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Mattar, M.

Publications and source records attributed to Mattar, M..

10 recordsLinked to original sources

Learning distributed representations with complementary components - A generative approximation framework for episodic memory encoding

Episodic memory must preserve detail while storing memories efficiently. We propose a framework of memory encoding in which generative neural network models approximate input through their frozen weights, yielding starting points from which the same weights can reinstate the input. This removes the need for mutually invertible cortical-hippocampal mappings, realizes a tradeoff between computational effort and mnemonic precision, and uses statistical regularities of the stimulus space to find representations that are distributed across the network. We implement this principle with a toy model and with large image-generation AI models, operationalizing mnemonic precision as closer approximation. Our model reproduces key findings from the Mnemonic Similarity Task: shallow encoding selectively impairs lure rejection, as observed in aging populations. Encoding further benefits from expertise: domain-finetuned models need fewer approximation steps for images from their own domain than for images from other domains. Finally, the representational geometry of latent starting points resembles medial temporal lobe but reinstatement through the weights of the network traverses the visual hierarchy in reverse order. Our framework offers a parsimonious and flexible account of memory encoding, where a generative search for a reinstatement-capable starting point finds a path for retrieval directly.

neuroscience↗

Stochastic Decision Policy Is Optimal Under Costly Control

Human and animal decisions are often noisy. This variability is usually attributed to noise that corrupts the decision evidence, a defect that an ideal decision maker would eliminate. Here we ask whether stochastic choice can instead be optimal once the cost of implementing prescribed policies is counted. We treat the decision maker as an ideal observer that maximizes expected gain but pays costs to sharpen its policy away from a random default. Using sequential sampling, a setting in which the optimal policy is precisely defined, we show that this trade-off makes a stochastic policy optimal, replacing the hard decision boundaries of classical theory with soft stopping zones whose softness is set by the price of control. This soft policy aligns with the strategy used in cutting-edge artificial learning agents for robustness. Noise that corrupts the agent's belief, an important confound of noisy behavior, produces superficially similar yet distinctive signatures in behavioral policies. Leveraging this, we recovered the policies of two macaques with low-dimensional recurrent neural networks and found that their behavior carries both a stochastic policy and belief noise. By separating variability in constructing a decision belief from stochasticity in selecting actions, these results establish that stochastic decision policies can themselves be optimal, offering a common principle for understanding behavioral variability in biological and artificial decision makers.

animal behavior and cognition↗

RRAS and RRAS2 mutations are oncogenic drivers in lung cancer and are sensitive to the pan-RAS inhibitor RMC-6236

IntroductionRRAS and RRAS2 encode a subfamily of RAS-like small GTPases that share considerable structural and functional similarities with KRAS, HRAS, and NRAS. Whether homologous RRAS/RRAS2 mutations are oncogenic and actionable drivers in lung cancer remains underexplored. MethodsAn institutional cohort of 8,488 non-small cell lung carcinomas (NSCLC) sequenced by comprehensive targeted DNA sequencing (MSK-IMPACT) between 2016-2024 was evaluated for RRAS/RRAS2 mutations. RRASQ87L or RRAS2Q72L were modeled in murine IL3-dependent Ba/F3 cells and immortalized human bronchiolar epithelial cells (HBECs). The oncogenic potential, signaling characteristics, and sensitivity to PI3K and MAPK pathway inhibitors, including the novel pan-RAS inhibitor RMC-6236, were evaluated in vitro and in vivo. ResultsRRASQ87L or RRAS2Q72L, homologous to KRAS-codon Q61 substitutions, were found in [~]0.45% of NSCLCs (38/8,488), with all but two lacking other MAPK pathway oncogenic drivers. RRASQ87L and RRAS2Q72L mutations transformed Ba/F3 and HBEC cells and robustly activated MAPK and PI3K-mTOR pathway signaling. RMC-6236 suppressed proliferation of RRASQ87L and RRAS2Q72L mutant cell lines, reduced ERK phosphorylation, induced apoptosis, and impeded cell-cycle progression. In vivo, RMC-6236 significantly inhibited growth of RRASQ87L/RRAS2Q72L-mutant HBEC-derived xenografts. ConclusionsRRASQ87L and RRAS2Q72L are recurrent, oncogenic, and potentially actionable drivers in NSCLC. Our study supports the inclusion of RRAS/RRAS2 into routine molecular diagnostic panels for precision oncology and provides preclinical rationale for investigating the potential therapeutic utility of pan-RAS inhibitors for patients with RRASQ87L/RRAS2Q72L-mutant lung cancers. Statement of translational relevanceTargeted therapies have transformed standard of care for oncogene-driven non-small cell lung carcinomas (NSCLC), yet a significant subset lacks actionable drivers. We identified recurrent RRASQ87L and RRAS2Q72L mutations which are mutually exclusive with other MAPK pathway drivers and found in [~]0.45% of NSCLC, comparable in prevalence to NTRK and NRG1 fusions. In preclinical models, these mutations activate canonical growth signaling, drive tumorigenic phenotypes, and confer sensitivity to RAS/MAPK-directed agents, including the novel pan-RAS inhibitor RMC-6236, currently in trials for patients with solid tumors harboring KRAS mutations. These data support RRASQ87L and RRAS2Q72L as bona fide lung cancer drivers and nominate RRAS/RRAS2-mutant tumors as candidates for pan-RAS-targeted therapeutics. Our findings provide a biologic rationale and preclinical evidence to inform molecular testing paradigms and to prioritize enrollment of patients with RRAS/RRAS2-mutant NSCLC into future clinical trials of pan-RAS inhibitors.

