Biology subjects

Biro, L.

Publications and source records attributed to Biro, L..

5 recordsLinked to original sources

bioRxiv2024

Pretrauma cognitive traits predict trauma-induced fear generalization and associated prefrontal functioning in a longitudinal model of posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition that develops in susceptible individuals exposed to traumatic stress, challenging clinicians to identify risk factors and mechanisms for mitigating vulnerability. Here we investigated behavioral predictors of high fear generalization, a core PTSD symptom, and its neural correlates longitudinally in rats. In a comprehensive behavioral test battery of emotional and cognitive function, pretrauma lower operant learning performance emerged as high predictor of fear generalization following trauma. Posttrauma operant training facilitated fear extinction, suggesting an overlap in neural circuits governing operant learning and fear expression. Neuronal activity mapping revealed significant changes in the medial prefrontal cortex (mPFC) in high fear generalizers, with alterations in CRH/VIP+ interneuron functioning. Silencing prefrontal Crh expression after fear memory consolidation enhanced mPFC activation and reduced fear expression, favoring resilience. These findings highlight operant learning and mPFC alterations as vulnerability markers and mediators of excessive fear generalization, with implications for prevention and targeted therapy in PTSD.

neuroscience↗

bioRxiv2024

Endocannabinoid biomarkers of vulnerability to the development of trauma-induced generalized fear responses

Traumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10-25% of exposed individuals. While human clinical studies suggest that susceptibility is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD susceptibility factors are poorly understood. Employing a rat model of PTSD, we characterized distinct resilient and susceptible subpopulations based on generalized fear, a core symptom of PTSD. In these groups, we assessed i.) eCB levels by mass spectrometry and expression variations of eCB system- and iii.) neuroplasticity-related genes by real-time quantitative PCR in the circuitry relevant in trauma-induced changes. Furthermore, employing supervised and semi-supervised machine learning based statistical analytical models, we assessed iv.) gene expression patterns with the most robust predictive power regarding PTSD susceptibility. According to our findings, in our model, generalized fear responses occurred with sufficient variability to characterize distinct resilient and susceptible subpopulations. Susceptible subjects showed lower prelimbic and higher ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG) compared to resilient subjects. Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, susceptibility was associated with i.) neuronal prefrontal, hippocampal and amygdalar hypoactivity, ii.) marked decrease in the expression of genes of transcription factors modulating neuroplasticity and iii.) an altered expression pattern of eCB-related genes, including enzymes involved in eCB metabolism. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding susceptibility. Taken together, the marked eCB and neuroplasticity changes in susceptible individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear. HighlightsO_LIWe assessed endocannabinoid and neuroplasticity correlates of PTSD susceptibility C_LIO_LIPosttrauma generalized fear strength separates susceptible and resilient individuals C_LIO_LISusceptible individuals show altered endocannabinoid levels in the fear circuitry C_LIO_LINeuroplasticity and endocannabinoid gene expression patterns predict susceptibility C_LI

neuroscience↗

bioRxiv2023

Persistently increased post-stress activity of paraventricular thalamic neurons is essential for the emergence of stress-induced maladaptive behavior

ABSTRACTTraumatic events can immediately lead to debilitating symptoms collectively called Acute Stress Disorder (ASD), however the mechanisms of ASD are poorly understood. Using a rodent model of ASD here we identify a crucial communication bottleneck between the brainstem and the forebrain, the calretinin-positive neurons in the paraventricular thalamus (PVT/CR+), that controls ASD. We show that following a single acute stress event, the pre-sleep behavior of the mice is altered for several days in parallel with a persistent increase in the firing rate of PVT/CR+ cells. Optogenetic inhibition of PVT/CR+ neuronal activity after the stress event for one hour was sufficient to rescue both the ASD symptoms and the prolonged increase in PVT/CR+ firing rate. Inhibition applied 5 days later was still able to ameliorate some of the symptoms. These data suggest that post-stress activity of PVT/CR+ neurons play a critical role in mediating the acute forms of stress-related affective dysfunctions. One-Sentence SummaryPost-stress inhibition of paraventricular thalamic neurons prevents the emergence of acute stressed phenotype.

neuroscience↗

bioRxiv2020

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

Excessive fear learning and extinction-resistant fear memories are core symptoms of anxiety and trauma-related disorders. Despite significant evidence from clinical studies reporting hyperactivity of the bed nucleus of stria terminalis (BNST) under these conditions, the role of BNST in fear learning and expression is still not clarified. Here, we tested how BNST modulates fear learning in mice using a chemogenetic approach. Activation of GABAergic neurons of BNST during fear acquisition, more specifically the consolidation phase, resulted in enhanced cued fear recall. Importantly, BNST activation had no acute impact on fear expression during conditioning or recalls, but it enhanced cued fear recall subsequently, potentially via altered activity of downstream regions as indicated by c-Fos. Enhanced fear memory consolidation could be replicated by selectively activating somatostatin neurons (but not corticotropin releasing factor neurons), suggesting significant modulation of fear memory strength by specific circuits of BNST.

neuroscience↗

bioRxiv2019

Conserved serotonergic background of experience-dependent challenge-responding in zebrafish (Danio rerio)

Forming effective responses to threatening stimuli requires the adequate and coordinated emergence of stress-related internal states. Such ability depends on early-life experiences and, in connection, the adequate formation of neuromodulatory systems, particularly serotonergic signaling. Here, we assess the serotonergic background of experience-dependent behavioral responsiveness employing a zebrafish (Danio rerio) model. For the first time, we have characterized a period during the behavioral metamorphosis in which zebrafish are highly reactive to their environment. Absence of social stimuli during this phase established by isolated rearing fundamentally altered the behavioral phenotype of post-metamorphic zebrafish in a challenge-specific manner, partially due to a decline in responsiveness and an inability to develop stress-associated arousal state. In line with this, isolation differently affected whole-brain 5-HT signaling in resting and stress-induced conditions, an effect that was present at the level of the dorsal pallium and was negatively associated with responsiveness. Administration of the 5HT1AR partial agonist buspirone prevented the isolation-induced serotonin response to novelty in the forebrain and rescued stress-induced arousal along with challenge-induced behaviors, which altogether indicates a functional connection between these changes. In summary, there is a consistent negative association between behavioral responsiveness and serotonergic signaling in zebrafish, which is well recognizable through the modifying effects of developmental perturbation and pharmacological manipulations as well. Our results imply a conserved serotonergic mechanism that context-dependently modulates environmental reactivity and is highly sensitive to experiences acquired during a specific early-life time-window, a phenomenon that was previously only suggested in mammals.\n\nSignificance statementThe ability to respond to challenges is a fundamental factor in survival. We show that zebrafish that lack appropriate social stimuli in a sensitive developmental period show exacerbated alertness in non-stressful conditions while failing to react adequately to stressors. This shift is reflected inversely by central serotonergic signaling, a system that is implicated in numerous mental disorders in humans. Serotonergic changes in brain regions modulating responsivity and behavioral impairment were both prevented by the pharmacological blockade of serotonergic function. These results imply a serotonergic mechanism in zebrafish that transmits early-life experiences to the later phenotype by shaping stress-dependent behavioral reactivity, a phenomenon that was previously only suggested in mammals. Zebrafish provide new insights into early-life-dependent neuromodulation of behavioral stress-responses.

neuroscience↗