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The spatial periodic computation of hippocampus-entorhinal circuit in navigation To achieve the computational goal of navigating in both physical and mental spaces, human brain employs a cognitive map constructed by the global metrics of the entorhinal cortex and the local locations of the hippocampus. However, how these two regions work collaboratively in navigation remains unclear. Here, we designed an object-matching task where human participants unknowingly manipulated object variants arranged in a ring-like structure around a central prototype. Functional MRI revealed a 3-fold spatial periodicity of hippocampal activity, which tracked the navigation path from the original object variants to the central prototype in the object space. Importantly, this spatial periodicity of the hippocampus was phase-locked with the well-documented 6-fold periodicity of the entorhinal cortex, suggesting a periodic scaffold connecting these two regions. In addition, a 3-fold periodicity was found embedded in human behavior, which fluctuated as a function of the navigation path and phase-locked with hippocampal activity. Finally, we proposed an E-H PhaseSync model to illustrate that the spatial periodicity originated from the population activity of entorhinal grid cells may serve as a scaffold in the hippocampal-entorhinal network, where hippocampal vector fields emerge as the neural basis for utilizing the cognitive map in navigation.

EEG markers of successful allocentric spatial working memory maintenance in humans Several brain regions in the frontal, occipital and medial temporal lobes are known to contribute to spatial information processing. In contrast, the oscillatory patterns contributing to allocentric spatial working memory maintenance are poorly understood, especially in humans. Here, we tested twenty-three 21- to 32-year-old and twenty-two 64- to 76-year-old healthy right-handed adults in a real-world, spatial working memory task and recorded electroencephalographic (EEG) activity during the maintenance period. We established criteria for designating recall trials as perfect (no errors) or failed (errors and random search) and identified 8 young and 13 older adults who had at least 1 perfect and 1 failed trial amongst 10 recall trials. Individual alpha frequency–based analyses were used to identify oscillatory patterns during the maintenance period of perfect and failed trials. Spectral scalp topographies showed that individual theta frequency band relative power was stronger in perfect than in failed trials in the frontal midline and posterior regions. Similarly, gamma band (30–40 Hz) relative power was stronger in perfect than in failed trials over the right motor cortex. Exact low-resolution brain electromagnetic tomography in the frequency domain identified greater theta power in perfect than in failed trials in the secondary visual area (BA19) and greater gamma power in perfect than in failed trials in the right supplementary motor area. The findings of this exploratory study suggest that theta oscillations in the occipital lobe and gamma oscillations in the secondary motor cortex (BA6) play a particular role in successful allocentric spatial working memory maintenance.

Human iPSC-Derived Neurons with Reliable Synapses and Large Presynaptic Action Potentials Understanding the function of the human brain requires determining basic properties of synaptic transmission in human neurons. One of the most fundamental parameters controlling neurotransmitter release is the presynaptic action potential, but its amplitude and duration remain controversial. Presynaptic action potentials have so far been measured with high temporal resolution only in a limited number of vertebrate but not in human neurons. To uncover properties of human presynaptic action potentials, we exploited recently developed tools to generate human glutamatergic neurons by transient expression of Neurogenin 2 (Ngn2) in pluripotent stem cells. During maturation for 3 to 9 weeks of culturing in different established media, the proportion of cells with multiple axon initial segments decreased, while the amount of axonal tau protein and neuronal excitability increased. Super-resolution microscopy revealed the alignment of the pre- and postsynaptic proteins, Bassoon and Homer. Synaptic transmission was surprisingly reliable at frequencies of 20, 50, and 100 Hz. The synchronicity of synaptic transmission during high-frequency transmission increased during 9 weeks of neuronal maturation. To analyze the mechanisms of synchronous high-frequency glutamate release, we developed direct presynaptic patch-clamp recordings from human neurons. The presynaptic action potentials had large overshoots to ∼25 mV and short durations of ∼0.5 ms. Our findings show that Ngn2-induced neurons represent an elegant model system allowing for functional, structural, and molecular analyses of glutamatergic synaptic transmission with high spatiotemporal resolution in human neurons. Furthermore, our data predict that glutamatergic transmission is mediated by large and rapid presynaptic action potentials in the human brain.

Synapse-type-specific competitive Hebbian learning forms functional recurrent networks Cortical networks exhibit complex stimulus–response patterns that are based on specific recurrent interactions between neurons. For example, the balance between excitatory and inhibitory currents has been identified as a central component of cortical computations. However, it remains unclear how the required synaptic connectivity can emerge in developing circuits where synapses between excitatory and inhibitory neurons are simultaneously plastic. Using theory and modeling, we propose that a wide range of cortical response properties can arise from a single plasticity paradigm that acts simultaneously at all excitatory and inhibitory connections—Hebbian learning that is stabilized by the synapse-type-specific competition for a limited supply of synaptic resources. In plastic recurrent circuits, this competition enables the formation and decorrelation of inhibition-balanced receptive fields. Networks develop an assembly structure with stronger synaptic connections between similarly tuned excitatory and inhibitory neurons and exhibit response normalization and orientation-specific center-surround suppression, reflecting the stimulus statistics during training. These results demonstrate how neurons can self-organize into functional networks and suggest an essential role for synapse-type-specific competitive learning in the development of cortical circuits.

