Altered GABAergic, glutamatergic and endocannabinoid signaling is accompanied by neuroinflammatory response in a zebrafish model of social withdrawal behavior

IntroductionDeficits in social communication are in the core of clinical symptoms characterizing many neuropsychiatric disorders such as schizophrenia and autism spectrum disorder. The occurrence of anxiety-related behavior, a common co-morbid condition in individuals with impairments in social domain, suggests the presence of overlapping neurobiological mechanisms between these two pathologies. Dysregulated excitation/inhibition balance and excessive neuroinflammation, in specific neural circuits, are proposed as common etiological mechanisms implicated in both pathologies.Methods and ResultsIn the present study we evaluated changes in glutamatergic/GABAergic neurotransmission as well as the presence of neuroinflammation within the regions of the Social Decision-Making Network (SDMN) using a zebrafish model of NMDA receptor hypofunction, following sub-chronic MK-801 administration. MK-801-treated zebrafish are characterized by impaired social communication together with increased anxiety levels. At the molecular level, the behavioral phenotype was accompanied by increased mGluR5 and GAD67 but decreased PSD-95 protein expression levels in telencephalon and midbrain. In parallel, MK-801-treated zebrafish exhibited altered endocannabinoid signaling as indicated by the upregulation of cannabinoid receptor 1 (CB1R) in the telencephalon. Interestingly, glutamatergic dysfunction was positively correlated with social withdrawal behavior whereas defective GABAergic and endocannabinoid activity were positively associated with anxiety-like behavior. Moreover, neuronal and astrocytic IL-1β expression was increased in regions of the SDMN, supporting the role of neuroinflammatory responses in the manifestation of MK-801 behavioral phenotype. Colocalization of interleukin-1β (IL-1β) with β2-adrenergic receptors (β2-ARs) underlies the possible influence of noradrenergic neurotransmission to increased IL-1β expression in comorbidity between social deficits and elevated anxiety comorbidity.DiscussionOverall, our results indicate the contribution of altered excitatory and inhibitory synaptic transmission as well as excessive neuroinflammatory responses in the manifestation of social deficits and anxiety-like behavior of MK-801-treated fish, identifying possible novel targets for amelioration of these symptoms

Early life stress induces long-term changes in limbic areas of a teleost fish: the role of catecholamine systems in stress coping

Early life stress (ELS) shapes the way individuals cope with future situations. Animals use cognitive flexibility to cope with their ever-changing environment and this is mainly processed in forebrain areas. We investigated the performance of juvenile gilthead seabream, previously subjected to an ELS regime. ELS fish showed overall higher brain catecholaminergic (CA) signalling and lower brain derived neurotrophic factor (bdnf) and higher cfos expression in region-specific areas. All fish showed a normal cortisol and serotonergic response to acute stress. Brain dopaminergic activity and the expression of the α2Α adrenergic receptor were overall higher in the fish homologue to the lateral septum (Vv), suggesting that the Vv is important in CA system regulation. Interestingly, ELS prevented post-acute stress downregulation of the α2Α receptor in the amygdala homologue (Dm3). There was a lack of post-stress response in the β2 adrenergic receptor expression and a downregulation in bdnf in the Dm3 of ELS fish, which together indicate an allostatic overload in their stress coping ability. ELS fish showed higher neuronal activity (cfos) post-acute stress in the hippocampus homologue (Dlv) and the Dm3. Our results show clear long-term effects on limbic systems of seabream that may compromise their future coping ability to environmental challenges.publishedVersio

Protective Effects of Currants (<i>Vitis vinifera</i>) on Corticolimbic Serotoninergic Alterations and Anxiety-like Comorbidity in a Rat Model of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of nigral dopaminergic neurons. Increasing evidence supports that PD is not simply a motor disorder but a systemic disease leading to motor and non-motor symptoms, including memory loss and neuropsychiatric conditions, with poor management of the non-motor deficits by the existing dopaminergic medication. Oxidative stress is considered a contributing factor for nigrostriatal degeneration, while antioxidant/anti-inflammatory properties of natural phyto-polyphenols have been suggested to have beneficial effects. The present study aimed to determine the contribution of monoaminergic neurotransmission on the anxiety-like phenotype in a rat rotenone PD model and evaluate the possible neuroprotective effects of black Corinthian currant, Vitis vinifera, consisting of antioxidant polyphenols. Rotenone-treated rats showed anxiety-like behavior and exploratory deficits, accompanied by changes in 5-HT, SERT and β2-ARs expression in the prefrontal cortices, hippocampus and basolateral amygdala. Importantly, the motor and non-motor behavior, as well as 5-HT, SERT and β2-ARs expression patterns of the PD-like phenotype were partially recovered by a supplementary diet with currants. Overall, our results suggest that the neuroprotective effects of Corinthian currants in rotenone-induced anxiety-like behavior may be mediated via corticolimbic serotonergic transmission

Early life stress induces long-term changes in limbic areas of a teleost fish: The role of catecholamine systems in stress coping

Early life stress (ELS) shapes the way individuals cope with future situations. Animals use cognitive flexibility to cope with their ever-changing environment and this is mainly processed in forebrain areas. We investigated the performance of juvenile gilthead seabream, previously subjected to an ELS regime. ELS fish showed overall higher brain catecholaminergic (CA) signalling and lower brain derived neurotrophic factor (bdnf) and higher cfos expression in region-specific areas. All fish showed a normal cortisol and serotonergic response to acute stress. Brain dopaminergic activity and the expression of the α2Α adrenergic receptor were overall higher in the fish homologue to the lateral septum (Vv), suggesting that the Vv is important in CA system regulation. Interestingly, ELS prevented post-acute stress downregulation of the α2Α receptor in the amygdala homologue (Dm3). There was a lack of post-stress response in the β2 adrenergic receptor expression and a downregulation in bdnf in the Dm3 of ELS fish, which together indicate an allostatic overload in their stress coping ability. ELS fish showed higher neuronal activity (cfos) post-acute stress in the hippocampus homologue (Dlv) and the Dm3. Our results show clear long-term effects on limbic systems of seabream that may compromise their future coping ability to environmental challenges