@article{pmid41362369,

title = {Stress-Induced Dysregulation of the Guidance Cue Receptor DCC Alters Corticolimbic Circuit Architecture},

author = {Ashraf Mahmud and Giovanni Hernandez and Fatme Abboud and Cecilia Flores},

doi = {10.1016/j.bpsgos.2025.100629},

issn = {2667-1743},

year  = {2026},

date = {2026-01-01},

journal = {Biol Psychiatry Glob Open Sci},

volume = {6},

number = {1},

pages = {100629},

abstract = {BACKGROUND: Elevated expression of the guidance cue receptor gene  in the adult prefrontal cortex (PFC) is a hallmark of major depressive disorder. DCC receptors regulate neuronal connectivity and plasticity in adulthood. In male mice,  knockout in the PFC promotes resilience to behavioral dysregulation following chronic social defeat stress (CSDS), whereas  upregulation increases susceptibility. However, the underlying mechanisms remain to be elucidated.nnMETHODS: We combined CSDS, behavioral tests (i.e., social interaction, nestlet shredding, and dark-light tests), retrograde neuronal tracing, and quantitative neuroanatomical analysis in adult male mice ( = 90) to investigate whether DCC receptors contribute to stress susceptibility/resilience by remodeling dendritic spine architecture of selective PFC neuronal networks.nnRESULTS: CSDS reduced both mature and newly formed spines on the apical, but not basal, dendrites of PFC pyramidal neurons. This effect was prevented by downregulating DCC receptors in these neurons, a manipulation that also prevented depression-like behaviors, suggesting a mechanistic link. DCC-expressing neurons in the PFC predominantly projected to the nucleus accumbens, and social defeat stress induced dendritic spine loss specifically in projections from the infralimbic PFC. Notably, knockout of DCC receptors in infralimbic PFC neurons projecting to the nucleus accumbens shell protected against stress-induced social avoidance.nnCONCLUSIONS: DCC receptors may influence susceptibility or resilience to social stress-induced depression-like behaviors by altering the apical dendritic architecture of PFC pyramidal neurons, particularly those projecting to the nucleus accumbens shell. This mechanism may be at play in the neurobiology of depression, pointing to DCC receptors as promising therapeutic targets.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40519638,

title = {Peripheral MicroRNA Signatures in Adolescent Depression},

author = {Alice Morgunova and Nicholas O'Toole and Fatme Abboud and Saché Coury and Gary Gang Chen and Maxime Teixeira and Eamon Fitzgerald and Gustavo Turecki and Anthony J Gifuni and Ian H Gotlib and Corina Nagy and Michael J Meaney and Tiffany C Ho and Cecilia Flores},

doi = {10.1016/j.bpsgos.2025.100505},

issn = {2667-1743},

year  = {2025},

date = {2025-07-01},

journal = {Biol Psychiatry Glob Open Sci},

volume = {5},

number = {4},

pages = {100505},

abstract = {BACKGROUND: Adolescent depression is linked to enduring maladaptive outcomes, chronic severity of symptoms, and poor treatment response. Identifying epigenetic signatures of adolescent depression is urgently needed to improve early prevention and intervention strategies. MicroRNAs (miRNAs) are epigenetic regulators of adolescent neurodevelopmental processes, but their role as markers and mediators of adolescent depression is unknown.nnMETHODS: Here, we examined miRNA profiles from dried blood spot samples of male and female adolescents with clinical depression and psychiatrically healthy male and female adolescents ( = 62). We processed and sequenced these samples using a small RNA protocol tailored for miRNA identification.nnRESULTS: We identified 9 differentially expressed (DE) miRNAs (adjusted  value < .05), all of which were upregulated in adolescents with depression. At future follow-ups post blood collection, expression of miR-3613-5p, mir-30c-2, and miR-942-5p were positively associated with depression severity but not anxiety, suggesting a stronger link to persistent depression symptoms. Expression of miR-32-5p inversely correlated with hippocampal volume, highlighting a potential neurobiological basis. Common predicted gene targets of the DE miRNAs are involved in neurodevelopment, cognitive processing, and depressive disorders.nnCONCLUSIONS: These findings lay the groundwork for identifying adolescent peripheral miRNA markers that reflect neurodevelopmental pathways that shape lifelong psychopathology risk.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39228790,

