Biology subjects

Tzanoulinou, S.

Publications and source records attributed to Tzanoulinou, S..

6 recordsLinked to original sources

bioRxiv2026

Individual behavioral signatures shape processing of context-dependent social fear

Context processing is an essential function in the cognitive repertoire of numerous species, including humans and mice, allowing them to learn from their environment and adapt their future behavior. Impairments or alterations in context processing are hypothesized to represent one of the core etiological mechanisms underlying trauma- and stressor-related disorders such as post-traumatic stress disorder (PTSD). Individual behavioral traits are key determinants of post-stress responses; however, how they influence distinct phases of contextual encoding and processing remains incompletely understood. This knowledge gap is further exacerbated by the limited availability of contextual fear protocols based on social stress, even though the latter is among the most frequent and impactful forms of stress exposure. Here, based on social defeat paradigms, we establish a longitudinal social conditioned place aversion (sCPA) protocol that leads to avoidance of the defeat-associated chamber in adult male mice. Prior characterization of mice according to anxiety-related phenotypes revealed that mice displaying high novelty-induced thigmotaxic (i.e. high anxiety-like) behavior showed lasting long-term memory of the defeat-associated chamber as denoted by persistent avoidance. On the other hand, lower levels of exploration/locomotor behaviors prior to stress exposure predicted greater avoidance of the defeat-associated chamber in the short-term. Finally, we reveal that inhibiting the activity of VTAVgat neurons during conditioning sessions abolished sCPA acquisition, while disrupting the predictive ability of locomotor/exploratory profiles derived prior to the sCPA. Our data establishes a robust temporally structured social stress-based conditioning protocol and reveals how prior individual anxiety- and exploration/locomotion-related traits influence distinct stages of context processing.

animal behavior and cognition↗

bioRxiv2025

Divergent modulation of dopaminergic neurons by hypocretin/orexin receptors-1 and -2 shapes dopaminergic cell activity and socio-emotional behavior

BACKGROUNDMany neuropsychiatric disorders involve dysregulation of the dopaminergic (DA) input to the forebrain. Of particular relevance are DA projections stemming from the midbrain ventral tegmental area (VTA). A key neuromodulatory influence onto DAVTA neurons arises from lateral hypothalamic area hypocretin/orexin (OX) neurons. Despite being a major input, the differential action of orexin peptides A and B (OXA and OXB) on orexin receptors 1 and 2 in DA cells is poorly understood. We recently identified profoundly divergent functions of OX1R vs OX2R in DA cells in regulating sleep/wake architecture, brain oscillations and cognitive behaviors. OX2R, but not OX1R, loss dramatically increased time in EEG theta-rich (alert) wakefulness, reward-driven learning and attentional skills, but impaired inhibitory control. METHODSUsing genetically engineered mice whose DA cells selectively lack OX input via Hcrtr1 (DAOx1R-KO) or Hcrtr2 (DAOx2R-KO), we assessed intrinsic excitability and electrophysiological responses of DAVTA neurons and evaluated behavioral phenotypes across multiple domains. RESULTSWe uncover previously unrecognized effects of OX peptides on DAVTA cell response. In WT and control mice, we show that while OXA enhances, OXB diminishes DAVTA neuronal excitability. OX1R-deficient DA cells lose OXA responding and OX2R-deficient DA cells lose OXB responding. DA Ox1R loss generates anxiety-like behavior and context-dependent hyperactivity. In contrast, OX2R loss decreases sociability and, despite exhibiting enhanced reward-driven learning, mice show highly compromised aversion-driven learning. CONCLUSIONSWe evidence strikingly distinct functions of OX1R vs OX2R signaling in modulating the intrinsic excitability of DAVTA neurons and influencing DA-related behaviors. These data implicate OX[->]DA signaling pathways in neuropsychiatric endophenotypes relevant to obsessive-compulsive, attention-deficit/hyperactivity, and autism spectrum disorders, and raise important considerations for the development of OXR-targeted therapeutics.

