Biology subjects

Cruz-Martin, A.

Publications and source records attributed to Cruz-Martin, A..

11 recordsLinked to original sources

bioRxiv2026

Environmental risk reshapes high-confidence schizophrenia risk genes during a developmental window of vulnerability

Rare coding variants and environmental exposures such as early-life stress contribute to schizophrenia risk, but whether environmental adversity alters the expression of genetically implicated genes remains unclear. Combining the limited bedding and nesting (LBN) model of early-life stress (ELS) with 24-plex single-cell mFISH registered to the Allen Mouse Brain Atlas, we profiled the ten genes identified in the original SCHEMA study, the complement gene C4b and activity markers in 1.29 million cells across four postnatal ages. Whole-brain risk-gene upregulation was greatest at postnatal day 21 (P21), with region- and cell-type-selective effects that prominently involved the hypothalamus. Sp4 and Cacna1g showed distinct temporal responses: Sp4 increased at P21 and decreased at P90 in hypothalamic oligodendrocytes, whereas Cacna1g decreased at P10. ELS-associated C4b upregulation extended across neuronal and glial populations, including oligodendrocytes and OPCs. Across regional cell types, P10 C4b effects were positively correlated with P21 Grin2a effects. These findings suggest that ELS perturbs the developmental expression of genes implicated in schizophrenia, identifying potential molecular links between environmental adversity and genetic vulnerability.

neuroscience↗

bioRxiv2026

Micro- and nanoplastics alter electrophysiological brain patterns and reshape human neurodevelopmental trajectories

Environmental microplastics and nanoplastics (MNPs) are emerging contaminants that accumulate in human tissues, including the brain, yet their mechanistic impact on the nervous system remains poorly understood. Converging postmortem evidence indicates increased MNP burden in brains from individuals with dementia, suggesting a potential link between plastic accumulation and disorders of the nervous system. However, whether MNPs directly contribute to brain aging and ensuing neurodegenerative processes, or disrupt neurodevelopment, is unknown. Here, we show that exposure to environmentally relevant MNPs induces cellular senescence and innate immune transcriptional programs in human brain organoids. Using region-specific cortical organoids, we demonstrate that synthetic polystyrene (PS), polyethylene terephthalate (PET), low-density polyethylene (LDPE), and high-density polyethylene (HDPE), as well as environmental ocean-derived MNPs (eMNPs) isolated from the coast of Hawaii, elicit a robust neuroinflammatory response. Transcriptomic analyses revealed activation of senescence-associated secretory phenotype (SASP) pathways. MNP exposure further disrupted neurodevelopmental trajectories, impairing neuroectodermal differentiation and redirecting lineage commitment toward mesoderm-like states, with concomitant enrichment of choroid plexus-like populations and a marked imbalance in neuronal and glial differentiation. These developmental alterations occurred in parallel with a pro-inflammatory and senescent microenvironment, suggesting coordinated disruption of developmental and aging programs. Importantly, high-density multielectrode array recordings revealed that MNP exposure altered electrophysiological activity and neuronal network dynamics, demonstrating that MNP-driven perturbations translate into dysfunctional neurological outcomes. Collectively, our findings identify MNPs as potent disruptors of human neurophysiology, linking plastic exposure to altered developmental trajectories, cellular senescence, neuroinflammation, and impaired neuronal network activity, providing mechanistic insights into how plastic accumulation may contribute to impaired brain dynamics.

neuroscience↗

bioRxiv2026

Temporal cortex astrocytic Gi-GPCR signaling regulates learned threat responses

Astrocytes are increasingly recognized as dynamic modulators of brain circuit function, memory processing, and behavior. Emerging evidence suggests that astrocytic G-protein-coupled receptors (GPCRs) are key regulators of these processes through their influence on intracellular signaling and neuron-glia interactions. Here, we show that the repertoire of functionally expressed GPCRs in cortical astrocytes is broader than previously appreciated. Yet, how distinct GPCR pathways contribute to behavioral regulation remains unknown for most brain areas and behavioral contexts. We therefore investigated the role of astrocytic GPCR signaling in the temporal cortex, a region that integrates multimodal sensory information and learned fear associations. Using chemogenetic tools to selectively activate distinct GPCR pathways in astrocytes, we demonstrate that Gi-coupled GPCR signaling, but not Gs- or Gq-coupled signaling, enhances fear memory retrieval. In vivo fiber photometry revealed that temporal cortex astrocytes exhibit robust Ca2+ transients to neutral, conditioned auditory and aversive sensory stimuli. Notably, astrocytic Gi-GPCR activation attenuated cue-evoked Ca2+ transients during memory retrieval. Together, these findings identify astrocytic GPCR signaling as a pathway-specific regulator of fear memory retrieval and suggest that astrocytic Gi-GPCR signaling modulates the processing of sensory cues to drive defensive behavior.

neuroscience↗

bioRxiv2023

C4 induces pathological synaptic loss by impairing AMPAR trafficking.

