significance Statement Understanding how vocal signals are processed and represented in the brain is fundamental to the study of animal communication. Songbirds provide a powerful model for investigating these processes due to their rich vocal behavior and well-characterized neural circuits. Through analysis of differentially expressed markers and mapping of activity-induced gene expression, we have uncovered how different domains and neuronal populations within a high-order auditory cortical area respond to acoustic features of song and other stimuli. Besides providing in-depth knowledge of the functional organization of a key avian brain area, these findings provide insights into how acoustic features of complex learned vocal signals are processed and represented in cortical circuits, including evidence of how basic aspects of this representation can be topographically organized.

The central nervous system is characterized by its limited regenerative potential, yet striking examples of functional recovery after injury in animal models and humans highlight its capacity for repair. Little is known about repair of pathways/circuits after traumatic brain injury (TBI), which results in disruption of connectivity. Here we utilize a mouse model of diffuse traumatic axonal injury (impact-acceleration TBI) in order to explore, for the first time, the evolution of structural and functional changes in the terminal fields of the injured visual system. Retinal ganglion cell (RGC) axons and synapses were genetically labeled via AAV transduction, while anterograde and transsynaptic tracers were used to mark terminals and postsynaptic cells. Functional connectivity and visual integrity were assessed by monitoring c-Fos expression following light stimulation and pattern-reversal visual evoked potentials (pVEPs). Our findings demonstrate that, although TAI results in an ∼50% loss of RGC axons and terminals, surviving RGCs undergo collateral sprouting, a form of compensatory branching of surviving axons, that restores terminal density to preinjury levels. Transsynaptic tracing and c-Fos mapping confirmed the reestablishment of connectivity, which was also associated with significant improvements in visual function as measured by pVEPs. Interestingly, the recovery process exhibited sexual dimorphism, with female mice showing delayed or incomplete repair. Moreover, collateral sprouting proceeded normally in Sarm1 knock-out mice, evidence of some independence from Wallerian degeneration. Our findings show that collateral sprouting may be an important mechanism of circuit repair in TAI and may represent a promising target for therapeutic interventions.

Working memory (WM) capacity has been claimed to be larger for meaningful objects than for simple features, possibly because richer semantic representations enhance item distinctiveness. However, prior demonstrations compared trial-unique meaningful objects with a small set of repeated simple features. This design confounds meaningfulness with proactive interference (PI), such that PI is minimal for trial-unique objects but substantial for repeated features. Therefore, superior performance for meaningful objects may reflect contributions from episodic long-term memory (LTM) rather than expanded WM capacity. To test this, Experiment 1 measured WM for repeated colors, repeated meaningful objects, and trial-unique meaningful objects from 31 human observers (18 females). The advantage for objects over colors was replicated in the trial-unique condition but eliminated for repeated objects that equated PI across stimulus types. Hierarchical Bayesian dual-process modeling revealed that this advantage reflected stronger familiarity signals, whereas recollection remained stable across stimulus types. Experiment 2 assessed WM storage directly using contralateral delay activity (CDA), an electrophysiological marker of the number of items stored, from 25 observers (14 females). Although trial-unique objects again yielded behavioral advantages, CDA activity across increasing set sizes revealed a common slope and plateau for trial-unique meaningful objects and repeated colors. The CDA difference between stimulus types was additive and did not vary with the set size, providing no evidence for increased WM storage. These findings suggest that object advantages in WM reflect reduced PI and enhanced contributions from LTM. When PI is equated, WM storage limits for simple and meaningful stimuli are equivalent.

Visual selective attention is not wired into the brain fully formed and immutable but is acquired and refined as animals learn by interacting with their environment. Here we investigated this process by studying neuronal activity in the superior colliculus (SC) of male and female mice that learned different meanings of the same visual stimuli. We recorded spiking activity of neurons across the superficial and deep SC layers in three cohorts of mice, each trained using a tailored set of task rules that attributed different levels of behavioral relevance to the visual stimuli. Experimental conditions across the three tasks were carefully matched for visual stimulation and task engagement. We found that several markers of attention-related activity depended on the level of learned behavioral relevance, with the strongest effects in deep SC. First, for activity evoked by cue onset, visual responses in superficial SC were larger in animals that exhibited higher learned relevance. In deep SC, the presence of visual onset responses depended entirely on the learned behavioral relevance. Second, traditional attention-related modulation, defined as enhanced steady-state activity for the visual stimulus at the cued location, was also stronger with higher learned relevance, and this effect was limited to deep SC. Finally, the response to the visual change at the cued location was virtually absent when learned behavioral relevance was low but was prominent after visual training. Together, these results reveal that several fundamental features of attention-related modulation depend on the behavioral relevance learned through task-specific training, including aspects of stimulus-driven attention.

N,N-Dimethyltryptamine (DMT) is a serotonergic psychedelic that is being investigated for the treatment of psychiatric disorders. Although the neurophysiological effects of DMT in humans are well characterized, similar studies in animal models and data on the neurochemical effects of DMT are generally lacking, which are critical for a mechanistic understanding. Here, we combined behavioral analysis, high-density (32-channel) electroencephalography, and ultrahigh-performance liquid chromatography-tandem mass spectrometry to simultaneously quantify changes in behavior, cortical neural dynamics, and levels of 17 neurochemicals in medial prefrontal and somatosensory cortices before, during, and after intravenous administration of DMT (0.75, 3.75, 7.5 mg/kg) in male and female adult rats. All three doses of DMT produced head twitch response with most twitches observed after the low dose. DMT caused dose-dependent increases in serotonin and dopamine levels in both cortical sites, a reduction in EEG spectral power in theta (4-10 Hz) and low gamma (25-55 Hz), and an increase in spectral power in delta (1-4 Hz), medium gamma (65-115 Hz), and high gamma (125-155 Hz) bands. Functional connectivity decreased in the delta band and increased across the gamma bands. We detected cortical DMT in baseline wake condition in 70-80% of the animals tested at levels comparable to serotonin and dopamine, which, together with a previous study in the occipital cortex, motivates cross-species studies to confirm endogenous presence of DMT. This study represents one of the most comprehensive characterizations of psychedelic drug action in rats and the first to be conducted with intravenous DMT.