cancer biology↗

Interpretable abstractions of artificial neural networks predict behavior and neural activity during human information gathering

It has been suggested that humans and other animals are driven by a fundamental desire to acquire information about opportunities available in their environments. Not only might such a desire explain pathological behaviors, but it may be needed to account for how everyday decisions are resolved. Here, we combine artificial neural networks (ANNs) with symbolic regression to extract an expressive yet interpretable model that specifies how human participants evaluate decision-relevant information during choice. This model accounts for behavior in our own data and in previous work, outperforming existing accounts of information sampling such as the Upper Confidence Bound heuristic. This modelling approach has broad potential for uncovering novel patterns in behavior and cognitive processes, while also specifying them in human-interpretable formats. We then used the value of information derived by our model, together with ultra-high field neuroimaging, to examine activity across a suite of subcortical neuromodulatory nuclei and two cortical regions that influence these nuclei. This established roles for midbrain dopaminergic nuclei, anterior cingulate cortex, and anterior insula in mediating the influence of value of information on behavior.

neuroscience↗

A Rational Information Gathering Account of Infant Habituation

Gaze is one of the primary experimental measures for studying cognitive development, especially in preverbal infants. However, the field is only beginning to develop a principled explanatory framework for making sense of the various factors affecting gaze. We approach this issue by addressing infant gaze from first principles, using rational information gathering. In particular, we revisit the influential descriptive account of Hunter and Ames (1988) (H&A), which posits a set of regularities argued to govern how gaze preference for a stimulus changes with experience and other factors. When the H&As model is reconsidered from the perspective of rational information gathering (as recently also proposed by other authors), one feature of the model emerges as surprising: that preference for a stimulus is not monotonic with exposure. This claim, which has at least some empirical support, is in contrast to most statistical measures of informativeness, which strictly decline with experience. We present a normative, computational theory of visual exploration that rationalizes this and other features of the classic account. Our account suggests that H&As signature nonmonotonic pattern is a direct manifestation of a ubiquitous principle of the value of information in sequential tasks, other consequences of which have recently been observed in a range of settings including deliberation, exploration, curiosity, and boredom. This is that the value of information gathering, putatively driving gaze, depends on the interplay of a stimulus informativeness (called Gain, the focus of other rationally motivated accounts) with a second factor (called Need) reflecting the estimated chance that information will be used in the future. This computational decomposition draws new connections between infant gaze and other cases of exploration, and offers novel, quantitative interpretations and predictions about the factors that may impact infant exploratory attention.

animal behavior and cognition↗

Leveraging CD39 To Identify Tumor-Reactive CD8 T cells In Human Lung Cancer

The repertoire of tumor-infiltrating lymphocytes (TILs) can be vast, and many of these TILs are not endowed with tumor reactivity. While a number of reports have shown that tumor-reactive TILs express CD39, few reports have demonstrated that conversely, CD39 can be leveraged to serve as a proxy of tumor-reactive CD8 T cells. Using single-cell CITE/RNA/TCRseq, we show that CD39+ CD8 T cells in human lung cancers demonstrate transcriptional and proteomic features of exhaustion, tumor reactivity, and clonal expansion. Moreover, TCR cloning revealed that CD39 enriched for tumor-reactive CD8 T cell clones. Flow cytometry of 440 lung cancer specimens revealed that CD39 level on CD8 T cells is only weakly correlated with tumoral features that currently guide lung cancer therapy, such as histology, driver mutation, PD-L1 and tumor mutation burden. PD-1 axis blockade, but not cytotoxic chemotherapy, increased intratumoral CD39+ CD8 T cells. CD39 correlated with PD-1 expression on CD8 T cells and high pre-treatment/early-on-treatment levels were associated with improved clinical outcomes, but not immune-related adverse events, from immune checkpoint blockade therapy. This comprehensive profiling of the clinical, pathological and molecular features highlights the utility of CD39 as a proxy for tumor-reactive CD8 T cells in human lung cancer.

immunology↗

Regional and clonal T cell dynamics at single cell resolution in immune checkpoint blockade

