Biology subjects

Smail, M. A.

Publications and source records attributed to Smail, M. A..

7 recordsLinked to original sources

bioRxiv2026

Pediatric traumatic brain injury elicits acute neuroinflammation and long-term changes in social, cognitive, and decision-making behaviors in male and female rats

Traumatic brain injury (TBI) is one of the leading causes of emergency room visits in children under 10. Children are potentially more vulnerable to the adverse effects of TBI, given that their brains are still developing at the time of injury. Indeed, early life TBI has been linked to cognitive, social, and mood-related impairments later in life. The neuroimmune system has been implicated in adult TBI mechanisms and plays numerous key roles in brain development, making it an interesting candidate for linking pediatric TBI and prolonged behavioral alterations. Here we establish a rat model of mild pediatric TBI to investigate the relationship between early life TBI, acute responses of neuroimmune cells, and chronic behavioral dysregulation. At postnatal day 15, which is roughly equivalent to toddler age, male and female rat pups received a TBI via lateral fluid percussion injury. At 3 days post injury, TBI increased microglia and astrocyte coverage locally in the Perilesional Cortex but not in more distant corticolimbic regions. However, the hippocampus and prefrontal cortex did exhibit increased expression of the phagocytic marker CD68 in microglia, suggesting widespread glial activation even in the absence of gross coverage change. TBI also impacted mast cells, early-response innate immune cells, increasing their number and degranulation in multiple regions. In the juvenile and early adult periods, TBI impaired cognitive function, reduced sociability, and increased avoidance, with no change in anxiety-like behavior. Later in adulthood, TBI continued to impact cognitive behavior, increasing risky decision-making and impairing optimization months after injury. Together, these results suggest that pediatric TBI causes lasting cognitive and social dysregulation, possibly via acute neuroimmune alterations following injury at a critical period of brain development.

neuroscience↗

bioRxiv2024

Sex-Specific Regulation of Behavioral Responses to Single Prolonged Stress: Role of PACAP

Post-Traumatic Stress Disorder (PTSD) is a debilitating condition in which a traumatic experience triggers symptoms related to re-experiencing, avoidance, arousal, and mood dysregulation. PTSD negatively impacts 6% of people during their lifetime, with women being disproportionally affected and exhibiting different, more severe symptoms than men. Despite this widespread impact, the molecular mechanisms underlying PTSD and its sex differences remain poorly understood. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a neuropeptide which participates in fine-tuning circuitry throughout the brain and has been associated with PTSD in humans, especially in women. Here, we use Single Prolonged Stress (SPS), an animal model of PTSD, to explore the roles of PACAP and sex in PTSD-like behaviors. Specifically, a PACAP agonist or antagonist was infused into the infralimbic (IL) prefrontal cortex, a region key to regulating fear- and anxiety-related behaviors, prior to SPS in male and female rats. One week later, rats were tested in open field/novel object, elevated plus maze, and social interaction. Utilizing a behavioral indexing method, we were able to uncover SPS effects in PTSD-related behavioral domains that were differentially impacted by PACAP manipulations in males and females. While both sexes exhibited increased threat avoidance and decreased threat assessment following SPS, females increased sociability while males decreased sociability. Males also appeared to be protected by IL PACAP antagonism while female SPS phenotypes were exacerbated by IL PACAP agonism. Furthermore, RNAscope revealed that PACAP in the prefrontal cortex responds differently to SPS in males and females. Together, these findings suggest complex relationships between SPS, sex, and IL PACAP which may have important implications for treating PTSD in men and women. HIGHLIGHTSO_LISPS induces different PTSD-like phenotypes in male and female rats C_LIO_LISPS increases threat avoidance and decreases threat appraisal in both sexes C_LIO_LISociability is decreased in males but increased in females following SPS C_LIO_LIIL PACAP manipulation exerts diverging SPS behavioral effects in males and females C_LIO_LIPrefrontal PACAP signaling plays a sex-specific role in SPS molecular mechanisms C_LI

neuroscience↗

bioRxiv2022

Molecular Neurobiology of Loss

Psychological loss is a common experience that erodes well-being and negatively impacts quality of life. The molecular underpinnings of loss are poorly understood. Here, we investigate the mechanisms of loss using an enrichment removal (ER) paradigm in rats. A comprehensive multi-omics investigation of the basolateral amygdala (BLA) revealed alterations in microglia and extracellular matrix (ECM). Follow-up studies indicated that ER decreased microglia size, complexity, and phagocytosis, suggesting reduced immune surveillance. Loss also substantially increased ECM coverage, specifically targeting perineuronal nets surrounding parvalbumin interneurons, suggesting decreased plasticity and increased inhibition in the BLA following loss. Behavioral analyses suggest that these molecular effects are linked to impaired BLA salience evaluation, reflecting emotional blunting observed in human loss. These loss-like behaviors could be rescued by depleting BLA ECM during removal, helping us understand the mechanisms underlying loss and revealing novel molecular targets to ameliorate its impact.

neuroscience↗

bioRxiv2021

Differential Vulnerability of Anterior Cingulate Cortex Cell-Types to Diseases and Drugs

