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It is now well-accepted that psychostimulants act on glial cells causing neuroinflammation and adding to the neurotoxic eects of such substances. Neuroinflammation can be described as an inflammatory response, within the CNS, mediated through several cytokines, reactive oxygen species, chemokines and other inflammatory markers. These inflammatory players, in particular cytokines, play important roles. Several studies have demonstrated that psychostimulants impact on cytokine production and release, both centrally and at the peripheral level. Nevertheless, the available data is often contradictory. Because understanding how cytokines are modulated by psychoactive substances seems crucial to perspective successful therapeutic interventions, here, we conducted a scoping review of the available literature. We have focused on how dierent psychostimulants impact on the cytokine profile. Publications were grouped according to the substance addressed (methamphetamine, cocaine, methylphenidate, MDMA or other amphetamines), the type of exposure and period of evaluation (acute, short- or long-term exposure, withdrawal, and reinstatement). Studies were further divided in those addressing central cytokines, circulating (peripheral) levels, or both. Our analysis showed that the classical pro-inflammatory cytokines TNF-α, IL-6, and IL-1β were those more investigated. The majority of studies have reported increased levels of these cytokines in the central nervous system after acute or repeated drug. However, studies investigating cytokine levels during withdrawal or reinstatement have shown higher variability in their findings. Although we have identified fewer studies addressing circulating cytokines in humans, the available data suggest that the results may be more robust in animal models than in patients with problematic drug use. As a major conclusion, an extensive use of arrays for relevant cytokines should be considered to better determine which cytokines, upon the classical ones, may be involved in the progression from episodic use to the development of addiction. A concerted eort is still necessary to address the link between peripheral and central immune players, including from a longitudinal perspective. Until there, the identification of new biomarkers and therapeutic targets to envision personalized immune-based therapeutics will continue to be unlikely. [ABSTRACT FROM AUTHOR]

Multiple studies show an association between anxiety disorders and dysregulation in the Autonomic Nervous System (ANS). Thus, understanding how informative the physiological signals are would contribute to effectively detecting anxiety. This study targets the classification of anxiety as an imbalanced binary classification problem using physiological signals collected from a sample of healthy subjects under a neutral condition. For this purpose, the Electrocardiogram (ECG), Electrodermal Activity (EDA), and Electromyogram (EMG) signals from the WESAD publicly available dataset were used. The neutral condition was collected for around 20 min on 15 participants, and anxiety scores were assessed through the shortened 6-item STAI. To achieve the described goal, the subsequent steps were followed: signal pre-processing; feature extraction, analysis, and selection; and classification of anxiety. The findings of this study allowed us to classify anxiety with discriminatory class features based on physiological signals. Moreover, feature selection revealed that ECG features play a relevant role in anxiety classification. Supervised feature selection and data balancing techniques, especially Borderline SMOTE 2, increased the performance of most classifiers. In particular, the combination of feature selection and Borderline SMOTE 2 achieved the best ROC-AUC with the Random Forest classifier. [ABSTRACT FROM AUTHOR]

Microglia binge on synapses: Alcohol abuse has detrimental cognitive and behavioral consequences. Binge drinking activates resident phagocytic immune cells in the brain called microglia in mice and is associated with anxiety in humans. Socodato et al. found that a binge drinking protocol in male mice induced microglia to selectively scavenge excitatory synapses between neurons in the prefrontal cortex. The loss of these connections did not cause neuronal death during the study but instead depressed neurotransmission and increased anxiety-like behaviors in the mice. These findings suggest that binge drinking induces anxiety by activating microglia that destroy neuronal connections. Alcohol abuse adversely affects the lives of millions of people worldwide. Deficits in synaptic transmission and in microglial function are commonly found in human alcohol abusers and in animal models of alcohol intoxication. Here, we found that a protocol simulating chronic binge drinking in male mice resulted in aberrant synaptic pruning and substantial loss of excitatory synapses in the prefrontal cortex, which resulted in increased anxiety-like behavior. Mechanistically, alcohol intake increased the engulfment capacity of microglia in a manner dependent on the kinase Src, the subsequent activation of the transcription factor NF-κB, and the consequent production of the proinflammatory cytokine TNF. Pharmacological blockade of Src activation or of TNF production in microglia, genetic ablation of Tnf, or conditional ablation of microglia attenuated aberrant synaptic pruning, thereby preventing the neuronal and behavioral effects of the alcohol. Our data suggest that aberrant pruning of excitatory synapses by microglia may disrupt synaptic transmission in response to alcohol abuse. [ABSTRACT FROM AUTHOR]

The differential expression of mRNAs containing tandem alternative 3′ UTRs, achieved by mechanisms of alternative polyadenylation and post-transcriptional regulation, has been correlated with a variety of cellular states. In differentiated cells and brain tissues there is a general use of distal polyadenylation signals, originating mRNAs with longer 3′ UTRs, in contrast with proliferating cells and other tissues such as testis, where most mRNAs contain shorter 3′ UTRs. Although cell type and state are relevant in many biological processes, how these mechanisms occur in specific brain cell types is still poorly understood. Rac1 is a member of the Rho family of small GTPases with essential roles in multiple cellular processes, including cell differentiation and axonal growth. Here we used different brain cell types and tissues, including oligodendrocytes, microglia, astrocytes, cortical and hippocampal neurons, and optical nerve, to show that classical Rho GTPases express mRNAs with alternative 3′ UTRs differently, by gene- and cell- specific mechanisms. In particular, we show that Rac1 originate mRNA isoforms with longer 3′ UTRs specifically during neurite growth of cortical, but not hippocampal neurons. Furthermore, we demonstrate that the longest Rac1 3′ UTR is necessary for driving the mRNA to the neurites, and also for neurite outgrowth in cortical neurons. Our results indicate that the expression of Rac1 longer 3′ UTR is a gene and cell-type specific mechanism in the brain, with a new physiological function in cortical neuron differentiation. [ABSTRACT FROM AUTHOR]