Paired T cell receptor and RNA single cell sequencing (scTCR/RNA-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scTCR/RNA-seq dataset of 162,062 single T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients who underwent resections for progressing lung cancers after immune checkpoint blockade (ICB). We found marked regional heterogeneity in tumor persistence that was associated with heterogeneity in CD4 and CD8 T cell phenotypes; regions with persistent cancer cells were enriched for follicular helper CD4 T cells (TFH), regulatory T cells (Treg), and exhausted CD8 T cells. Clonal analysis demonstrated that highly-expanded T cell clones were predominantly of the CD8 subtype, were ubiquitously present across all sampled regions, found in the peripheral circulation, and expressed gene signatures of large and dual-expanded clones that have been predictive of response to ICB. Longitudinal tracking of CD8 T cell clones in the peripheral blood revealed that the persistence of ubiquitous CD8 T cell clones, as well as phenotypically distinct clones with tumor-reactive features, correlated with systemic tumor control. Finally, tracking CD8 T cell clones across tissues revealed the presence of TCF-1+ precursor exhausted CD8 T cells in tumor draining LNs that were clonally linked to expanded exhausted CD8 T cells in tumors. Altogether, this comprehensive scTCR/RNA-seq dataset with regional, longitudinal, and clonal resolution provides fundamental insights into the tissue distribution, persistence, and differentiation trajectories of ICB-responsive T cells that underlie clinical responses to ICB.

immunology↗

Caveolin-1 temporal modulation enhances trastuzumab and trastuzumab-drug conjugate efficacy in heterogeneous gastric cancer

Resistance mechanisms and heterogeneity in HER2-positive gastric cancers (GC) limit trastuzumab benefit in 32% of patients, and other targeted therapies have failed in clinical trials. Using genomic data from patient tissue, patient-derived xenografts (PDXs), partially humanized biological models, and HER2-targeted imaging we identified caveolin-1 (CAV1) as a complementary biomarker in GC selection for trastuzumab therapy. In retrospective analyses of samples from patients enrolled on trastuzumab trials, the CAV1-high profile was associated with low membrane HER2 density and reduced patient survival. We found a negative correlation between CAV1 tumoral protein levels - a major protein of cholesterol-rich membrane domains - and trastuzumab-drug conjugate TDM1 tumor uptake. Finally, CAV1 depletion using knockdown or pharmacologic approaches was shown to increase HER2-directed immunoPET uptake and TDM1 efficacy in GC with incomplete HER2 membranous reactivity. In support of these findings, background statin use in patients is associated with enhanced antibody efficacy. Together, this work provides mechanistic justification and clinical evidence that require prospective investigation of HER2-targeted therapies combined with statins to delay drug resistance in GC. SIGNIFICANCEThis study identifies how CAV1 protein expression and statin use relate to GC response in HER2-targeted imaging and therapeutic approaches. In addition, to support the synergy of CAV1 depletion with TDM1 observed in mouse models, we demonstrate that statin users had better clinical responses to antibody-based therapies in HER2+ GC.

cancer biology↗

Single cell profiling reveals novel tumor and myeloid subpopulations in small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively), which are associated with distinct therapeutic vulnerabilities. To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 54,523 cellular transcriptomes from 21 human biospecimens. Our single-cell SCLC atlas reveals tumor diversity exceeding lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discovered a PLCG2-high tumor cell population with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival, and manipulation of PLCG2 expression in cells confirms correlation with key metastatic markers. Treatment and subtype are associated with substantial phenotypic changes in the SCLC immune microenvironment, with greater T-cell dysfunction in SCLC-N than SCLC-A. Moreover, the recurrent, PLCG2-high subclone is associated with exhausted CD8+ T-cells and a pro-fibrotic, immunosuppressive monocyte/macrophage population, suggesting possible tumor-immune coordination to promote metastasis.

cancer biology↗

Experience replay supports non-local learning

To make effective decisions we need to consider the relationship between actions and outcomes. They are, however, often separated by time and space. The biological mechanism capable of spanning those gaps remains unknown. One promising, albeit hypothetical, mechanism involves neural replay of non-local experience. Using a novel task, that segregates direct from indirect learning, combined with magnetoencephalography (MEG), we tested the role of neural replay in non-local learning in humans. Following reward receipt, we found significant backward replay of non-local experience, with a 160 msec state-to-state time lag, and this replay facilitated learning of action values. This backward replay, combined with behavioural evidence of non-local learning, was more pronounced in experiences that were of greater benefit for future behavior, as predicted by theories of prioritization. These findings establish rationally targeted non-local replay as a neural mechanism for solving complex credit assignment problems during learning. One Sentence SummaryReverse sequential replay is found, for the first time, to support non-local reinforcement learning in humans and is prioritized according to utility.

neuroscience↗