title = {BDNF-dependent nano-organization of Neogenin and the WAVE regulatory complex promotes actin remodeling in dendritic spines},

author = {Belal Shohayeb and Kai Sempert and Tristan P Wallis and Frédéric A Meunier and Nela Durisic and Elizabeth A O'Brien and Cecilia Flores and Helen M Cooper},

doi = {10.1016/j.isci.2024.110621},

issn = {2589-0042},

year  = {2024},

date = {2024-09-01},

journal = {iScience},

volume = {27},

number = {9},

pages = {110621},

abstract = {Synaptic structural plasticity, the expansion of dendritic spines in response to synaptic stimulation, is essential for experience-dependent plasticity and is driven by branched actin polymerization. The WAVE regulatory complex (WRC) is confined to nanodomains at the postsynaptic membrane where it catalyzes actin polymerization. As the netrin/RGM receptor Neogenin is a critical regulator of the WRC, its nanoscale organization may be an important determinant of WRC nanoarchitecture and function. Using super-resolution microscopy, we reveal that Neogenin is highly organized on the spine membrane at the nanoscale level. We show that Neogenin binding to the WRC promotes co-clustering into nanodomains in response to brain-derived neurotrophic factor (BDNF), indicating that nanoclustering occurs in response to synaptic stimulation. Disruption of Neogenin/WRC binding not only prevents BDNF-mediated actin remodeling but also inhibits BDNF-induced calcium signaling. We conclude that the assembly of Neogenin/WRC nanodomains is a prerequisite for BDNF-mediated structural and synaptic plasticity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39056276,

title = {The scheduling of adolescence with Netrin-1 and UNC5C},

author = {Daniel Hoops and Robert Kyne and Samer Salameh and Del MacGowan and Radu Gabriel Avramescu and Elise Ewing and Alina Tao He and Taylor Orsini and Anais Durand and Christina Popescu and Janet Mengyi Zhao and Kelcie Shatz and LiPing Li and Quinn Carroll and Guofa Liu and Matthew J Paul and Cecilia Flores},

doi = {10.7554/eLife.88261},

issn = {2050-084X},

year  = {2024},

date = {2024-07-01},

journal = {Elife},

volume = {12},

abstract = {Dopamine axons are the only axons known to grow during adolescence. Here, using rodent models, we examined how two proteins, Netrin-1 and its receptor, UNC5C, guide dopamine axons toward the prefrontal cortex and shape behaviour. We demonstrate in mice () that dopamine axons reach the cortex through a transient gradient of Netrin-1-expressing cells - disrupting this gradient reroutes axons away from their target. Using a seasonal model (Siberian hamsters; ) we find that mesocortical dopamine development can be regulated by a natural environmental cue (daylength) in a sexually dimorphic manner - delayed in males, but advanced in females. The timings of dopamine axon growth and UNC5C expression are always phase-locked. Adolescence is an ill-defined, transitional period; we pinpoint neurodevelopmental markers underlying this period.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38036858,

title = {Rewiring the future: drugs abused in adolescence may predispose to mental illness in adult life by altering dopamine axon growth},

author = {Radu Gabriel Avramescu and Giovanni Hernandez and Cecilia Flores},

doi = {10.1007/s00702-023-02722-6},

issn = {1435-1463},

year  = {2024},

date = {2024-05-01},

journal = {J Neural Transm (Vienna)},

volume = {131},

number = {5},

pages = {461--467},

abstract = {Adolescence is a period of increased exploration and novelty-seeking, which includes new social behaviors, as well as drug experimentation, often spurred on by peer pressure. This is unfortunate, as the immature state of the adolescent brain makes it particularly susceptible to the negative developmental impact of drug use. During adolescence, dopamine terminals, which have migrated from the ventral tegmental area, pause in the nucleus accumbens, before segregating by either forming local connections or growing towards the prefrontal cortex (PFC). This developmentally late and lengthy process renders adolescent dopamine axon pathfinding vulnerable to disruption by substance use. Indeed, exposure to stimulant drugs in adolescent male mice, but not females, triggers dopamine axons to mistarget the nucleus accumbens and to grow ectopically to the PFC. Some evidence suggests that at this novel site, the functional organization of the ectopic dopamine axons mirrors that of the intended target. The structural rewiring dysregulates local synaptic connectivity, leading to poor impulse control ability, deficits of which are a core symptom of substance-use disorders. In the present commentary, we argue that different substances of abuse induce dopamine mistargeting events with the off-target trajectory prescribed by the type of drug, leading to psychiatric outcomes later in life.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38557733,

