Biology subjects

Dumitriu, D.

Publications and source records attributed to Dumitriu, D..

8 recordsLinked to original sources

bioRxiv2026

Sex-Specific Stress Outcomes Following Acute and Chronic Social Defeat Stress

Stressful experiences are a major risk factor for the development of neuropsychiatric disorders in vulnerable individuals. Identifying features that can distinguish stress-susceptible from resilient individuals remains a central goal in stress neurobiology. Due to the routine exclusion of female subjects from stress research or the use of male-defined criteria in behavioral characterization of subjects post-stress, female stress responses and vulnerability profiles remain poorly understood. This work aimed to gain a better understanding of sex-specific stress responses to social defeat stress. Here, we used a novel paired male-female social defeat paradigm and tracked subjects longitudinally in a ''two-hit'' design to evaluate responses to both acute social defeat stress (ASDS) and chronic social defeat stress (CSDS), and to determine how prior stress exposure influences subsequent vulnerability. We found that both ASDS and CSDS induces changes in social avoidance/approach behavior in males but not females, as measured by a classic social interaction ratio. Prior ASDS exposure enhanced susceptibility to subsequent CSDS most clearly in males, with females displaying specific changes in corner zone occupancy. Furthermore, we observed divergent anxiety profiles between males and females in a post-stress behavioral battery. Finally, females exhibited specific stress-related locomotor responses following ASDS. Together, these findings suggest that females may adopt distinct behavioral strategies following social defeat stress.

neuroscience↗

bioRxiv2026

Temporal Dynamics of Parvalbumin Interneurons and Perineuronal Nets During Learned Helplessness

This study followed the recruitment of medial prefrontal cortex parvalbumin (PV+) interneurons and their perineuronal nets (PNN) across the two stages of the learned helplessness (LH) paradigm: the initial uncontrollable stress experience and the later expression of helpless or resilient coping. Combining TRAP2-based activity mapping with a staggered-endpoint design, three main findings emerged on the functional and structural neuronal correlates in prelimbic (PL) and infralimbic (ILA) subregions during LH paradigm. First, prefrontal recruitment during the first inescapable shock session already predicted the coping strategy that would be expressed two days later during escape avoidance test, before any behavioral divergence was observable. Second, the expression of parvalbumin protein (PV) in this cortical subpopulation of interneurons followed a dynamic trajectory rather than a static stress change, transiently reduced across all shocked animals at the escape test, and back to baseline over the following week in both PL and ILA, except in animals that went on to be classified as helpless. Third, PNN intensity temporal patterns did not track stress exposure in either subregion, yet PNN and PV became correlated with one another specifically in ILA in stressed animals, pointing to a stress-induced structural coupling rather than a constitutive relationship between the two markers.

neuroscience↗

bioRxiv2022

A Novel Localized Tracing Technique to Explore Intra-Amygdala Functional and Structural Connectivity Patterns as Mediators of Individual Variability in Stress Response

Neuropsychiatric disorders including anxiety and depression can be induced by stress, but not all individuals exposed to stress develop psychopathology. Therefore, probing the neural substrates that underlie trait vulnerability to stress may open the door for preventive approaches that use biological markers to identify at-risk populations. Here, we developed a novel tracing technique to probe local connectivity patterns as predictors of individual variability in stress responses. Specifically, we combined a retrograde transsynaptic rabies tracing system with cFos colocalization immediately after an acute stressor to elucidate local structural and stress-activated (functional) differences in connectivity within the amygdala complex in female and male mice along a spectrum of social approach/avoidance following acute social defeat stress. While we find no structural or functional connections within the amygdala complex as predictors of individual variability in our behavioral readout, our methods provide a novel approach to investigating cellular and behavioral individual variability in stress responses. Furthermore, we identify overall stress-activation as a predictor of social approach/avoidance in two subregions, medial amygdala and piriform-amygdala area, which may serve as potential biological markers of trait vulnerability, with possible clinical applicability. Significance StatementExposure to stress is ubiquitous, but the outcomes of stress exposure vary greatly between individuals. Our work introduces a novel tracing technique to probe for structural and functional connectivity patterns across a broad spectrum of behavioral responses to social stress. Utilizing pre-clinical classification in conjunction with representative behavioral classification introduces to the field a mechanism to identify potential clinical targets for preventative screening for neuropsychiatric disorders as well as further individualized treatment. Notably, our work identifies two intra-amygdalar neural correlates of social stress, opening the door for future investigation of the role these regions play in mediating social stress.

