Biology subjects

Miller, D. S.

Publications and source records attributed to Miller, D. S..

9 recordsLinked to original sources

bioRxiv2026

The Cost to Scroll: Short-form Video Use and Episodic Memory

Short-form video platforms expose users to rapid streams of novel content; these features are posited to place heavy demands on cognitive processes. In a preregistered online study, we used device-reported screen time to examine whether short-form video use is associated with sustained attention and episodic memory in participants aged 18-24 yrs (N = 502). During a sustained attention task, participants made indoor/outdoor decisions on scene stimuli, with 90% frequent trials and 10% infrequent trials; the subsequent surprise recognition test assessed memory for these items. Among participants with device-reported TikTok or Instagram use (N = 398), short-form video use was not associated with attention performance. By contrast, greater short-form video use was associated with poorer episodic memory; this relationship was driven by poorer recognition of infrequent-category items. These findings connect heavier short-form video consumption with poorer episodic memory in young adults, showing how daily digital habits co-vary with memory function.

neuroscience↗

bioRxiv2026

Dissociable structural and molecular pathways of age-related change in sustained attention

Sustained attention, the capacity to maintain goal-directed attention over extended periods, declines with age but with substantial individual variability across cognitively unimpaired (CU) older adults. We sought to determine the contributions of microstructural deterioration of the superior longitudinal fasciculus (SLF), the principal white-matter tract coupling prefrontal and parietal nodes of the dorsal attention network, as well as markers of preclinical Alzheimers disease (AD) to individual differences in sustained attention in ageing. In 162 CU older adults (mean (SD) age = 73.0 (4.9), %F = 64.8) drawn from two Stanford ageing cohorts, we measured sustained attention using the gradual-onset Continuous Performance Task (gradCPT). Performance was indexed by a composite score (Att-Z) derived from discriminability (d') and response-time variability (RTV). We used diffusion MRI tractography to quantify SLF fractional anisotropy (FA) and mean diffusivity (MD) alongside two control tracts, the corticospinal tract (CST) and cingulum (CGC). NULISA multiplex plasma immunoassays were used to measured AD-related pathology (pTau-181, pTau-217), neuroaxonal injury (NfL), and astrocytic reactivity (GFAP; plasma subsample N = 146). Parallel mediation and commonality analyses tested whether structural and plasma biomarker pathways contribute independently to individual differences in sustained attention function. Older age was associated with lower Att-Z ({beta} = -0.315, p < 0.001). In simultaneous three-tract regression models, only SLF microstructure uniquely predicted Att-Z (FA: {beta} = +0.275, p < 0.001; MD: {beta} = -0.320, p < 0.001). SLF microstructure mediated the age-attention relationship (FA indirect {beta}unstandardised = -0.01, pboot <0.01, MD indirect {beta}unstandardised = -0.009 to -0.01, pboot <0.05). Plasma pTau-181 ({beta} = -0.212, pFDR < 0.03), pTau-217 ({beta} = -0.163, pFDR < 0.05), and NfL ({beta} = -0.156, pFDR < 0.05) were negatively associated with Att-Z and each mediated effects of age on performance (pTau-181 indirect {beta}unstandardised = -0.008, pboot < 0.01; pTau-217 indirect {beta}unstandardised= -0.006, pboot< 0.05; NfL indirect {beta}unstandardised = -0.011, pboot< 0.05), whereas GFAP showed no association with sustained attention in any model. SLF microstructure was negatively associated with age (FA {beta} = -0.207, p < 0.01; MD {beta} = +0.270, p < 0.001) but was not significantly associated with plasma biomarkers (all p > 0.10). In parallel mediation models, SLF microstructure and plasma pTau exhibited significant independent indirect effects on Att-Z (SLF FA indirect {beta}unstandardised= -0.010, pboot< 0.01; SLF MD indirect {beta}unstandardised = -0.009 to -0.010, pboot< 0.05; pTau-181 indirect {beta}unstandardised = -0.008 to -0.009, pboot< 0.01; pTau-217 indirect {beta}unstandardised= -0.006 to -0.007, pboot< 0.05). Effects of NfL were attenuated when combined in a model with pTau (indirect {beta}unstandardised = -0.005 to -0.008, pboot> 0.15), suggesting shared variance among these markers. These findings reveal multiple pathways that contribute to individual differences in sustained attention in ageing that are detectable before clinical impairment, including SLF white matter integrity -- which is linked to the structural disconnection of the dorsal attention network -- and preclinical AD pathology. The independence of these pathways identifies two separable biological targets for preserving attentional capacity in CU older adults.