title = {Social Defeat Stress Model for Adolescent C57BL/6 Male and Female Mice},

author = {Andrea Harée Pantoja-Urbán and Samuel Richer and Michel Giroux and Dominique Nouel and Cecilia Flores},

doi = {10.3791/66455},

issn = {1940-087X},

year  = {2024},

date = {2024-03-01},

journal = {J Vis Exp},

number = {205},

abstract = {Social adversity in adolescence is prevalent and can negatively impact mental health trajectories. Modeling social stress in adolescent male and female rodents is needed to understand its effects on ongoing brain development and behavioral outcomes. The chronic social defeat stress paradigm (CSDS) has been widely used to model social stress in adult C57BL/6 male mice by leveraging on the aggressive behavior displayed by an adult male rodent to an intruder invading its territory. An advantage of this paradigm is that it allows to categorize defeated mice into resilient and susceptible groups based on their individual differences in social behavior 24 h after the last defeat session. Implementing this model in adolescent C57BL/6 mice has been challenging because adult or adolescent mice do not typically attack early adolescent male or female mice and because adolescence is a short period of life, encompassing discreet temporal windows of vulnerability. This limitation was overcome by adapting an accelerated version of the CSDS to be used for adolescent male and female mice. This 4-day stress paradigm with 2 physical attack sessions per day uses a C57BL/6 male adult to prime the CD-1 mouse for aggressiveness such that it readily attacks the male or female adolescent mouse. This model was termed accelerated social defeat stress (AcSD) for adolescent mice. Adolescent exposure to AcSD induces social avoidance 24 h later in both males and females, but only in a subset of defeated mice. This vulnerability occurs despite the number of attacks being consistent across sessions between resilient and susceptible groups. The AcSD model is short enough to allow exposure during discrete periods within adolescence, allows the segregation of mice according to the presence or absence of social avoidance behavior, and is the first model available to study social defeat stress in adolescent C57BL/6 female mice.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38692693,

title = {Disproportionate neuroanatomical effects of  haploinsufficiency in adolescence compared with adulthood: links to dopamine, connectivity, covariance, and gene expression brain maps in mice},

author = {Daniel Hoops and Yohan Yee and Christopher Hammill and Sammi Wong and Colleen Manitt and Barry J Bedell and Lindsay Cahill and Jason P Lerch and Cecilia Flores and John G Sled},

doi = {10.1503/jpn.230106},

issn = {1488-2434},

year  = {2024},

date = {2024-01-01},

journal = {J Psychiatry Neurosci},

volume = {49},

number = {3},

pages = {E157--E171},

abstract = {BACKGROUND: Critical adolescent neural refinement is controlled by the DCC (deleted in colorectal cancer) protein, a receptor for the netrin-1 guidance cue. We sought to describe the effects of reduced  on neuroanatomy in the adolescent and adult mouse brain.nnMETHODS: We examined neuronal connectivity, structural covariance, and molecular processes in a -haploinsufficient mouse model, compared with wild-type mice, using new, custom analytical tools designed to leverage publicly available databases from the Allen Institute.nnRESULTS: We included 11 -haploinsufficient mice and 16 wild-type littermates. Neuroanatomical effects of  haploinsufficiency were more severe in adolescence than adulthood and were largely restricted to the mesocorticolimbic dopamine system. The latter finding was consistent whether we identified the regions of the mesocorticolimbic dopamine system a priori or used connectivity data from the Allen Brain Atlas to determine de novo where these dopamine axons terminated. Covariance analyses found that  haploinsufficiency disrupted the coordinated development of the brain regions that make up the mesocorticolimbic dopamine system. Gene expression maps pointed to molecular processes involving the expression of ,  (encoding DCC's co-receptor), and  (encoding its ligand, netrin-1) as underlying our structural findings.nnLIMITATIONS: Our study involved a single sex (males) at only 2 ages.nnCONCLUSION: The neuroanatomical phenotype of  haploinsufficiency described in mice parallels that observed in -haploinsufficient humans. It is critical to understand the haploinsufficient mouse as a clinically relevant model system.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37668732,