In psychiatric disorders, mismatches between disease-states and therapeutic strategies are highly pronounced, largely because of unanswered questions regarding specific vulnerabilities of different cell-types and therapeutic responses. Which cellular events (housekeeping or salient) are most affected? Which cell-types succumb first to challenges, and which exhibit the strongest response to drugs? Are these events coordinated between cell-types? How does the disease-state and drug affect this coordination? To address these questions, we analyzed single-nucleus-RNAseq (sn-RNAseq) data from the human anterior cingulate cortex--a region involved in many psychiatric disorders. Density index, a metric for quantifying similarities and dissimilarities across functional profiles, was employed to identify common (housekeeping) or salient functional themes across all cell-types. Cell-specific signatures were integrated with existing disease and drug-specific signatures to determine cell-type-specific vulnerabilities, druggabilities, and responsiveness. Clustering of functional profiles revealed cell-types jointly participating in these events. SST and VIP interneurons were found to be most vulnerable, whereas pyramidal neurons were least vulnerable. Overall, the disease-state is superficial layer-centric, largely influences cell-specific salient themes, strongly impacts disinhibitory neurons, and influences astrocyte interaction with a subset of deep-layer pyramidal neurons. Drug activities, on the other hand, are deep layer-centric and involve activating a distinct subset of deep-layer pyramidal neurons to circumvent the disinhibitory circuit malfunctioning in the disease-state. These findings demonstrate a novel application of sn-RNAseq data to explain drug and disease action at a systems level, suggests a targeted drug development and reevaluate various postmortem-based findings.

neuroscience↗

bioRxiv2021

Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy.

We probed a transcriptomic dataset of pilocarpine-induced TLE using various ontological, machine-learning, and systems-biology approaches. We showed that, underneath the complex and penetrant changes, moderate-to-subtle upregulated homeostatic and downregulated synaptic changes associated with the dentate gyrus and hippocampal subfields could not only predict TLE but various other forms of epilepsy. At the cellular level, pyramidal neurons and interneurons showed disparate changes, whereas the proportion of non-neuronal cells increased steadily. A probabilistic Bayesian network demonstrated an aberrant and oscillating physiological interaction between oligodendrocytes and interneurons in driving seizures. Validating the Bayesian inference, we showed that the cell types driving the seizures were associated with known antiepileptic and epileptic drugs. These findings provide predictive biomarkers of epilepsy, insights into the cellular connections and causal changes associated with TLE and a drug discovery method focusing on these events.

systems biology↗

bioRxiv2020

Similarities and dissimilarities between psychiatric cluster disorders

The common molecular mechanisms underlying psychiatric disorders are not well understood. Prior attempts to assess the pathological mechanisms responsible for psychiatric disorders have been limited by biased selection of comparable disorders, datasets as well as challenges associated with data normalization. However, publicly available databases offer a unique opportunity to expand such investigations both in terms of the number and types of diseases. Here, we used DisGeNET, a database of over 24,000 gene-disease associations to investigate the similarities and dissimilarities associated with enrichment of pathways, cell-types, drug targets, and human chromosomes within an unbiased cluster of psychiatric disorders. We show that cognition and neurotransmission related pathways are involved across all disorders, whereas those associated with immune system and signal-response coupling (cell-surface receptors, signal-transduction, gene-expression, and metabolic process) are associated with few disorders of the cluster. The drug-target based enrichment confirms the involvement of neurotransmission related changes across these disorders. At cell-type level, dendrite targeting interneurons, across all layers, are most involved across all disorders. Finally, using a clustering-based similarity index, we showed that the similarity between the disorders are influenced most at chromosomal level and to some extent at cellular level. Collectively, the results provide a comprehensive comparison of many psychiatric diseases in an unbiased manner and expand our understanding of the cellular and molecular pathologies associated with similar and comorbid psychiatric disorders.

bioinformatics↗

bioRxiv2020

Persistence: Using Protein Turnover to Expand the Applications of Transcriptomics

ABSTRACTOne of the major issues with RNA sequencing is the lack of reproducibility between RNA and protein expression. Transcriptomics offers a holistic view of the molecular landscape of a tissue at an RNA level. However, RNA and protein expression are often at odds when measured in the same sample, raising the question whether or not changes in RNA expression translate to functional differences. This problem creates a need to devise a way to approximate protein abundance from transcriptomics data, in order to create a more complete picture of the functional landscape of a tissue. One additional measure that could be useful here is protein turnover or half-life. Once RNA is transcribed into protein, that protein can either be quickly degraded or remain in the cell for an extended period of time. The longer a protein’s half-life, the more influence it can have on its surroundings. Recently, a study used stable isotope labeling in mammals (SILAM) in combination with mass spectrometry to determine the turnover ratio of ∼2200 protein in mouse synaptosomes. This data offers a valuable opportunity to integrate protein turnover with RNA expression to gain deeper insight into the functional meaning of RNA expression changes. Here, we present the concept of this combination of protein turnover and RNA expression, which we coined as persistence. We then demonstrate the application of persistence using schizophrenia (SCZ) transcriptomics datasets. Calculating persistence for these datasets greatly improved our ability to predict protein expression from RNA expression. Furthermore, this approach successfully identified persistent genes and pathways known to have impactful changes in SCZ. These results suggest that persistence is a valuable metric for improving the functional insight that can be gained from transcriptomics data.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioinformatics↗