Biology subjects

Tal, A.

Publications and source records attributed to Tal, A..

15 recordsLinked to original sources

bioRxiv2026

Distinct Hippocampal Cellular Pathologies Influence Cognition Across Diagnostic Categories, also distinguishing Schizophrenia from Affective Psychoses

Introduction: Total and social cognition deficits independently predict functioning in psychosis, but targeting these in clinical trials are unsuccessful in improving function. The admixture of schizophrenia and affective psychoses cases could be a roadblock if these differ in cellular pathology. Methods: We examined cognitive functioning (MATRICS) and hippocampal cellular pathologies based on metabolite biomarker concentrations (1H-MRSI), using categorical and transdiagnostic classifications in 80 participants: 22 non-psychotic affective disorder (NP-aff), 25 healthy controls (HC), and 33 with psychosis (Psy), including 20 schizophrenia and 13 affective psychoses (aff-P) cases. Results: NP-aff and HC had similar total cognition (46.64{+/-}12.01 vs 41.10{+/-}17.88), both superior to Psy (28.34{+/-} 12.34; p's<0.01). Mean metabolite concentrations were similar across all groups but showed significant within-group associations to cognitive tests. For HC, total cognition, working memory and reasoning deficits were associated with reduced neuronal integrity (-.414, -.422, -.433, p's<.05), although no biomarker predicted total cognition in the clinical groups. FFor NP-aff, elevated myelin/membrane concentrations accompanied cognitive deficits; significantly so for visual learning deficits (.446, p<.05), which were also associated with decreased glia (-.503, p<.05). Opposite NP-aff, reduced myelin/membrane concentrations predicted cognitive deficits in Psy (-.514, p<.05). Separating schizophrenia from aff-P on social cognition showed reduced glutamate/excitation in schizophrenia (-.673, p<.05) ibut higher myelin/membrane turnover and neuronal integrity concentrations in aff-P (.575, .581, p's<.05). Conclusions: Schizophrenia and affective psychosis significantly differed for biomarkers of cellular pathology related to social cognition. Distinctly different underpinnings for cognition were also identified for other groups, aligning with DSM-5 and ICD disorder based categories. These findings include support for heterogeneous, but not transdiagnostic, conceptualizations of cognition and psychosis.

pathology↗

bioRxiv2026

Do Symptom Domains Have Similar Cellular Underpinnings Across Psychiatric Diagnoses: Evidence from 3D Hippocampal MR Spectroscopy

Introduction: The NIMH Research Domain Criteria (RDoC) posits similar cellular pathologies for particular symptom domains across diagnostic categories. Conversely, knowledge that these differ could advance treatment discovery, especially for affective and non-affective psychoses, as studies usually intermix them. Methods: We tested this by comparing metabolite biomarker concentrations for cellular pathologies from whole hippocampal proton magnetic spectroscopic imaging (1H MRSI) with symptoms from the original and five factor PANSS, and the Hamilton Depression and Young Mania Scales. Participants were 26 healthy controls; 22 non-psychotic affective cases (NP-aff); and 33 with psychosis (including 20 schizophrenia (Scz) and 13 affective psychosis (aff-P) cases). Results: PANSS activation factor was related to reductions in all cellular component biomarkers in Scz, including glia, membrane turnover, neural integrity, glutaminergic neurotransmission, and energy metabolism (p's<.05), but only to energy metabolism in NP-aff (p=.03). Biomarkers for mood symptoms also varied across categories, suggesting gliosis for mania and depression in HC (p's[≤].025), but increased membrane turnover for mania in aff-P (p=.015), and decreased neural integrity and energy metabolism for depression in Scz (p's<.05). In contrast, negative symptoms and autistic preoccupation were related to reduced glia in both NP-aff and aff-P (p's<.05). Autistic preoccupation in Scz was related to both reduced glia and membrane turnover (p's<.05). Only Scz showed a significant finding for positive symptoms, specifically reduced membrane turnover (p=.018). Discussion: These results suggest both distinct and similar cellular pathologies for symptoms across diagnoses, including affective and non-affective psychoses. The differences support categorizing disorders and stratifying different psychoses in research rather than transdiagnostic approaches.