title = {Axo-glial interactions between midbrain dopamine neurons and oligodendrocyte lineage cells in the anterior corpus callosum},

author = {Megan Caldwell and Vanessa Ayo-Jibunoh and Josue Criollo Mendoza and Katherine R Brimblecombe and Lauren M Reynolds and Xin Yan Zhu Jiang and Colin Alarcon and Elizabeth Fiore and Jacquelyn N Tomaio and Greg R Phillips and Susana Mingote and Cecilia Flores and Patrizia Casaccia and Jia Liu and Stephanie J Cragg and Dan P McCloskey and Leora Yetnikoff},

doi = {10.1007/s00429-023-02695-y},

issn = {1863-2661},

year  = {2023},

date = {2023-09-01},

journal = {Brain Struct Funct},

abstract = {Oligodendrocyte progenitor cells (OPCs) receive synaptic innervation from glutamatergic and GABAergic axons and can be dynamically regulated by neural activity, resulting in activity-dependent changes in patterns of axon myelination. However, it remains unclear to what extent other types of neurons may innervate OPCs. Here, we provide evidence implicating midbrain dopamine neurons in the innervation of oligodendrocyte lineage cells in the anterior corpus callosum and nearby white matter tracts of male and female adult mice. Dopaminergic axon terminals were identified in the corpus callosum of DAT-Cre mice after injection of an eYFP reporter virus into the midbrain. Furthermore, fast-scan cyclic voltammetry revealed monoaminergic transients in the anterior corpus callosum, consistent with the anatomical findings. Using RNAscope, we further demonstrate that ~ 40% of Olig2 + /Pdfgra + cells and ~ 20% of Olig2 + /Pdgfra- cells in the anterior corpus callosum express Drd1 and Drd2 transcripts. These results suggest that oligodendrocyte lineage cells may respond to dopamine released from midbrain dopamine axons, which could affect myelination. Together, this work broadens our understanding of neuron-glia interactions with important implications for myelin plasticity by identifying midbrain dopamine axons as a potential regulator of corpus callosal oligodendrocyte lineage cells.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37419977,

title = {Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism in mice},

author = {Lauren M Reynolds and Giovanni Hernandez and Del MacGowan and Christina Popescu and Dominique Nouel and Santiago Cuesta and Samuel Burke and Katherine E Savell and Janet Zhao and Jose Maria Restrepo-Lozano and Michel Giroux and Sonia Israel and Taylor Orsini and Susan He and Michael Wodzinski and Radu G Avramescu and Matthew Pokinko and Julia G Epelbaum and Zhipeng Niu and Andrea Harée Pantoja-Urbán and Louis-Éric Trudeau and Bryan Kolb and Jeremy J Day and Cecilia Flores},

doi = {10.1038/s41467-023-39665-1},

issn = {2041-1723},

year  = {2023},

date = {2023-07-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {4035},

abstract = {Initiating drug use during adolescence increases the risk of developing addiction or other psychopathologies later in life, with long-term outcomes varying according to sex and exact timing of use. The cellular and molecular underpinnings explaining this differential sensitivity to detrimental drug effects remain unexplained. The Netrin-1/DCC guidance cue system segregates cortical and limbic dopamine pathways in adolescence. Here we show that amphetamine, by dysregulating Netrin-1/DCC signaling, triggers ectopic growth of mesolimbic dopamine axons to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to enduring cognitive deficits. In adolescent females, compensatory changes in Netrin-1 protect against the deleterious consequences of amphetamine on dopamine connectivity and cognitive outcomes. Netrin-1/DCC signaling functions as a molecular switch which can be differentially regulated by the same drug experience as function of an individual's sex and adolescent age, and lead to divergent long-term outcomes associated with vulnerable or resilient phenotypes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37431265,

title = {Relationship between insulin and Netrin-1/DCC guidance cue pathway regulation in the prefrontal cortex of rodents exposed to prenatal dietary restriction},

author = {Aashita Batra and Santiago Cuesta and Marcio Bonesso Alves and Jose Maria Restrepo and Michel Giroux and Daniela Pereira Laureano and Amanda Brondani Mucellini Lovato and Patrícia Maidana Miguel and Tania Diniz Machado and Roberta Dalle Molle and Cecilia Flores and Patricia Pelufo Silveira},