neuroscience↗

bioRxiv2021

A severe form of maternal separation in rat consisting of nineteen-day 6-hour daily separation at unpredictable times minimally affects behavior across lifespan and possibly confers protection against some maladaptive outcomes

Maternal separation (MS), a type of early life stress, has been associated with adverse socioemotional and behavioral outcomes throughout the lifespan across multiple species. Comprehensive longitudinal biobehavioral characterization of MS in rats is sparse and conflicting, warranting more studies. We conducted an MS paradigm involving 6-hour daily separation at unpredictable start times from P2 to P21. We hypothesized this severe form of MS would lead to developmentally emerging maladaptive biobehavioral consequences from juvenile through adult periods compared to Controls (C), especially in social behaviors. We tested: (1) own dam odor preference shortly after weaning; (2) juvenile and adult anxiety-like, sociability, and play behaviors using the light-dark test, three-chambered social interaction test, and video-coded juvenile play behavior; and (3) adult coping behaviors and neuroendocrine response using the forced swim test and blood corticosterone responses. Our results show minimal effects on biobehavioral outcomes across the lifespan. Recently weaned MS male rats had a stronger preference for their dams odor. Juvenile MS females spent more time in rough-and-tumble play than C female rats. No differences in sociability were found in the juvenile or adult periods. MS promoted a decrease in anxiety-like behavior that persisted from juvenile to adult periods. Finally, MS led to deficits in coping behavior in male adults, but basal and reactive corticosterone levels were unaltered by MS. More studies are needed to validate our surprising findings and probe the neural mechanisms underlying some of the observed protective effects. Significance StatementMaternal separation (MS), a type of early life stress, has been shown to lead to short and long-term adverse socioemotional consequences in humans and biobehavioral outcomes in rodents. Available data on MS exposed rats are sparse, conflicting, and often lack longitudinal outcomes. We designed a 6-hour unpredictable daily MS paradigm from postnatal day (P2) to P21 to severely disrupt normal dam-pup interactions. Our results show MS leads to increased preference for own dam odor, persisting reductions in anxiety-like behaviors from juvenile to adulthood, and no effects on sociability. Adverse effects on coping behaviors were uniquely identified in males. The present study warrants reevaluation of the central dogma that MS leads to maladaptive biobehavioral outcomes.

neuroscience↗

bioRxiv2021

Mouse brain-wide mitochondrial connectivity anchored in gene, brain and behavior

The brain and behavior are under energetic constraints, limited by mitochondrial energy transformation capacity. However, the mitochondria-behavior relationship has not been systematically studied on a brain-wide scale. Here we examined the association between multiple features of mitochondrial respiratory chain capacity and stress-related behaviors in mice with diverse behavioral phenotypes. Miniaturized assays of mitochondrial respiratory chain enzyme activities and mitochondrial DNA (mtDNA) content were deployed on 571 samples across 17 brain areas, defining specific patterns of mito-behavior associations. By applying multi-slice network analysis to our brain-wide mitochondrial dataset, we identified three large-scale networks of brain areas with shared mitochondrial signatures. A major network composed of cortico-striatal areas exhibited the strongest mitochondria-behavior correlations, accounting for up to 50% of animal-to-animal behavioral differences, suggesting that this mito-based network is functionally significant. The mito-based brain networks also overlapped with regional gene expression and structural connectivity and quantitatively diverged in their molecular mitochondrial phenotype signatures. Therefore, this work provides convergent multimodal evidence anchored in enzyme activities, gene expression, and animal behavior that distinct, behaviorally-relevant mitochondrial phenotypes exist across the mouse brain.

neuroscience↗

bioRxiv2021

Maternal separation affects fronto-cortical activity in rat pups during dam-pup interactions and behavioral transitions