pathology↗

bioRxiv2025

Dynamics of Macrophage Polarization Reveal Unique Phenotypes During Mouse Postpartum Uterine Remodeling

BackgroundMacrophages play essential roles in uterine physiology during pregnancy and the postpartum (PP) period. In various organ systems, macrophages exhibit distinct M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization states, the balance of which is key not only in scarless wound healing but also in pathological fibrosis. While macrophages are central players in PP uterine remodeling, their polarization dynamics during this period and associated spatial distribution remain largely unknown. MethodsUterine tissues were collected from C57BL/6J wild-type mice at various PP days (PPD 1, 3, 7, 14, 21, 28) and non-pregnant controls. Multicolor flow cytometry was used to analyze immune populations and macrophage polarization states. Macrophage polarization was determined using CD86 (M1 marker) and CD206 (M2 marker). Immunofluorescence (IF) and immunohistochemistry (IHC) were used to examine the colocalization of M1 and/or M2 markers alongside F4/80 to assess macrophage polarization status and tissue distribution. ResultsOn PPD1, uterine macrophage numbers were higher compared to all other time points, with significantly increased M2 macrophages (CD86-CD206+) (43% p<0.0001) compared to PPD3 (5.1%), PPD7 (2.4%), PPD14 (2.3%), and non-pregnant (1.9%). A rapid polarization shift to M1 macrophages (CD86+CD206-) occurred on PPD3 (50.6%), PPD7 (66.5%), and PPD14 (58.8%) compared to PPD1 (11.9% p<0.0001). Additionally, there was a trend of increased M2 macrophages on PPD21 (10%) and PPD28 (5%). We observed a unique macrophage subset of mixed phenotype (co-expressing CD86+CD206+) significantly higher on PPD 1 (37.2% p<0.05) compared to NP (7.8%), PPD7 (11.6%), and PPD14 (26.4%). IF co-staining confirmed these dynamics, showing the highest percentage of macrophages co-expressing CD206+F4/80+ on PPD1 (77.2%), significantly higher than all other time points. IHC revealed the specific temporal and spatial distribution of F4/80+ and CD206+ cells within the uterine endometrial stroma adjacent to the myometrial junction in the early PP period. ConclusionsThe predominance of M2-polarized macrophages on PPD1 followed by a rapid shift to M1 phenotype from PPD3 to PPD14 indicates an evolving inflammatory response during the early postpartum period. Repolarization to M2 profile on PPD21, along with increased abundance of a mixed population (M1/M2), uncovers the dynamic complexity of macrophage polarization during PP uterine remodeling, providing new insights into scarless uterine tissue repair.

immunology↗

bioRxiv2025

Characterizing representational shaping of individual motor and object representations after sequence learning

Learning temporal regularities between pairs of events has been shown to shape neural representations in the medial temporal lobe, but it remains unclear whether representational changes generalize across memory domains. Here we used fMRI and multivoxel pattern similarity analyses to examine representational shaping as a consequence of motor and object sequence learning. Across two sessions, participants incidentally learned a fixed four-element sequence of finger movements or visual objects. We compared the pattern of blood oxygen level-dependent activity evoked by each object and finger movement before and after sequence learning. Analyses were performed on bilateral ROIs, including primary motor cortex (M1), lateral occipital complex (LOC), premotor cortex (PMC), striatum (STR) and the hippocampus (HC). Behaviorally, participants successfully learned the sequence in both domains. At the neural level, motor representations became more differentiated with learning in M1, PMC, STR, and HC, but not in LOC. This global differentiation was not specific to the sequence condition and was also observed after repeated co-occurrence of movements in a pseudorandom order. Critically, the HC differentiated between motor representations in the learned sequence in a unidirectional predictive manner whereby movements became more differentiated from the preceding than from the following element in the sequence. In contrast, object representations remained stable across sequence repetitions in all brain regions, even though participants successfully learned their temporal order.