doi = {10.1017/S204017442300017X},

issn = {2040-1752},

year  = {2023},

date = {2023-07-01},

journal = {J Dev Orig Health Dis},

pages = {1--7},

abstract = {Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and /-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in  mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a  gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting  expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37519472,

title = {Novel Functional Genomics Approaches Bridging Neuroscience and Psychiatry},

author = {Jose M Restrepo-Lozano and Cecilia Flores and Patricia P Silveira},

doi = {10.1016/j.bpsgos.2022.07.005},

issn = {2667-1743},

year  = {2023},

date = {2023-07-01},

journal = {Biol Psychiatry Glob Open Sci},

volume = {3},

number = {3},

pages = {351--361},

abstract = {The possibility of establishing a metric of individual genetic risk for a particular disease or trait has sparked the interest of the clinical and research communities, with many groups developing and validating genomic profiling methodologies for their potential application in clinical care. Current approaches for calculating genetic risk to specific psychiatric conditions consist of aggregating genome-wide association studies-derived estimates into polygenic risk scores, which broadly represent the number of inherited risk alleles for an individual. While the traditional approach for polygenic risk score calculation aggregates estimates of gene-disease associations, novel alternative approaches have started to consider functional molecular phenotypes that are closer to genetic variation and are less penalized by the multiple testing required in genome-wide association studies. Moving the focus from genotype-disease to genotype-gene regulation frameworks, these novel approaches incorporate prior knowledge regarding biological processes involved in disease and aggregate estimates for the association of genotypes and phenotypes using multi-omics data modalities. In this review, we discuss and list different functional genomics tools that can be used and integrated to inform researchers and clinicians for a better understanding and diagnosis of psychopathology. We suggest that these novel approaches can help generate biologically driven hypotheses for polygenic signals that can ultimately serve the clinical community as potential biomarkers of psychiatric disease susceptibility.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37355003,

title = {Gains and Losses: Resilience to Social Defeat Stress in Adolescent Female Mice},

author = {Andrea Harée Pantoja-Urbán and Samuel Richer and Amelie Mittermaier and Michel Giroux and Dominique Nouel and Giovanni Hernandez and Cecilia Flores},

doi = {10.1016/j.biopsych.2023.06.014},

issn = {1873-2402},

year  = {2023},

date = {2023-06-01},

journal = {Biol Psychiatry},

abstract = {BACKGROUND: Adolescence is a unique period of psychosocial growth during which social adversity can negatively influence mental health trajectories. Understanding how adolescent social stress impacts males and females and why some individuals are particularly affected is becoming increasingly urgent. Social defeat stress models for adolescent male mice have been effective in reproducing some physical/psychological aspects of bullying. Designing a model suitable for females has proven challenging.nnMETHODS: We report a version of the adolescent male accelerated social defeat stress (AcSD) paradigm adapted for females. Early adolescent C57BL/6J female mice (N = 107) were exposed to our modified AcSD procedure twice a day for 4 days and categorized as resilient or susceptible based on a social interaction test 24 hours later. Mice were then assessed for changes in Netrin-1/DCC guidance cue expression in dopamine systems, for inhibitory control in adulthood using the Go/No-Go task, or for alterations in dopamine connectivity organization in the matured prefrontal cortex.nnRESULTS: Most adolescent females showed protection against stress-induced social avoidance, but in adulthood, these resilient females developed inhibitory control deficits and showed diminution of prefrontal cortex presynaptic dopamine sites. Female mice classified as susceptible were protected against cognitive and dopaminergic alterations. AcSD did not alter Netrin-1/DCC in early adolescent females, contrary to previous findings with males.nnCONCLUSIONS: Preserving prosocial behavior in adolescent females may be important for survival advantage but seems to come at the price of developing persistent cognitive and dopamine deficiencies. The female AcSD paradigm produced findings comparable to those found in males, allowing mechanistic investigation in both sexes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36471064,

title = {Reduced dopamine release in Dcc haploinsufficiency male mice abolishes the rewarding effects of cocaine but not those of morphine and ethanol},

author = {Emmanuel Darcq and Dominique Nouel and Giovanni Hernandez and Matthew Pokinko and Polina Ash and Luc Moquin and Alain Gratton and Brigitte Kieffer and Cecilia Flores},

