Allen Institute for Brain Science

Dopamine is a monoamine neurotransmitter that regulates neuronal activity and synaptic transmission. While dopaminergic activity is known to suppress action potential-dependent glutamate release in certain brain regions, the modulatory effect of dopaminergic tone on spontaneous glutamate release is unclear. Here, we used primary rat ventral tegmental area-cortex co-cultures to assess how decreased dopaminergic tone affects spontaneous synaptic glutamate release using whole-cell patch-clamp electrophysiology. We found that an acute decrease in dopaminergic tone increases the frequency of spontaneous glutamate release, driven by a surge in basal presynaptic calcium. This presynaptic calcium surge results from disinhibition of voltage-gated calcium channels (VGCCs) due to reduced Gβγ subunit activity downstream of D2 receptor signaling. While acute reduction in dopaminergic tone has robust presynaptic effects, chronic reduction results in homeostatic synaptic plasticity, characterized by postsynaptic insertion of calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, a process known as synaptic upscaling. Notably, chronic antagonism of both D1 and D2 receptors using selective antagonists, as well as long-term treatment with first- and second-generation antipsychotics haloperidol, chlorpromazine, olanzapine, clozapine, and aripiprazole, promoted robust synaptic upscaling. These findings reveal a novel mechanism of action for antipsychotic medications and suggest that antipsychotics do not solely act on counteracting hyperdopaminergia, but also tune glutamatergic neurotransmission by activating homeostatic plasticity mechanisms.

The retrosplenial cortex (RSC) integrates sensory and mnemonic information to support spatial orientation and navigation, yet how visuospatial processing differs across its subregions remains unclear. Here, we combined cellular imaging in navigating mice with brain-wide anatomical input tracing to characterize how multimodal sensory and positional signals are integrated along the anterior–posterior axis of dorsal RSC. We identified consistent differences between anterior and posterior subregions in both functional response properties and long-range connectivity. Anterior RSC neurons displayed sharper and more reliable position tuning during tactile-cued navigation and preferential sensitivity to fast, low–spatial-frequency visual motion. In contrast, posterior RSC neurons showed broader position selectivity, stronger responses to slow, high–spatial-frequency visual patterns, and enhanced tuning in visually immersive virtual environments. Consistent with these differences, anterior RSC received denser projections from motor, somatosensory, and parietal areas, whereas posterior RSC received stronger input from primary and posteromedial visual cortices. Together, these findings identify an anterior–posterior functional gradient in RSC, with subregions differing in how they integrate sensory and positional signals during navigation.

Handwriting is a complex cognitive and motor skill supported by a distributed brain network involving cortical, subcortical, and cerebellar regions responsible for planning, execution, and sensorimotor integration. Beyond its communicative role, handwriting provides biologically meaningful information about brain function and motor control, serving as a sensitive marker of both normal and pathological changes. Age-related alterations, such as reduced fine motor precision, impaired sensory feedback, and cognitive slowing, contribute to the progressive decline in handwriting fluency and legibility. Importantly, distinctive handwriting patterns may be associated with early signs of neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and Multiple Sclerosis, reflecting disease-specific alterations in motor and cognitive circuits. Advances in digital technology now enable high-resolution, quantitative analysis of handwriting kinematics, offering promising and scalable tools for diagnosis, longitudinal monitoring, and personalized rehabilitation. Furthermore, interventions incorporating fine motor and visuomotor coordination exercises, adaptive writing, and cognitive training may help preserve handwriting abilities and promote adaptive neural changes. In this review, we synthesize current evidence on the neural, behavioral, and technological mechanisms underlying handwriting across aging and neurodegenerative conditions. We provide an integrated overview of neural substrates, age- and disease-related alterations, and emerging digital approaches for assessment and intervention, highlighting their relevance for research and clinical practice. Overall, handwriting has the potential to offer a powerful, non-invasive window into brain health, bridging neuroscience, aging research, and digital medicine.