neuroscience↗

bioRxiv2024

Inhibition of DKK-1 by WAY262611 Inhibits Osteosarcoma Metastasis

Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood. Patients who present with metastatic disease at diagnosis or relapse have a very poor prognosis, and this has not changed over the past four decades. The Wnt signaling pathway plays a role in regulating osteogenesis and is implicated in OS pathogenesis. DKK-1 inhibits the canonical Wnt signaling pathway, causing inhibition of osteoblast differentiation and disordered bone repair. Our lab previously demonstrated that a monoclonal antibody against DKK-1 prevented metastatic disease in a mouse model. This study expands upon those findings by demonstrating similar results with a small molecule inhibitor of DKK-1, WAY262611, both in vitro and in vivo. WAY262611 was evaluated in vitro on osteosarcoma cell lines, including proliferation, caspase activation, cell cycle analysis, and signaling pathway activation. We utilized our orthotopic implantation-amputation model of osteosarcoma metastasis in vivo to determine the impact of WAY262611 on primary tumor progression and metastatic outgrowth of disseminated tumor cells. Differentiation status was determined using single cell RNA sequencing. We show here that WAY262611 activates canonical Wnt signaling, enhances nuclear localization and transcriptional activity of beta-catenin, and slows proliferation of OS cell lines. We also show that WAY262611 induces osteoblastic differentiation of an OS patient-derived xenograft in vivo, as well as inhibiting metastasis. This work credentials DKK-1 as a therapeutic target in OS, allowing for manipulation of the Wnt signaling pathway and providing preclinical justification for the development of new biologics for prevention of osteosarcoma metastasis.

cancer biology↗

bioRxiv2024

Integrated Ising Model with global inhibition for decision making

Humans and other organisms make decisions choosing between different options, with the aim to maximize the reward and minimize the cost. The main theoretical framework for modeling the decision-making process has been based on the highly successful drift-diffusion model, which is a simple tool for explaining many aspects of this process. However, new observations challenge this model. Recently, it was found that inhibitory tone increases during high cognitive load and situations of uncertainty, but the origin of this phenomenon is not understood. Motivated by this observation, we extend a recently developed model for decision making while animals move towards targets in real space. We introduce an integrated Ising-type model, that includes global inhibition, and use it to explore its role in decision-making. This model can explain how the brain may utilize inhibition to improve its decision-making accuracy. Compared to experimental results, this model suggests that the regime of the brains decision-making activity is in proximity to a critical transition line between the ordered and disordered. Within the model, the critical region near the transition line has the advantageous property of enabling a significant decrease in error with a small increase in inhibition and also exhibits unique properties with respect to learning and memory decay.

biophysics↗

bioRxiv2024

Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans

Immunotherapy leads to cancer eradication despite the tumors immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules. The craters harbor the highest density of CD8+ T cells in the tumor. In zebrafish, CD8+ T cells formed prolonged interactions with melanoma cells within craters, characteristic of antigen recognition. Following immunostimulatory treatment, the craters enlarged and became the major site of activated CD8+ T cell accumulation and tumor killing that was B2M dependent. In humans, craters predicted immune response to ICB therapy, showing response better than high T cell infiltration. This marks craters as potential new diagnostic tool for immunotherapy success and targets to enhance ICB response.

cancer biology↗

bioRxiv2024

Inhibitory mechanisms in the prefrontal-cortex differentially mediate Putamen activity during valence-based learning