doi = {10.1007/s00213-022-06288-1},

issn = {1432-2072},

year  = {2023},

date = {2023-03-01},

journal = {Psychopharmacology (Berl)},

volume = {240},

number = {3},

pages = {637--646},

abstract = {RATIONALE: The Netrin-1/DCC guidance cue pathway is critically involved in the adolescent organization of the mesocorticolimbic dopamine circuitry. Adult mice heterozygous for Dcc show reduced dopamine release in the nucleus accumbens in response to amphetamine and, in turn, blunted sensitivity to the rewarding effects of this drug.nnOBJECTIVE: Here, we tested whether the protective effects of Dcc haploinsufficiency are specific to stimulant drugs of abuse or instead extrapolate to opioids and ethanol.nnMETHODS: We used the place preference paradigm to measure the rewarding effects of cocaine (20 mg/kg), morphine (5 or 10 mg/Kg), or ethanol (20%) in adult (PND 75) male Dcc haploinsufficient mice or their wild-type litter mates. In a second experiment, we compared in these two genotypes, in vivo dopamine release in the nucleus accumbens after a single i.p. injection of morphine (10 mg/kg).nnRESULTS: We found reduced morphine-induced dopamine release in the nucleus accumbens of Dcc haploinsufficient male mice, but, contrary to the effects of stimulant drugs, there is no effect of genotype on morphine-induced conditioned preference.nnCONCLUSION: These findings show that reduced drug-induced mesolimbic dopamine in Dcc haploinsufficient male mice protects specifically against the rewarding effects of stimulant drugs, but not against the rewarding properties of morphine and ethanol. These results suggest that these drugs exert their rewarding effect via different brain circuits.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37901452,

title = {Preparation and processing of dried blood spots for microRNA sequencing},

author = {Alice Morgunova and Pascal Ibrahim and Gary Gang Chen and Saché M Coury and Gustavo Turecki and Michael J Meaney and Anthony Gifuni and Ian H Gotlib and Corina Nagy and Tiffany C Ho and Cecilia Flores},

doi = {10.1093/biomethods/bpad020},

issn = {2396-8923},

year  = {2023},

date = {2023-01-01},

journal = {Biol Methods Protoc},

volume = {8},

number = {1},

pages = {bpad020},

abstract = {Dried blood spots (DBS) are biological samples commonly collected from newborns and in geographic areas distanced from laboratory settings for the purposes of disease testing and identification. MicroRNAs (miRNAs)-small non-coding RNAs that regulate gene activity at the post-transcriptional level-are emerging as critical markers and mediators of disease, including cancer, infectious diseases, and mental disorders. This protocol describes optimized procedural steps for utilizing DBS as a reliable source of biological material for obtaining peripheral miRNA expression profiles. We outline key practices, such as the method of DBS rehydration that maximizes RNA extraction yield, and the use of degenerate oligonucleotide adapters to mitigate ligase-dependent biases that are associated with small RNA sequencing. The standardization of miRNA readout from DBS offers numerous benefits: cost-effectiveness in sample collection and processing, enhanced reliability and consistency of miRNA profiling, and minimal invasiveness that facilitates repeated testing and retention of participants. The use of DBS-based miRNA sequencing is a promising method to investigate disease mechanisms and to advance personalized medicine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37928069,

title = {RGMa and Neogenin control dendritic spine morphogenesis via WAVE Regulatory Complex-mediated actin remodeling},

author = {Kai Sempert and Belal Shohayeb and Vanessa Lanoue and Elizabeth A O'Brien and Cecilia Flores and Helen M Cooper},