neuroscience↗

bioRxiv2025

Anti-activin treatment increases T cell infiltration in breast and pancreatic tumours and promotes survival in a SMAD4-null mouse pancreatic cancer model

Activin A and B share the same downstream signalling pathway (activation of SMAD2/3) as TGF-{beta} and consequently elicit many of the same functional responses as TGF-{beta}, including immune suppression, activation of cancer-associated fibroblasts (CAFs) and extracellular matrix production and remodelling. However, activins role in tumourigenesis has been relatively overlooked compared to TGF-{beta}s. We generated and characterized a dual specificity human antibody that recognizes both activin A and B and compared its activity in syngeneic mouse models of breast cancer and pancreatic ductal adenocarcinoma (PDAC) with an activin A-specific antibody. We demonstrate that activin A and B are central to the function of CAFs and therapeutic inhibition of activin results in a reduction of collagen rich desmoplastic barriers, enabling the infiltration of cytotoxic T cells. This is correlated with an upregulation of the T cell chemoattractant CXCL10, which is normally repressed by activin signalling. Interestingly, despite greater T cell infiltration, activin A inhibition resulted in poorer survival in the KPC mouse model of PDAC and slightly larger tumours in the breast cancer model, indicating a tumour suppressive role of activin A-rich CAFs. Strikingly, however, treatment with the same anti-activin A antibody of PDAC tumours where SMAD4 is deleted in the tumour cells, resulted in increased survival, which was potentiated with additional treatment with immune checkpoint inhibitors. These results suggest that anti-activin therapy has potential for the cohort of PDAC patients exhibiting inactivation of SMAD4.

cancer biology↗

bioRxiv2024

Intestinal serotonergic vagal signaling as a mediator of microbiota-induced hypertension

Hypertension is a pervasive global health challenge, impacting over a billion individuals worldwide. Despite strides in therapeutic strategies, a significant proportion of patients remain resistant to the currently available therapies. While conventional treatments predominantly focus on cardiac, renal, and cerebral targets, emerging research underscores the pivotal role of the gut and its microbiota. Yet, the precise mechanisms governing interactions between the gut microbiota and the host blood pressure remain unclear. Here we describe a neural host-microbiota interaction that is mediated by the intestinal serotonin (5-HT) signaling via vagal 5HT3a receptors and which is crucial for maintenance of blood pressure homeostasis. Notably, a marked decrease in both intestinal 5-HT and vagal 5HT3aR signaling is observed in hypertensive rats, and in rats subjected to fecal microbiota transplantation from hypertensive rats. Leveraging an intersectional genetic strategy in a Cre rat line, we demonstrate that intestinal 5HT3aR vagal signaling is a crucial link between the gut microbiota and blood pressure homeostasis and that recovery of 5-HT signaling in colon innervating vagal neurons can alleviate hypertension. This paradigm-shifting finding enhances our comprehension of hypertensive pathophysiology and unveils a promising new therapeutic target for combating resistant hypertension associated with gut dysbiosis.

physiology↗

bioRxiv2023

The representational geometry of cognitive maps under dynamic cognitive control

Recent work has shown that the brain abstracts non-spatial relationships between entities or task states into representations called cognitive maps. Here, we investigate how cognitive control enables flexible top-down selection of goal-relevant information from multidimensional cognitive maps retrieved from memory. We examine the relationship between cognitive control and representational geometry by conducting parallel analyses of functional magnetic resonance imaging data and recurrent neural network models trained to perform the same task. We find both stable map-like representations in a medial temporal lobe and orbitofrontal cortical network that reflect both task-relevant and irrelevant dimensions and context-dependent, orthogonal representations of only task-relevant dimensions in a frontoparietal network. These representational motifs also emerge with distinct temporal profiles over the course of training in the recurrent neural network, with map-like representations appearing first. We further show that increasing control demands due to incongruence (conflicting responses) between current task-relevant and irrelevant dimensions impact the geometry of subjective representations, and the degree of this effect further accounts for individual differences in cognitive control. Taken together, our findings show how complementary representational geometries balance stability and behavioral flexibility, and reveal an intricate relationship between cognitive control and cognitive map geometry.