Learning from appetitive and aversive stimuli involves interactions between the prefrontal cortex and subcortical structures. Preclinical and theoretical studies indicate that inhibition is essential in regulating the relevant neural circuitry. Here, we demonstrate that GABA, the main inhibitory neurotransmitter in the central nervous system, differentially affects how the dACC interacts with subcortical structures during appetitive and aversive learning in humans. Participants engaged in tasks involving appetitive and aversive learning, while using functional magnetic resonance spectroscopy (MRS) at 7T to track GABA concentrations in the dACC, alongside whole-brain fMRI scans to assess BOLD activation. During appetitive learning, dACC GABA concentrations were negatively correlated with learning performance and BOLD activity measured from the dACC and the Putamen. These correlations were absent during aversive learning, where dACC GABA concentrations negatively correlated with the connectivity between the dACC and the Putamen. Our results show that inhibition in the dACC mediates appetitive and aversive learning in humans through distinct mechanisms.

neuroscience↗

bioRxiv2023

Simultaneous multi-transient linear-combination modeling of MRS data improves uncertainty estimation

PurposeThe interest in applying and modeling dynamic MRS has recently grown. 2D modeling yields advantages for the precision of metabolite estimation in interrelated MRS data. However, it is unknown whether including all transients simultaneously in a 2D model without averaging (presuming a stable signal) performs similarly to 1D modeling of the averaged spectrum. Therefore, we systematically investigated the accuracy, precision, and uncertainty estimation of both described model approaches. MethodsMonte Carlo simulations of synthetic MRS data were used to compare the accuracy and uncertainty estimation of simultaneous 2D multi-transient LCM with 1D-LCM of the average. 2,500 datasets per condition with different noise representations of a 64-transient MRS experiment at 6 signal-to-noise levels for two separate spin systems (scyllo-inositol and GABA) were analyzed. Additional datasets with different levels of noise correlation were also analyzed. Modeling accuracy was assessed by determining the relative bias of the estimated amplitudes against the ground truth, and modeling precision was determined by standard deviations and Cramer-Rao Lower Bounds (CRLB). ResultsAmplitude estimates for 1D- and 2D-LCM agreed well and showed similar level of bias compared to the ground truth. Estimated CRLBs agreed well between both models and with ground truth CRLBs. For correlated noise the estimated CRLBs increased with the correlation strength for the 1D-LCM but remained stable for the 2D-LCM. ConclusionOur results indicate that the model performance of 2D multi-transient LCM is similar to averaged 1D-LCM. This validation on a simplified scenario serves as necessary basis for further applications of 2D modeling.

neuroscience↗

bioRxiv2023

The reach of reactivation: Effects of consciously-triggered versus unconsciously-triggered reactivation of associative memory

Newly formed memories are not passively stored for future retrieval; rather, they are reactivated offline and thereby strengthened and transformed. However, reactivation is not a uniform process: it occurs throughout different states of consciousness, including conscious rehearsal during wakefulness and unconscious processing during both wakefulness and sleep. In this study, we explore the consequences of reactivation during conscious and unconscious awake states. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., multiple fruits, vehicles, musical instruments) which allowed us to examine the consequences of reactivation on semantically-related memories. After an extensive learning phase, some triads were reactivated consciously, through cued retrieval, or unconsciously, through subliminal priming. In both conditions, the adjective was used as the cue. Reactivation impacted memory for the most distal association (i.e., the spatial position of associated objects) in a consciousness-dependent and memory-strength-dependent manner. First, conscious reactivation of a triad resulted in a weakening of other semantically related memories, but only those that were initially more accurate (i.e., memories with lower pre-reactivation spatial errors). This is similar to what has been previously demonstrated in studies employing retrieval-induced forgetting designs. Unconscious reactivation, on the other hand, benefited memory selectively for weak cued items. Semantically linked associations were not impaired, but rather integrated with the reactivated memory. Taken together, our results demonstrate that conscious and unconscious reactivation of memories during wakefulness have qualitatively different consequences on memory for distal associations. Effects are memory-strength-dependent, as has been shown for reactivation during sleep. Results support a consciousness-dependent inhibition account, according to which unconscious reactivation involves less inhibitory dynamics than conscious reactivation, thus allowing more liberal spread of activation. Our findings set the stage for additional exploration into the role of consciousness in memory structuring.