During development, activation of the complement pathway, an extracellular proteolytic cascade, results in microglia-dependent synaptic elimination via complement receptor 3 (CR3). Here, we report that decreased connectivity caused by overexpression of C4 (C4-OE), a schizophrenia-associated gene, is CR3 independent. Instead, C4-OE triggers GluR1 degradation through an intracellular mechanism involving endosomal trafficking protein SNX27, resulting in pathological synaptic loss. Moreover, the connectivity deficits associated with C4-OE were rescued by increasing levels of SNX27, linking excessive complement activity to an intracellular endolysosomal recycling pathway affecting synapses.

neuroscience↗

bioRxiv2023

REVEALS: An Open Source Multi Camera GUI For Rodent Behavior Acquisition

Understanding the rich behavioral data generated by mice is essential for deciphering the function of the healthy and diseased brain. However, the current landscape lacks effective, affordable, and accessible methods for acquiring such data, especially when employing multiple cameras simultaneously. We have developed REVEALS (Rodent BEhaVior Multi-camErA Laboratory AcquiSition), a graphical user interface (GUI) written in python for acquiring rodent behavioral data via commonly used USB3 cameras. REVEALS allows for user-friendly control of recording from one or multiple cameras simultaneously while streamlining the data acquisition process, enabling researchers to collect and analyze large datasets efficiently. We release this software package as a stand-alone, open-source framework for researchers to use and modify according to their needs. We describe the details of the GUI implementation, including the camera control software and the video recording functionality. We validate results demonstrating the GUIs stability, reliability, and accuracy for capturing and analyzing rodent behavior using DeepLabCut pose estimation in both an object and social interaction assay. REVEALS can also be incorporated into other custom pipelines to analyze complex behavior, such as MoSeq. In summary, REVEALS provides an interface for collecting behavioral data from one or multiple perspectives that, combined with deep learning algorithms, will allow the scientific community to discover and characterize complex behavioral phenotypes to understand brain function better.

neuroscience↗

bioRxiv2021

Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice

The opioid epidemic led to an increase in the number of Neonatal Opioid Withdrawal Syndrome (NOWS) cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice were administered morphine (15mg/kg, s.c.) twice daily for postnatal days (P) 1-14, an approximate of the third trimester of human gestation. Male and female mice underwent behavioral testing on P7 and P14 to determine the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal on P14 for RNA-sequencing. Morphine induced weight loss from P2-14, which persisted during adolescence (P21) and adulthood (P50). USVs markedly increased at P7 in females, emerging earlier than males. On P7 and P14, both morphine exposed female and male mice displayed hyperalgesia on the hot plate and tail flick assays, with females having greater hyperalgesia than males. Morphine-exposed mice exhibited increased anxiety-like behavior in the open-field arena at P21. Transcriptome analysis of the brainstem (medulla plus pons), an area implicated in opioid withdrawal and NOWS, identified pathways enriched for noradrenergic signaling in females and males. We also found sex-specific pathways related to mitochondrial function and neurodevelopment in females and circadian entrainment in males. Sex-specific transcriptomic neuroadaptations implicate unique neurobiological mechanisms underlying NOWS-like behaviors. SIGNIFICANCE STATEMENTNeonatal opioid withdrawal syndrome (NOWS) is a poorly understood condition that has both a genetic and environmental component and is thought to be mechanistically distinct from opioid withdrawal in adults. The development of murine models for measuring neurobehavioral responses is critical for informing the neurobiological adaptations underlying NOWS. Using outbred mice that more closely model human genetic variation, we discovered a surprising degree of sexual dimorphism in behavioral timing and severity of NOWS-model behaviors as well as transcriptomic adaptations in brain tissue that together suggest distinct mechanisms and sex-specific therapeutics for reversing withdrawal symptoms and restoring brain function.

neuroscience↗

bioRxiv2021

Large-scale cellular-resolution imaging of neural activity in freely behaving mice

Miniaturized microscopes for head-mounted fluorescence imaging are powerful tools for visualizing neural activity during naturalistic behaviors, but the restricted field of view of first-generation miniscopes limits the size of neural populations accessible for imaging. Here we describe a novel miniaturized mesoscope offering cellular-resolution imaging over areas spanning several millimeters in freely moving mice. This system enables comprehensive visualization of activity across entire brain regions or interactions across areas.

