bioRxiv Science⌕ Search

Biology subjects

Haller, G.

Publications and source records attributed to Haller, G..

3 recordsLinked to original sources

Data-Driven Reduced Modeling of Recurrent Neural Networks

Artificial Recurrent Neural Networks (RNNs) are widely used in neuroscience to model the collective activity of neurons during behavioral tasks. The high dimensionality of their parameter and activity spaces, however, often make it challenging to infer and interpret the fundamental features of their dynamics. In this study, we employ recent nonlinear dynamical system techniques to uncover the core dynamics of several RNNs used in contemporary neuroscience. Specifically, using a data-driven approach, we identify Spectral Submanifolds (SSMs), i.e., low-dimensional attracting invariant manifolds tangent to the eigenspaces of fixed points. The internal dynamics of SSMs serve as nonlinear models that reduce the dimensionality of the full RNNs by orders of magnitude. Through low-dimensional, SSM-reduced models, we give mathematically precise definitions of line and ring attractors, which are intuitive concepts commonly used to explain decision-making and working memory. The new level of understanding of RNNs obtained from SSM reduction enables the interpretation of mathematically well-defined and robust structures in neuronal dynamics, leading to novel predictions about the neural computations underlying behavior.

neuroscience↗

Global cerebrospinal fluid circulation mapping using gold nanoparticle enhanced X-ray microtomography reveals region-specific brain and spinal cord CSF pathways

Cerebrospinal fluid (CSF) movement within the brain interstitium is essential for the development and functioning of the brain. However, the interstitium has largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with CSF. Here, we developed a novel technique for CSF tracking, gold nanoparticle enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF pathways during development. Using this method and subsequent histological analysis, we map global CSF pathways and present novel particle size-dependent circulation patterns through the CNS. We identify an intraparenchymal CSF circulation that targets stem cell-rich and cholinergic neuronal populations. CSF solute distribution to these areas is mediated by CSF flow along projections from the basal cisterns which is altered in posthemorrhagic hydrocephalus. Our study uncovers region-specific patterns in a biologically driven CSF circulation that has implications for normal brain development and the pathophysiology of hydrocephalus and neurodegenerative disorders.

neuroscience↗

ATRAID, a genetic factor that regulates the clinical action of nitrogen-containing bisphosphonates on bone.

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation. Yet it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Lastly, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare non-synonymous coding variants in patients with ONJ or AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people. One Sentence SummaryATRAID is essential for responses to the commonly prescribed osteoporosis drugs nitrogen-containing bisphosphonates. OverlineBONE

genomics↗