neuroscience↗

bioRxiv2023

Increased cortical inhibition immediately following brief motor memory reactivation supports reconsolidation and overnight offline learning gains

Practicing motor skills stabilizes and strengthens motor memories by repeatedly reactivating and reconsolidating them. The conventional view, by which a repetitive practice is required for substantially improving skill performance, has been recently challenged by behavioral experiments, in which even brief reactivations of the motor memory have led to significant improvements in skill performance. However, the mechanisms which facilitate brief reactivation-induce skill improvements remain elusive. While initial memory consolidation has been repeatedly associated with increased neural excitation and dis-inhibition, reconsolidation has been shown to involve a poorly-understood mixture of both excitatory and inhibitory alterations. Here, we followed a three-day reactivation-reconsolidation framework, to examine whether the excitatory/inhibitory mechanisms which underlie brief reactivation and repetitive practice differ. Healthy volunteers practiced a motor sequence learning task using either brief reactivation or repetitive practice and were assessed using ultra-high field (7T) magnetic resonance spectroscopy at the primary motor cortex (M1). We found that increased inhibition (GABA concentrations) and decreased excitation/inhibition (glutamate/GABA ratios) immediately following the brief reactivation were associated with overnight offline performance gains. These gains were on-par with those exhibited following repetitive practice, where no correlations with inhibitory or excitatory changes were observed. Our findings suggest that brief reactivation and repetitive practice depend on fundamentally different neural mechanisms, and that early inhibition - and not excitation - is particularly important in supporting the learning gains exhibited by brief reactivation.

neuroscience↗

bioRxiv2022

Early excitatory and inhibitory modifications in the motor cortex following skill learning support motor memory consolidation and cortical plasticity overnight

The learning of new motor skills constitutes an inseparable part of our lives. Motor consolidation refers to the offline processing of motor memories following the acquisition of new motor skills. The animal literature suggests that the primary motor cortex (M1) plays a key role in motor memory consolidation, and structural and functional plasticity in M1 following motor consolidation have been demonstrated. However, the mechanisms supporting motor memory consolidation and plasticity in the human M1 are not well understood. Initial human neuroimaging studies show that the initial stages of motor learning in humans are accompanied by short-term temporal dynamics of the brains main excitatory and inhibitory neurotransmitters - Glutamate (Glu) and GABA - in M1, but it remains unclear how these relate to the question of motor memory consolidation. Here, we show that early Glu and GABA modifications in M1 following motor skill learning may play vital roles in supporting motor memory consolidation and neural plasticity that take place over longer time scales. Using a multimodal magnetic resonance approach implemented on ultra-high field 7T scanner in healthy young adults (n=36), we found increased Glu and decreased GABA in M1 during the initial offline period following learning to support consolidation-related local and inter-regional functions of M1, such as motor memory reactivation and increased functional connectivity with the striatum. These neurochemical changes also correlated with overnight structural and functional plasticity expressed as increased M1 grey matter volume and functional connectivity, while Glu modifications also correlated with adaptive behavior, as reflected by improvements in skill performance. Our results provide intriguing microscale mechanistic evidence to the potential distinctive roles of Glu and GABA in promoting motor memory consolidation and plasticity in the human M1. They also highlight a role for early neurochemical modifications to memory consolidation and plasticity in the human brain and may hold important clinical implications in rehabilitative settings such as in stroke and brain injury.

neuroscience↗

bioRxiv2022

The Future is 2D: Spectral-Temporal Fitting of Dynamic Magnetic Resonance Spectroscopy Data Provides Exponential Gains in Precision Over Conventional Approaches