neuroscience↗

bioRxiv2020

Distinct VIP interneurons in the cingulate cortex encode anxiogenic and social stimuli

A hallmark of higher-order cortical regions is their functional heterogeneity, but it is not well understood how these areas encode such diverse information. The anterior cingulate cortex (ACC), for example, is important in both emotional regulation and social cognition. Previous work shows activation of the ACC to anxiety-related and social stimuli, but it is unknown how subpopulations or microcircuits within the ACC simultaneously encode these distinct stimuli. One type of inhibitory interneuron, which is positive for vasoactive intestinal peptide (VIP), is known to alter the activity of many cells in local cortical microcircuits, but it is unknown whether the activity of VIP cells in the ACC (VIPACC) encodes anxiety-related or social information. Using in vivo calcium imaging and miniscopes in freely behaving mice to monitor VIPACC activity, we identified distinct, non-overlapping subpopulations of VIPACC that preferentially activated to either anxiogenic, anxiolytic, social, or non-social stimuli. We determined that stimulus-selective cells encode the animals behavioral states and VIP interneuron clusters may co-activate, improving this encoding. Finally, we used trans-synaptic tracing to show that VIPACC receive widespread inputs from regions implicated in emotional regulation and social cognition. These findings demonstrate not only that the ACC is not homogeneous in its function, but also that there is marked functional heterogeneity even within disinhibitory interneuron populations. This work contributes to our understanding of how the cortex encodes information across diverse contexts and provides insight into the complexity of neural processes involved in anxiety and social behavior.

neuroscience↗

bioRxiv2019

Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction

Schizophrenia is a severe mental disorder with an unclear pathophysiology. Increased expression of the immune gene C4 has been linked to a greater risk of developing schizophrenia; however, it is unknown whether C4 plays a causative role in this brain disorder. Using confocal imaging and whole-cell electrophysiology, we demonstrate that overexpression of C4 in mouse prefrontal cortex neurons leads to perturbations in dendritic spine development and hypoconnectivity, which mirror neuropathologies found in schizophrenia. We find evidence that microglia-neuron interactions and microglia-mediated synaptic engulfment are enhanced with increased expression of C4. We also show that C4-dependent circuit dysfunction in the frontal cortex leads to decreased social interactions in juvenile mice. These results demonstrate that increased expression of the schizophrenia-associated gene C4 causes aberrant circuit wiring in the developing prefrontal cortex and leads to deficits in early social behavior, suggesting that altered C4 expression contributes directly to schizophrenia pathogenesis.

neuroscience↗

bioRxiv2018

A Sparse Unreliable Distributed Code Underlies the Limits of Behavioral Discrimination

The cortical code that underlies perception must enable subjects to perceive the world at timescales relevant for behavior. We find that mice can integrate visual stimuli very quickly (<100 ms) to reach plateau performance in an orientation discrimination task. To define features of cortical activity that underlie performance at these timescales, we measured single unit responses in the mouse visual cortex at timescales relevant to this task. In contrast to high contrast stimuli of longer duration, which elicit reliable activity in individual neurons, stimuli at the threshold of perception elicit extremely sparse and unreliable responses in V1 such that the activity of individual neurons do not reliably report orientation. Integrating information across neurons, however, quickly improves performance. Using a linear decoding model, we estimate that integrating information over 50-100 neurons is sufficient to account for behavioral performance. Thus, at the limits of perception the visual system is able to integrate information across a relatively small number of highly unreliable single units to generate reliable behavior.

neuroscience↗

bioRxiv2017

Songbird organotypic culture as an in vitro model for interrogating sparse sequencing networks

Sparse sequences of neuronal activity are fundamental features of neural circuit computation; however, the underlying homeostatic mechanisms remain poorly understood. To approach these questions, we have developed a method for cellular-resolution imaging in organotypic cultures of the adult zebra finch brain, including portions of the intact song circuit. These in vitro networks can survive for weeks, and display mature neuron morphologies. Neurons within the organotypic slices exhibit a diversity of spontaneous and pharmacologically induced activity that can be easily monitored using the genetically encoded calcium indicator GCaMP6. In this study, we primarily focus on the classic song sequence generator HVC and the surrounding areas. We describe proof of concept experiments including physiological, optical, and pharmacological manipulation of these exposed networks. This method may allow the cellular rules underlying sparse, stereotyped neural sequencing to be examined with new degrees of experimental control.\n\nHighlightsO_LIOrganotypic brain slices from adult zebra finch (Taeniopygia guttata), expressing the calcium indicator GCaMP6, can be cultured and maintained for at least several weeks and display spontaneous and evoked calcium transients.\nC_LI

neuroscience↗