Reelin, a secreted glycoprotein, plays a crucial role in guiding neocortical neuronal migration, dendritic outgrowth and arborization, and synaptic plasticity in the adult brain. Reelin primarily operates through the canonical lipoprotein receptors apolipoprotein E receptor 2 (Apoer2) and very low-density lipoprotein receptor (Vldlr). Reelin also engages with noncanonical receptors and unidentified coreceptors; however, the effects of which are less understood. Using high-throughput tandem mass tag (TMT) liquid chromatography tandem mass spectrometry (LC-MS/MS)-based proteomics and gene set enrichment analysis (GSEA), we identified both shared and unique intracellular pathways activated by Reelin through its canonical and noncanonical signaling in primary murine neurons of either sex during dendritic growth and arborization. We observed pathway cross talk related to regulation of cytoskeleton, neuron projection development, protein transport, and actin filament-based process. We also found enriched gene sets exclusively by the noncanonical Reelin pathway including protein translation, mRNA metabolic process, and ribonucleoprotein complex biogenesis suggesting Reelin fine-tunes neuronal structure through distinct signaling pathways. A key discovery is the identification of aldolase A, a glycolytic enzyme and actin-binding protein, as a novel effector of Reelin signaling. Reelin induced de novo translation and mobilization of aldolase A from the actin cytoskeleton. We demonstrated that aldolase A is necessary for Reelin-mediated dendrite growth and arborization in primary murine neurons and mouse brain cortical neurons. Interestingly, the function of aldolase A in dendrite development is independent of its known role in glycolysis. Altogether, our findings provide new insights into the Reelin-dependent signaling pathways and effector proteins that are crucial for dendritic development.

Neural circuits supporting innate behaviors, such as feeding, exploration, and social interaction, intermingle in the lateral hypothalamus (LH). Although previous studies have shown that individual LH neurons change their firing relative to the baseline during one or more behaviors, the firing rate dynamics of LH populations within behavioral episodes and the coordination of behavior-related LH populations remain largely unknown. Here, using unsupervised graph-based clustering of LH neurons firing rate dynamics in freely behaving male mice, we identified distinct populations of cells whose activity corresponds to feeding, specific times during feeding bouts, or other innate behaviors—social interaction and novel object exploration. Feeding-related cells fired together with a higher probability during slow and fast gamma oscillations (30–60 and 60–90 Hz) than during nonrhythmic epochs. In contrast, the cofiring of neurons signaling other behaviors than feeding was overall similar between slow gamma and nonrhythmic epochs but increased during fast gamma oscillations. These results reveal a neural organization of ethological hierarchies in the LH and point to behavior-specific motivational systems, the dysfunction of which may contribute to mental disorders.

Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4b^M220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone–shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4b^M220T mice. At 24 h post-trauma, Pde4b^M220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4b^M220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.

Low-intensity transcranial focused ultrasound stimulation (TUS) is a novel technique for noninvasive brain stimulation (NIBS). TUS delivered in a theta (5 Hz) burst pattern (tbTUS) induces plasticity in the human primary motor cortex (M1) for 30–60 min, showing promise for therapeutic development. Metaplasticity refers to activity-dependent changes in neural functions governing synaptic plasticity; depotentiation is the reversal of long-term potentiation (LTP) by a subsequent protocol with no effect alone. Metaplasticity can enhance plasticity induction and clinical efficacy of NIBS protocols. In our study, we compared four NIBS protocol combinations to investigate metaplasticity on tbTUS in humans of either sex. We delivered four interventions: (1) sham continuous theta burst stimulation with 150 pulses (cTBS150) followed by real tbTUS (tbTUS only), (2) real cTBS150 followed by sham tbTUS (cTBS only), (3) real cTBS150 followed by real tbTUS (metaplasticity), and (4) real tbTUS followed by real cTBS150 (depotentiation). We measured motor-evoked potential amplitude, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation (ICF), and short-interval intracortical facilitation before and up to 90 min after plasticity intervention. Plasticity effects lasted at least 60 min longer when tbTUS was primed with cTBS150 compared with tbTUS alone. Plasticity was abolished when cTBS150 was delivered after tbTUS. cTBS150 alone had no significant effect. No changes in M1 intracortical circuits were observed. Plasticity induction by tbTUS can be modified in manners consistent with homeostatic metaplasticity and depotentiation. This substantiates evidence that tbTUS induces LTP-like processes and suggests that metaplasticity can be harnessed in the therapeutic development of TUS.

In demanding listening situations, a listener's motivational state may affect their cognitive investment. Here, we aim to delineate how domain-specific sensory processing, domain-general neural alpha power, and pupil size as a proxy for cognitive investment encode influences of motivational state under demanding listening. Participants (male and female) performed an auditory gap-detection task while the pupil size and the magnetoencephalogram were simultaneously recorded. Task demand and a listener's motivational state were orthogonally manipulated through changes in gap duration and monetary-reward prospect, respectively. Whereas task difficulty impaired performance, reward prospect enhanced it. The pupil size reliably indicated the modulatory impact of an individual's motivational state. At the neural level, the motivational state did not affect auditory sensory processing directly but impacted attentional postprocessing of an auditory event as reflected in the late evoked-response field and alpha-power change. Both pregap pupil dilation and higher parietal alpha power predicted better performance at the single-trial level. The current data support a framework wherein the motivational state acts as an attentional top–down neural means of postprocessing the auditory input in challenging listening situations.