doi = {10.3389/fnmol.2023.1253801},

issn = {1662-5099},

year  = {2023},

date = {2023-01-01},

journal = {Front Mol Neurosci},

volume = {16},

pages = {1253801},

abstract = {Structural plasticity, the ability of dendritic spines to change their volume in response to synaptic stimulation, is an essential determinant of synaptic strength and long-term potentiation (LTP), the proposed cellular substrate for learning and memory. Branched actin polymerization is a major force driving spine enlargement and sustains structural plasticity. The WAVE Regulatory Complex (WRC), a pivotal branched actin regulator, controls spine morphology and therefore structural plasticity. However, the molecular mechanisms that govern WRC activation during spine enlargement are largely unknown. Here we identify a critical role for Neogenin and its ligand RGMa (Repulsive Guidance Molecule a) in promoting spine enlargement through the activation of WRC-mediated branched actin remodeling. We demonstrate that Neogenin regulates WRC activity by binding to the highly conserved Cyfip/Abi binding pocket within the WRC. We find that after Neogenin or RGMa depletion, the proportions of filopodia and immature thin spines are dramatically increased, and the number of mature mushroom spines concomitantly decreased. Wildtype Neogenin, but not Neogenin bearing mutations in the Cyfip/Abi binding motif, is able to rescue the spine enlargement defect. Furthermore, Neogenin depletion inhibits actin polymerization in the spine head, an effect that is not restored by the mutant. We conclude that RGMa and Neogenin are critical modulators of WRC-mediated branched actin polymerization promoting spine enlargement. This study also provides mechanistic insight into Neogenin's emerging role in LTP induction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37035502,

title = {Awakening the dormant: Role of axonal guidance cues in stress-induced reorganization of the adult prefrontal cortex leading to depression-like behavior},

author = {Ashraf Mahmud and Radu Gabriel Avramescu and Zhipeng Niu and Cecilia Flores},

doi = {10.3389/fncir.2023.1113023},

issn = {1662-5110},

year  = {2023},

date = {2023-01-01},

journal = {Front Neural Circuits},

volume = {17},

pages = {1113023},

abstract = {Major depressive disorder (MDD) is a chronic and disabling disorder affecting roughly 280 million people worldwide. While multiple brain areas have been implicated, dysfunction of prefrontal cortex (PFC) circuitry has been consistently documented in MDD, as well as in animal models for stress-induced depression-like behavioral states. During brain development, axonal guidance cues organize neuronal wiring by directing axonal pathfinding and arborization, dendritic growth, and synapse formation. Guidance cue systems continue to be expressed in the adult brain and are emerging as important mediators of synaptic plasticity and fine-tuning of mature neural networks. Dysregulation or interference of guidance cues has been linked to depression-like behavioral abnormalities in rodents and MDD in humans. In this review, we focus on the emerging role of guidance cues in stress-induced changes in adult prefrontal cortex circuitry and in precipitating depression-like behaviors. We discuss how modulating axonal guidance cue systems could be a novel approach for precision medicine and the treatment of depression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35388180,

title = {Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children},

author = {Jose M Restrepo-Lozano and Irina Pokhvisneva and Zihan Wang and Sachin Patel and Michael J Meaney and Patricia P Silveira and Cecilia Flores},

doi = {10.1038/s41380-022-01533-7},

issn = {1476-5578},

year  = {2022},

date = {2022-06-01},

journal = {Mol Psychiatry},

volume = {27},

number = {6},

pages = {2742--2750},

abstract = {Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. The communication- as well as the connectivity- between corticolimbic regions of the brain are fundamental for eliciting inhibitory control behaviors, but early markers of vulnerability to this behavioral trait are yet to be discovered. The gradual maturation of the prefrontal cortex (PFC), in particular of the mesocortical dopamine innervation, mirrors the protracted development of inhibitory control; both are present early in life, but reach full maturation by early adulthood. Evidence suggests the involvement of the Netrin-1/DCC signaling pathway and its associated gene networks in corticolimbic development. Here we investigated whether an expression-based polygenic score (ePRS) based on corticolimbic-specific DCC gene co-expression networks associates with impulsivity-related phenotypes in community samples of children. We found that lower ePRS scores associate with higher measurements of impulsive choice in 6-year-old children tested in the Information Sampling Task and with impulsive action in 6- and 10-year-old children tested in the Stop Signal Task. We also found the ePRS to be a better overall predictor of impulsivity when compared to a conventional PRS score comparable in size to the ePRS (4515 SNPs in our discovery cohort) and derived from the latest GWAS for ADHD. We propose that the corticolimbic DCC-ePRS can serve as a novel type of marker for impulsivity-related phenotypes in children. By adopting a systems biology approach based on gene co-expression networks and genotype-gene expression (rather than genotype-disease) associations, these results further validate our methodology to construct polygenic scores linked to the overall biological function of tissue-specific gene networks.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}