Early-life stress is known to impair neurodevelopment. Prior work from our group showed that prolonged physical and emotional separation necessitated by the medical needs of preterm infants (born <37 weeks) is associated with lower electroencephalogram (EEG) power in frontal areas, and that trend can be reversed by an intervention that enhances the physical and emotional contact between preterm infant and mother. Here we sought to model the changes in preterm infant frontal EEG power in a rodent model. We examined effects of daily maternal separation (MS) on frontal cortex electrophysiological (electrocorticography [EcoG]) activity in neonatal rats. We also explored the effects of dam-pup behavioral interactions on EcoG activity. From postnatal days (P) 2-10, rat pups were separated daily from their dam and isolated from their littermates for 3 hours. Control rats were normally reared. On P10, pups were implanted with telemetry devices and an electrode placed on the left frontal dura. EcoG activity was recorded during daily sessions over the next four days while pups remained in the home cage, as well as in response to a pup-dam isolation-reunion paradigm at P12. EcoG power was computed in 1 Hz frequency bins between 1-100 Hz. Dam and pup behavioral interactions during recording sessions were coded and synchronized to EcoG data. MS pups showed lower EcoG power during dam-pup interactions. These data parallel human and provide evidence of lower fronto-cortical activity as an early marker of early-life stress and possible mechanism for long-term effects of maternal separation on neurobehavioral development.

neuroscience↗

bioRxiv2020

Prelimbic-amygdala overexcitability mediates trait vulnerability in a novel mouse model of acute social defeat stress

BACKGROUNDDepression is a debilitating neuropsychiatric disorder with 20% lifetime prevalence in the developed world but only approximately half of afflicted individuals respond to currently available therapies. While there is growing understanding of the neurobiological underpinnings of the depressed brain, much less is known about the preexisting circuitry leading to selective vulnerability versus resilience. Elucidating these networks could lead to novel preventative approaches. METHODSWe developed a model of acute social defeat stress (ASDS) that allows classification of male mice into "susceptible" (socially avoidant) versus "resilient" (expressing control-level social approach) one hour after exposure to six minutes of social stress. Using circuit tracing and high-resolution confocal imaging, we explored differences in activation and dendritic spine density and morphology in the prelimbic to basolateral amygdala (PL[->]BLA) circuit in resilient versus susceptible mice. To test the functional relevance of identified structure/function differences to divergent behavioral responses, we used an intersectional chemogenetic approach to inhibit the PL[->]BLA circuit during or prior to ASDS. RESULTSSusceptible mice had greater PL[->]BLA recruitment during ASDS and activated PL[->]BLA neurons from susceptible mice had more and larger mushroom spines compared to resilient mice. Inhibition of the PL[->]BLA circuit led to a population shift towards resilience. CONCLUSIONPreexisting PL[->]BLA structure/function differences mediate divergent behavioral responses to ASDS in male mice. These results support the PL[->]BLA circuit as a biomarker of trait vulnerability and potential target for prevention of stress-induced psychopathology.

neuroscience↗

bioRxiv2020

MouseCircuits.org: An online repository to guide the circuit era of disordered affect

Affective disorders rank amongst the most disruptive and prevalent psychiatric diseases, resulting in enormous societal and economic burden, and immeasurable personal costs. Novel therapies are urgently needed but have remained elusive. The era of circuit-mapping in rodent models of disordered affect, ushered in by recent technological advancements allowing for precise and specific neural control, has reenergized the hope for precision psychiatry. Here, we present a novel whole-brain cumulative network and critically access the progress made to-date on circuits mediating affective-like behaviors in rodents to seek unifying principles of this cumulative data. We identified 106 original manuscripts in which optogenetics or chemogenetics were used to dissect behaviors related to fear-like, depressive-like or anxiety-like behaviors in rodents. Focusing on the 60 manuscripts that investigated pathways rather than regions, we identified emergent themes. We found that while a few pathways have been validated across similar behaviors and multiple labs, the data is mostly disjointed, with evidence of bidirectional effects of several pathways. Additionally, there is a need for analysis informed by observation prior to perturbation. Given the complex nature of brain connectivity, we argue that the compartmentalized viewpoint that develops as a consequence of fragmented pathway-specific manipulations does not readily lend itself to an integrative picture. To address this, we launched an interactive online consortium, MouseCircuits.org, an open-source platform for consolidated circuit data. This tool aims to support the shared vision of informed circuit dissection that ultimately leads to prevention and treatment of human disorders.

neuroscience↗