neuroscience↗

bioRxiv2022

Abnormal CCK/CB1R axon targeting in mouse models of dystroglycanopathy

Dystroglycan (Dag1) is a transmembrane glycoprotein that links the extracellular matrix to the actin cytoskeleton. Mutations in Dag1 or the genes required for its glycosylation result in dystroglycanopathy, a type of congenital muscular dystrophy characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairment. We investigated interneuron (IN) development, synaptic function, and associated seizure susceptibility in multiple mouse models that reflect the wide phenotypic range of dystroglycanopathy neuropathology. Mice that model severe dystroglycanopathy due to forebrain deletion of Dag1 or Pomt2, which is required for Dystroglycan glycosylation, show significant impairment of CCK+/CB1R+ IN development. CCK+/CB1R+ IN axons failed to properly target the somatodendritic compartment of pyramidal neurons in the hippocampus, resulting in synaptic defects and increased seizure susceptibility. Mice lacking the intracellular domain of Dystroglycan have milder defects in CCK+/CB1R+ IN axon targeting, but exhibit dramatic changes in inhibitory synaptic function, indicating a critical postsynaptic role of this domain. In contrast, CCK+/CB1R+ IN synaptic function and seizure susceptibility was normal in mice that model mild dystroglycanopathy due to partially reduced Dystroglycan glycosylation. Collectively, these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy, and show that Dystroglycan plays an important role in organizing functional inhibitory synapse assembly.

neuroscience↗

bioRxiv2021

Neuronal Dystroglycan regulates postnatal development of CCK/cannabinoid receptor-1 interneurons

The development of functional neural circuits requires the precise formation of synaptic connections between diverse neuronal populations. The molecular pathways that allow GABAergic interneuron subtypes in the mammalian brain to recognize their postsynaptic partners remain largely unknown. The transmembrane glycoprotein Dystroglycan is localized to inhibitory synapses in pyramidal neurons, where it is required for the proper function of CCK+ interneurons. We show that deletion of Dystroglycan from pyramidal neurons selectively impairs CCK+ interneuron development during the first postnatal week. In the absence of postsynaptic Dystroglycan, presynaptic CCK+ interneurons fail to elaborate their axons and largely disappear from the cortex, hippocampus, amygdala, and olfactory bulb. Bax deletion did not rescue CCK+ interneurons, suggesting that they are not eliminated by canonical apoptosis in Dystroglycan mutants. Rather, we observed an increase in CCK+ interneuron innervation of the striatum, suggesting that the remaining CCK+ interneurons re-directed their axons to neighboring areas where Dystroglycan expression remained intact. Together these findings identify Dystroglycan as a critical regulator of CCK+ interneuron development.

neuroscience↗

bioRxiv2020

Novel Inferences in a Multidimensional Social Network Use a Grid-like Code

Generalizing experiences to guide decision making in novel situations is a hallmark of flexible behavior. It has been hypothesized such flexibility depends on a cognitive map of an environment or task, but directly linking the two has proven elusive. Here, we find that discretely sampled abstract relationships between entities in an unseen two-dimensional (2-D) social hierarchy are reconstructed into a unitary 2-D cognitive map in the hippocampus and entorhinal cortex. We further show that humans utilize a grid-like code in several brain regions, including entorhinal cortex and medial prefrontal cortex, for inferred direct trajectories between entities in the reconstructed abstract space during discrete decisions. Moreover, these neural grid-like codes in the entorhinal cortex are associated with neural decision value computations in the medial prefrontal cortex and temporoparietal junction area during choice. Collectively, these findings show that grid-like codes are used by the human brain to infer novel solutions, even in abstract and discrete problems, and suggest a general mechanism underpinning flexible decision making and generalization.

neuroscience↗

bioRxiv2019

Map making: Constructing, combining, and navigating abstract cognitive maps

Cognitive maps are thought to enable model-based inferences from limited experience that can guide novel decisions-a hallmark of behavioral flexibility. We tested whether the hippocampus (HC), entorhinal cortex (EC), and ventromedial prefrontal cortex (vmPFC)/medial orbitofrontal cortex (mOFC) organize abstract and discrete relational information into a cognitive map to guide novel inferences. Subjects learned the status of people in two separate unseen 2-D social hierarchies defined by competence and popularity piecemeal from binary comparisons, with each dimension learned on a separate day. Although only one dimension was ever behaviorally relevant, multivariate activity patterns in HC, EC and vmPFC/mOFC were linearly related to the Euclidean distance between people in the mentally reconstructed 2-D space. Hubs created unique comparisons between the two hierarchies, enabling inferences between novel pairs of people. We found that both behavior and neural activity in EC and vmPFC/mOFC reflected the Euclidean distance to the retrieved hub, which was reinstated in HC. These findings reveal how abstract and discrete relational structures are represented, combined, and enable novel inferences in the human brain.

neuroscience↗