The persistent HIV reservoir constitutes the main obstacle to curing HIV/AIDS disease. Our understanding of how non-productive HIV infections are established in primary human CD4+ T cells during the first round of infection remains, however, incomplete. In this study, we leveraged the HIV reporter virus pMorpheus-V5 to delineate cellular expression patterns that are upregulated in non-productively infected primary CD4+ T memory stem cells (TSCM). We found that CD4+ TSCM harboring non-productive proviruses displayed a distinct transcriptomic signature comprising 118 upregulated genes. This non-productive expression profile was distinct from that of productively infected cells as well as from negative-exposed and mock-infected cells. Among the cellular genes most upregulated in CD4+ T cells harboring non-productive proviruses were CCR4-binding migratory chemokines (CCL22, CCL17), tryptophan catabolic enzymes (IDO1, KYNU), and genes encoding cytoskeletal rearrangement proteins (BASP1, TNFAIP2). Intracellular flow cytometry-based analyses confirmed that non-productively infected CD4+ TSCM cells were enriched for CCL22 and IDO1 co-expression compared to the other CD4+ memory subsets, underscoring a clear CD4+ T cell subset specificity for the upregulation of these two immune gene sets associated with non-productive infections. These findings suggest that primary human CD4+ TSCM harboring non-productive proviruses display a distinct immunoregulatory phenotype which may facilitate immune evasion and contribute to the persistence of the HIV reservoir.

Purpose: This paper examines how ancestral geography, defined through cultural lineage persistence, historical settlement continuity, mobility structures, and governance quality, shapes contemporary global earnings inequality. The study aims to determine whether inequality is primarily driven by long-standing historical forces rather than only modern economic dynamics. Methodology: The study harmonizes cross-national datasets from seven countries covering the period 2010 to 2024. Data were drawn from the World Inequality Database, United Nations demographic and migration databases, UNESCO cultural records, UN geospatial settlement archives, and the V-Dem governance dataset. Variables were standardized on a 0 to 1 scale. Linear interaction models were employed to estimate the direct and moderating effects of ancestral geography and governance on multiple dimensions of earnings inequality. Results/Analysis: Findings indicate that strong cultural lineage persistence and dense historical settlement continuity are positively associated with wider wage distribution gaps, greater occupational stratification, lower intergenerational mobility, and higher regional income divergence. Mobility, both internal and international, weakens inherited structural disparities. Governance quality moderates the relationship between ancestral structures and inequality by reducing the transmission of historical rigidities into present-day wage differentials. The results confirm that historical identity and spatial persistence exert measurable long-term effects on income distribution. Originality/Value: The study introduces the concept of ancestral geography as an integrated framework combining lineage continuity, settlement systems, mobility patterns, and institutional quality. Unlike prior research that treats these factors separately, this work consolidates them into a unified empirical model to explain global earnings inequality. It extends inequality theory by demonstrating how historical, cultural, and spatial persistence interact with governance to shape contemporary labor market outcomes. Type of paper: Empirical research paper.

Background and Objectives Observational data can provide evidence of treatment effects in a low-burden, cost-effective manner. Using a causal inference framework to address selection bias, we illustrate the approach in ALS by examining previously researched associations, baseline function and sex, and evaluating metformin’s survival benefits. Methods Data are from the ALS Natural History Study collected in the United States, Israel, and Italy from 2015 to 2025. We employ propensity score matching, two approaches to address loss to follow-up (i.e. a naive exclusion and principal stratification), and randomization-based inference to evaluate difference in 18-month restricted mean survival time. Results For the function investigation, estimated survival is 16.39, 16.14, 16.09, and 16.24 months for the high ALSFRS-R group and 14.04, 14.42, 14.72, and 14.60 months for the low ALSFRS-R group using the non imputed and imputed datasets 1-3, respectively (p<0.0001, N=450; p<0.00001, N=1,485; p<0.00001, N=1,492; p<0.00001, N=1,600). Using principal stratification, estimated survival is 16.38, 16.14, 16.09, and 16.23 months for the high ALSFRS-R group and 14.04, 14.42, 14.72, and 14.59 months for the low ALSFRS-R group with the non imputed and imputed datasets 1-3, respectively (p<0.0001, N=449; p<0.00001, N=1,483; p< 0.00001, N=1,491; p<0.00001, N=1,596). For the sex investigation, estimated survival is 15.20, 15.16, 15.20, and 15.17 months for females and 15.41, 14.84, 14.91, and 14.97 months for males using the non imputed and imputed datasets 1-3, respectively (p≈0.594, N=612; p≈0.155, N=2,081; p≈0.200, N=2,104; p≈0.359, N=2,111). Using principal stratification, estimated survival is 15.20, 15.16, 15.20, and 15.17 months for females and 15.41, 14.83, 14.91, and 14.97 months for males with the non imputed and imputed datasets 1-3, respectively (p≈0.598, N=612; p≈0.146, N=2,079; p≈0.195, N=2,102; p≈0.364, N=2,110). For the metformin investigation, estimated survival is 14.77, 14.87, and 14.57 months for metformin users and 14.59, 14.43, and 13.97 months for non metformin users using imputed datasets 1-3, respectively (p≈0.391, N=289; p≈0.257, N=279; p≈0.191, N=301). Using principal stratification, estimated survival is 14.75, 14.85, and 14.55 months for metformin users and 14.68, 14.58, and 13.97 months for non metformin users with imputed datasets 1-3, respectively (p≈0.458, N=286; p≈0.351, N=275; p≈0.201, N=300). Discussion We reject the sharp null hypothesis for the function investigation and fail to reject it for the sex and metformin investigations. Trial Registration Information ClinicalTrials.gov Identifier: NCT05966038 .