Systemic study of pathogenic pathways and interrelationships underlying genes associated with Alzheimer's disease (AD) facilitates the identification of new targets for effective treatments. Recently available large-scale multiomics datasets provide opportunities to use computational approaches for such studies. Here, we devised a novel disease gene identification (digID) computational framework that consists of a semi-supervised deep learning classifier to predict AD-associated genes and a protein–protein interaction (PPI) network-based analysis to prioritize the importance of these predicted genes in AD. digID predicted 1,529 AD-associated genes and revealed potentially new AD molecular mechanisms and therapeutic targets including GNAI1 and GNB1, two G-protein subunits that regulate cell signaling, and KNG1, an upstream modulator of CDC42 small G-protein signaling and mediator of inflammation and candidate coregulator of amyloid precursor protein (APP). Analysis of mRNA expression validated their dysregulation in AD brains but further revealed the significant spatial patterns in different brain regions as well as among different subregions of the frontal cortex and hippocampi. Super-resolution STochastic Optical Reconstruction Microscopy (STORM) further demonstrated their subcellular colocalization and molecular interactions with APP in a transgenic mouse model of both sexes with AD-like mutations. These studies support the predictions made by digID while highlighting the importance of concurrent biological validation of computationally identified gene clusters as potential new AD therapeutic targets.

Estimating the direction of functional connectivity (FC) can help further elucidate complex brain function. However, the estimation of directed FC at the voxel level in fMRI data, and evaluating its performance, has yet to be done. We therefore developed a novel directed seed-based connectivity analysis (SCA) method based on normalized pairwise Granger causality that provides greater detail and accuracy over ROI-based methods. We evaluated its performance against 145 cortical retrograde tracer injections in male and female marmosets that were used as ground truth cellular connectivity on a voxel-by-voxel basis. The receiver operating characteristic (ROC) curve was calculated for each injection, and we achieved area under the ROC curve of 0.95 for undirected and 0.942 for directed SCA in the case of high cell count threshold. This indicates that SCA can reliably estimate the strong cellular connections between voxels in fMRI data. We then used our directed SCA method to analyze the human default mode network (DMN) and found that dlPFC (dorsolateral prefrontal cortex) and temporal lobe were separated from other DMN regions, forming part of the language-network that works together with the core DMN regions. We also found that the cerebellum (Crus I-II) was strongly targeted by the posterior parietal cortices and dlPFC, but reciprocal connections were not observed. Thus, the cerebellum may not be a part of, but instead a target of, the DMN and language-network. Summarily, our novel directed SCA method, visualized with a new functional flat mapping technique, opens a new paradigm for whole-brain functional analysis.

Impaired inhibitory synapse development is suggested to drive neuronal hyperactivity in autism spectrum disorders (ASD) and epilepsy. We propose a novel mechanism by which astrocytes control the development of parvalbumin (PV)-specific inhibitory synapses in the hippocampus, implicating ephrin-B/EphB signaling. Here, we utilize genetic approaches to assess functional and structural connectivity between PV and pyramidal cells (PCs) through whole-cell patch–clamp electrophysiology, optogenetics, immunohistochemical analysis, and behaviors in male and female mice. While inhibitory synapse development is adversely affected by PV-specific expression of EphB2, a strong candidate ASD risk gene, astrocytic ephrin-B1 facilitates PV->PC connectivity through a mechanism involving EphB signaling in PV boutons. In contrast, the loss of astrocytic ephrin-B1 reduces PV->PC connectivity and inhibition, resulting in increased seizure susceptibility and an ASD-like phenotype. Our findings underscore the crucial role of astrocytes in regulating inhibitory circuit development and discover a new role of EphB2 receptors in PV-specific inhibitory synapse development.

A new book reveals striking images from six decades of the beloved Wildlife Photographer of the Year competition

The work of Diné artist DY Begay, now on view at the National Museum of the American Indian, blends tradition and modernity

The Smithsonian Design Triennial presents 25 commissions that explore the physical and conceptual ideas of shelter and refuge

A Smithsonian curator reflects back on the artistic legend, a "Renaissance man" with 28 Grammys to his name, who died Sunday at 91 years old

Written by the former chief historian of NASA, the book examines the evolution of our cosmic understanding—from early civilizations to the present day

The work, now on view at the Smithsonian American Art Museum, tells the story of two characters on the island—the last people alive in the world

Tens of thousands of farmers are bringing in their first rice harvest just six months after one of the worst typhoons to ever hit the Philippines left their fields in [...]

Prince Laurent of Belgium was today appointed FAO Special Ambassador for Forests and the Environment.

The announcement was made by FAO Director-General José Graziano da Silva at the Organization’s Committee on [...]

FAO, IFAD and WFP/Burkina [...]