Cortical Face-Selective Responses Emerge Early in Human Infancy In human adults, multiple cortical regions respond robustly to faces, including the occipital face area (OFA) and fusiform face area (FFA), implicated in face perception, and the superior temporal sulcus (STS) and medial prefrontal cortex (MPFC), implicated in higher level social functions. When in development does face selectivity arise in each of these regions? Here, we combined two awake infant functional magnetic resonance imaging (fMRI) datasets to create a sample size twice the size of previous reports (n = 65 infants, 2.6-9.6 months). Infants watched movies of faces, bodies, objects, and scenes while fMRI data were collected. Despite variable amounts of data from each infant, individual subject whole-brain activation maps revealed responses to faces compared to non-face visual categories in the approximate location of OFA, FFA, STS, and MPFC. To determine the strength and nature of face selectivity in these regions, we used cross-validated functional region of interest (fROI) analyses. Across this larger sample size, face responses in OFA, FFA, STS, and MPFC were significantly greater than responses to bodies, objects, and scenes. Even the youngest infants (2-5 months) showed significantly face-selective responses in FFA, STS, and MPFC, but not OFA. These results demonstrate that face selectivity is present in multiple cortical regions within months of birth, providing powerful constraints on theories of cortical development.

The role of frontal cortex in novel-word learning and consolidation: Evidence from focal transcranial direct current stimulation Previous studies have demonstrated that conventional transcranial direct current stimulation (tDCS) can enhance novel-word learning. However, because of the widespread current that is induced by these setups and lack of appropriate control conditions, little is known about the underlying neural mechanisms. In the present double-blinded and sham-tDCS controlled study, we investigated for the first time if regionally precise focal tDCS targeting two key nodes of the novel-word learning network at different time points would result in regionally and temporally distinct effects. 156 participants completed a contextual novel-word-learning paradigm and learning success was probed immediately after the acquisition period and 30-min later. Participants were randomly assigned to six stimulation conditions: Active tDCS (1.5 mA) was administered to left inferior frontal (IFG) or middle temporal gyrus (MTG), either during acquisition or delayed recall. Control groups received sham-tDCS either during acquisition or delayed recall (50% IFG/MTG). Data were analyzed with a generalized linear mixed model with a binomial link function in a Bayesian framework. Our results showed that frontal tDCS selectively increased accuracy gains from immediate to delayed recall, irrespective of timing of the stimulation. There was no evidence for beneficial effects of middle temporal gyrus tDCS. Our findings confirm that IFG tDCS can enhance novel-word learning in a regionally, but not timing specific way. Tentatively, this may be explained by enhancement of semantic selection processes resulting in more effective consolidation and/or retrieval. Future studies using longer time intervals between assessments are required to clarify the potential contribution of neurophysiological after-effects of IFG tDCS administered during acquisition to enhanced consolidation.

Microglia aging in the hippocampus advances through intermediate states that drive inflammatory activation and cognitive decline During aging, microglia – the resident macrophages of the brain – exhibit dystrophic phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia dystrophy have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis. Single-cell RNA-Seq and pseudotime analysis revealed age-related transcriptional heterogeneity in hippocampal microglia and identified intermediate states of microglial aging that also emerge following heterochronic parabiosis. We tested the functionality of intermediate stress response states via TGFβ1 and translational states using pharmacological approaches in vitro to reveal their modulation of the progression to an inflammatory state. Furthermore, we utilized single-cell RNA-Seq in conjunction with an in vivo adult microglia-specific Tgfb1 conditional genetic knockout mouse model, to demonstrate that microglia advancement through intermediate aging states drives inflammatory activation and associated hippocampal-dependent cognitive decline.

Perceptual task drives later fixations and long latency saccades, while early fixations and short latency saccades are more automatic We used a simple stimulus, dissociating perceptually relevant information in space, to differentiate between bottom-up and task-driven fixations. Six participants viewed a dynamic scene showing the reaction of an elastic object fixed to the ceiling being hit. In one condition they had to judge the object’s stiffness and in the other condition its lightness. The results show that initial fixations tend to land in the centre of an object, independent of the task. After the initial fixation, participants tended to look at task diagnostic regions. This fixation behaviour correlates with high perceptual performance. Similarly, low-latency saccades lead to fixations that do not depend on the task, whereas higher latency does.