Cytoplasmic TDP-43 pathology is a pathological sign of ALS/ALS-FTD and a converging disease event across different genotypes, phenotypes and CNS areas. To understand this process and target it therapeutically, we need to define which cell types are affected and which cell-type specific effects make them particularly vulnerable. We coupled flow-cytometry nuclear sorting and sequencing with single-nucleus multi-omic ATAC-seq and RNA-seq and spatial transcriptomics to define the transcriptional cell type of affected neurons in the post-mortem ALS/ALS-FTD motor cortex (30 ALS, 20 ALS-FTD & 32 control samples). Here, we show that mainly excitatory cortical neurons are affected by TDP-43 pathology and define the cell types that are affected the most: intratelencephalic L2-L3-LINC00507-FREM3, L3-L5-RORB-LNX2, L3-L5-RORB-ADGRL4 & L6-THEMIS-LINC00343 neurons and extratelencephalic L5-FEZF2-NTNG1 neurons. Transcriptional aberrations by TDP-43 pathology, like cryptic exon inclusion, are cell-type specific and affect distinct gene sets in each cell type, highlighting the need to address TDP-43 pathology in a cell-type specific manner.

Repetitive mild traumatic brain injury (rmTBI) produces cumulative cellular stress that can lead to progressive brain dysfunction, yet the mechanisms governing vulnerability to repeated injury remain unclear. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) regulates cellular proteostasis through the unfolded protein response and is implicated in neurodegeneration and acute brain injury. Here, we directly tested the role of PERK deficiency in shaping the brain’s response to rmTBI. Using a mouse model of neuronal PERK deficiency, we combined spatial proteomics and tissue analyses with resting-state functional MRI and diffusion tensor imaging to assess molecular, functional, and structural outcomes after rmTBI. PERK deficiency increased susceptibility to rmTBI-induced disruption of protein homeostasis, altered large-scale functional connectivity, and exacerbated white matter microstructural changes consistent with axonal and myelin damage. Molecular alterations were spatially aligned with imaging-defined network and white matter abnormalities. These findings identify PERK signaling as a key determinant of brain resilience to repetitive mild injury and link ER stress dysregulation to network-level dysfunction following rmTBI.

Long-term potentiation (LTP), the best-characterized form of Hebbian synaptic plasticity, is well known to be under strong circadian regulation. In mice and rats, both nocturnal species, most studies indicate that LTP in the hippocampal CA1 region is more robust when induced during the dark phase. Our examination of the underlying mechanisms at the CA3→CA1 synapse in mice of all sexes indicates that the capacity to support LTP does not differ between the light and dark phases of the 24 h day. Instead, the magnitude of theta burst stimulation-induced LTP (TBS-LTP) correlates with daily fluctuations in the ratio of synaptic excitation to inhibition (E/I ratio): both the E/I ratio and TBS-LTP are higher during the dark phase. On the other hand, LTD induced with low-frequency stimulation did not change across the circadian cycle. Consistent with a causal relationship between the E/I ratio and TBS-LTP, blockade of inhibition abolishes the light-dark difference in TBS-LTP induction. Likewise, pairing-induced LTP, which is not constrained by inhibitory recruitment, does not differ between cycles. Supporting this, in the APP/PS1 model of AD neither the E/I ratio nor TBS-LTP varies across the light-dark cycle, despite preserved circadian regulation of locomotor activity. Finally, we made the intriguing observation that these daily oscillations reverse direction after puberty in WT mice, shifting from being larger in the dark cycle of 2-month-old mice to being larger in the light cycle in 8-month-old mice. This developmental switch may reflect an age-dependent reorganization of circadian control over hippocampal plasticity.