neuroscience↗

bioRxiv2025

Solriamfetol enhances alertness and cognitive performance in mice

Solriamfetol [(R)-2-amino-3-phenylpropylcarbamate hydrochloride], a phenylalanine derivative initially developed as potential antidepressant, was shown by our group in 2009 to have potent, dose-dependent wake-promoting activity in mice. Solriamfetol (Sunosi(R)) is used since 2019 to counteract excessive daytime sleepiness (EDS) in patients with narcolepsy and obstructive sleep apnea (OSA). It has several advantages over other stimulants, notably that it is not associated with strong psychomotor activity, does not induce behavioral stereotypies and anxiety-related behaviors, in contrast to amphetamines and modafinil. Its mode-of-action remains incompletely solved. It was reported to act as dual dopamine-and-noradrenaline-reuptake-inhibitor (DNRI), and more recently, to have TAAR1 agonist activity. In our early mouse study, we showed that, at 150 mg/kg, Solriamfetol induces a state of wakefulness featuring a dramatic upregulation of EEG gamma activity, a cognitive biomarker, and the expression of genes implicated in neural plasticity, learning and memory. Besides being prescribed to treat EDS, central nervous system stimulants are commonly used as smart drugs to enhance cognition in normal individuals. Therefore, based on Solriamfetols ability to potently induce wakefulness, EEG and molecular markers of learning and memory, we aimed to determine whether it could improve the cognitive performance of wild-type mice. Because at doses of 50-150 mg/kg, Solriamfetol induced an alert waking state associated with low mobility, thus precluding behavioral testing, we used lower doses (1-3 mg/kg) to assess cognition in a battery of tests evaluating short- or long-term memory and spatial navigation. We found that compared to saline, Solriamfetol 3 mg/kg consistently improves sustained attention for a novel object, as well as spatial memory. Next, to determine the brain activity correlates of enhanced cognition, we performed EEG/EMG recording while the mice performed the novel object recognition (NOR) task. Power spectral density (PSD) analysis revealed that 3 mg/kg Solriamfetol reduced EEG delta (an index of sleepiness) during exposure to a novel context, and enhanced EEG fast-gamma (an index of mental concentration) during execution of the NOR task. Taken together, our data demonstrate that low-dose Solriamfetol improves memory and attentional performance in wild-type mice.

animal behavior and cognition↗

bioRxiv2021

Inhibition of TRPV4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

Autism spectrum disorder is a neurodevelopmental disease characterized by social deficits and repetitive behaviors. The high heterogeneity of the disease may be explained by gene and environmental interactions and potential risk factors include immune dysfunctions and immune-mediated co-morbidities. Mutations in the SHANK3 gene have been recognized as a genetic risk factor for ASD. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioural deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the NAc promotes D1R-MSN hyperexcitability and upregulates Trpv4 to impair social behaviour. Interestingly, genetically vulnerable Shank3+/- mice, when challenged with Lipopolysaccharide to induce inflammatory response, showed similar circuit and behavioural alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.

neuroscience↗

bioRxiv2020

Programming effects of peripubertal stress on spatial learning

Exposure to adversity during early life can have profound influences on brain function and behavior later in life. The peripubertal period is emerging as an important time-window of susceptibility to stress, with substantial evidence documenting long-term consequences in the emotional and social domains. However, little is known about how stress during this period impacts subsequent cognitive functioning. Here, we assessed potential long-term effects of peripubertal stress on spatial learning and memory using the water maze task. In addition, we interrogated whether individual differences in stress-induced behavioral and endocrine changes are related to the degree of adaptation of the corticosterone response to repeated stressor exposure during the peripubertal period. We found that, when tested at adulthood, peripubertally stressed animals displayed a slower learning rate. Strikingly, the level of spatial orientation in the water maze completed on the last training day was predicted by the degree of adaptation of the recovery -and not the peak-of the corticosterone response to stressor exposure (i.e., plasma levels at 60 min post-stressor) across the peripubertal stress period. In addition, peripubertal stress led to changes in emotional and glucocorticoid reactivity to novelty exposure, as well as in the expression levels of the plasticity molecule PSA-NCAM in the hippocampus. Importantly, by assessing the same endpoints in another peripubertally stressed cohort tested during adolescence, we show that the observed effects at adulthood are the result of a delayed programming manifested at adulthood and not protracted effects of stress. Altogether, our results support the view that the degree of stress-induced adaptation of the hypothalamus-pituitary-adrenal axis responsiveness at the important transitional period of puberty relates to the long-term programming of cognition, behavior and endocrine reactivity.

neuroscience↗

bioRxiv2018

SHANK3 downregulation in the VTA accelerates the extinction of contextual associations induced by non-familiar conspecific interaction

Conditioned place preference (CPP) paradigms, traditionally adopted to study the reinforcing properties of drugs of abuse, have been developed to investigate the neurobiological mechanisms underlying the reinforcing properties of social stimuli. These protocols are largely based on single-housing before and/or during the social stimulus-contextual cues acquisition phase. Here, based on previously established social interaction-induced CPP paradigms, we characterize a place preference task relying on the reinforcing properties of free interaction with a non-familiar (novel) conspecific. The formation of contextual associations induced by the interaction with a novel social stimulus does not require single-housing, necessitates dopamine (DA) receptor 2/3 (D2/3R) activation and undergoes extinction. Interestingly, while extinction of CPP responses is reduced by single-housing, it is accelerated by the downregulation of the autism spectrum disorder (ASD)-related protein SHANK3 in the ventral tegmental area (VTA). Thus, inspired by the literature on drug of abuse-induced contextual learning, we propose that acquisition and extinction of CPP might be used as behavioral assays to assess social-induced contextual association and \"social-seeking\" dysfunctions in animal models of psychiatric disorders.

neuroscience↗