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSPurposeC_ST_ABSMany MRS paradigms produce 2D spectral-temporal datasets, including diffusion-weighted, functional, hyperpolarized and enriched (13C, 2H) experiments. Conventionally, temporal parameters - such as T2, T1, or diffusion constants - are assessed by first fitting each spectrum independently, and subsequently fitting a temporal model (1D fitting). We investigated whether simultaneously fitting the entire dataset using a single spectral-temporal model (2D fitting) would improve the precision of the relevant temporal parameter. MethodsWe derived a Cramer Rao Lower Bound for the temporal parameters for both 1D and 2D approaches, for two experiments: A multi-echo (MTE) experiment, designed to estimate metabolite T2s; And a functional (fMRS) experiment, designed to estimate fractional change ({delta}) in metabolite concentrations. We investigated the dependence of the relative standard deviation of T2 in MTE and{delta} in fMRS. ResultsWhen peaks were spectrally distant, 2D fitting improved precision by approximately 20% relative to 1D fitting, regardless of the experiment and other parameter values. These gains increased exponentially as peaks drew closer. Dependence on temporal model parameters was weak to negligible. ConclusionOur results strongly support a 2D approach to MRS fitting where applicable, and particularly in nuclei such as 1H and 2H, which exhibit substantial spectral overlap.

bioengineering↗

bioRxiv2022

Adaptive Magnetic Resonance

Nuclear magnetic resonance is one of the cornerstones of modern medicine and biomedical research. Over the past several decades, the speed and precision of in-vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) have increased by leaps and bounds, by utilizing sophisticated excitation and acquisition techniques, from parallel imaging and compressed sensing to magnetic resonance fingerprinting. However, these approaches have all been static in nature, fixing measurement parameters in advance, in anticipation of a wide range of expected tissue parameter values, and are therefore sub-optimal for any given subject. We depart from the conventional framework of magnetic resonance and propose a new approach - termed adaptive magnetic resonance - which binds acquisition and excitation, by using the measured signal to update and fine-tune the measurement parameters in real time. This targets the specific tissue characteristics of the subject while they are being scanned. Adaptive magnetic resonance provides a completely new and previously-untapped avenue for improving the sensitivity and specificity of in-vivo magnetic resonance across all tissue contrast mechanisms. Equivalently, it can accelerate data acquisition compared to non-adaptive schemes, by obtaining the same precision using fewer, optimally tuned excitations. We demonstrate that an adaptive pulse sequence for measuring the transverse relaxation time (T2) of metabolites in-vivo improves upon the precision of static approaches by a factor of {approx} 1.7 - or, alternatively, accelerates acquisition 2.5-fold.

bioengineering↗

bioRxiv2018

Inhibitory and excitatory mechanisms in the human cingulate-cortex support reinforcement learning

The dorsal anterior cingulate cortex (dACC) is crucial for motivation, reward- and error-guided decision-making, yet its excitatory and inhibitory mechanisms remain poorly explored in humans. In particular, the balance between excitation and inhibition (E/I), demonstrated to play a role in animal studies, is difficult to measure in behaving humans. Here, we used magnetic-resonance-spectroscopy (1H-MRS) to examine these mechanisms during reinforcement learning with three different conditions: high cognitive load (uncertainty); probabilistic discrimination learning; and a control null-condition. Subjects learned to prefer the gain option in the discrimination phase and had no preference in the other conditions. We found increased GABA levels during the uncertainty condition, suggesting recruitment of inhibitory systems during high cognitive load when trying to learn. Further, higher GABA levels during the null (baseline) condition correlated with improved discrimination learning. Finally, excitatory and inhibitory levels were correlated during high cognitive load. The result suggests that availability of dACC inhibitory resources enables successful learning. Our approach establishes a novel way to examine the contribution of the balance between excitation and inhibition to learning and motivation in behaving humans.

neuroscience↗