Ketamine administration has been associated with controversial behavioural impairments and psychotic episodes. Even though ketamine alone and in combination with midazolam or dexmedetomidine are frequently used in laboratory animals, the side-effects of such protocols are not well known. Therefore, our aim was to evaluate the effects of ketamine alone and in combination with midazolam or dexmedetomidine on emotional reactivity, as well as the effects on learning and memory in adult rats at least 48 h after anaesthesia. The evaluation of the potential influence of 100 mg/kg ketamine administered alone and in combination with midazolam (5 mg/kg), or dexmedetomidine (0.25 mg/kg) on spatial learning and recognition memory was studied in adult Wistar rats using the radial maze as well as object recognition and location tests. The influence of these combinations on emotional reactivity was investigated using the new exploration test and the elevated plus maze. Results showed that ketamine alone or in combination with midazolam or dexmedetomidine affected neither spatial and recognition memory, nor emotional reactivity. These results reinforce the safe clinical use of ketamine and its combinations in rats in a research context since the administration of these anaesthetic combinations did not produce significant changes with regard to spatial and recognition memory or emotional reactivity. Furthermore, these results indicate that the quality of scientific data produced in adult rat neurobehavioural research is not jeopardized by the use of these anaesthetic protocols. [ABSTRACT FROM AUTHOR]

Bone repair is a specialized type of wound repair controlled by complex multi-factorial events. The nervous system is recognized as one of the key regulators of bone mass, thereby suggesting a role for neuronal pathways in bone homeostasis. However, in the context of bone injury and repair, little is known on the interplay between the nervous system and bone. Here, we addressed the neuropeptide Y (NPY) neuronal arm during the initial stages of bone repair encompassing the inflammatory response and ossification phases in femoral-defect mouse model. Spatial and temporal analysis of transcriptional and protein levels of NPY and its receptors, Y1R and Y2R, reported to be involved in bone homeostasis, was performed in bone, dorsal root ganglia (DRG) and hypothalamus after femoral injury. The results showed that NPY system activity is increased in a time- and space-dependent manner during bone repair. Y1R expression was trigged in both bone and DRG throughout the inflammatory phase, while a Y2R response was restricted to the hypothalamus and at a later stage, during the ossification step. Our results provide new insights into the involvement of NPY neuronal pathways in bone repair. [ABSTRACT FROM AUTHOR]

Exposure to methamphetamine (Meth) has been classically associated with damage to neuronal terminals. However, it is now becoming clear that addiction may also result from the interplay between glial cells and neurons. Recently, we demonstrated that binge Meth administration promotes microgliosis and microglia pro-inflammation via astrocytic glutamate release in a TNF/IP3R2-Ca2+-dependent manner. Here, we investigated the contribution of neuronal cells to this process. As the crosstalk between microglia and neurons may occur by contact-dependent and/or contact-independent mechanisms, we developed co-cultures of primary neurons and microglia in microfluidic devices to investigate how their interaction affects Meth-induced microglia activation. Our results show that neurons exposed to Meth do not activate microglia in a cell-autonomous way but require astrocyte mediation. Importantly, we found that neurons can partially prevent Meth-induced microglia activation via astrocytes, which seems to be achieved by increasing arginase 1 expression and strengthening the CD200/CD200r pathway. We also observed an increase in synaptic individual area, as determined by co-localization of pre- and post-synaptic markers. The present study provides evidence that contact-dependent mechanisms between neurons and microglia can attenuate pro-inflammatory events such as Meth-induced microglia activation. [ABSTRACT FROM AUTHOR]

ABSTRACT Many adolescents often take ethanol (EtOH) in combination with 3,4-methylenedioxymethylamphetamine (MDMA). In the present work, we used a mouse model to study the effect of repeated pre-exposure during adolescence to EtOH (2 g/kg), MDMA (10 or 20 mg/kg) or EtOH + MDMA on the rewarding and reinstating effects of MDMA in the conditioned place preference (CPP) paradigm. Pre-exposure to EtOH, MDMA or both increased the rewarding effects of a low dose of MDMA (1.25 mg/kg). These pre-treatments did not affect the acquisition of the CPP induced by 5 mg/kg of MDMA. However, the CPP was more persistent in mice pre-exposed to both doses of MDMA or to EtOH + MDMA20. After extinction of the CPP induced by 5 mg/kg of MDMA, reinstatement was observed in all groups with a priming dose of 2.5 mg/kg of MDMA, in the groups pre-exposed to EtOH or MDMA alone with a priming dose of 1.25 mg/kg, and in the groups pre-treated with MDMA alone with a priming dose of 0.625 mg/kg. Pre-treatment during adolescence with MDMA or EtOH induced long-term changes in the level of biogenic amines [dihydroxyphenyl acetic acid, homovanillic acid, dopamine turnover, serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the striatum, and 5-HT and 5-HIAA in the cortex] after the first reinstatement test, although these effects depended on the dose used during conditioning. These results suggest that exposure to EtOH and MDMA during adolescence reinforces the addictive properties of MDMA. [ABSTRACT FROM AUTHOR]

The administration of a neurotoxic dose of 3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) to the rat results in mitochondrial oxidative damage in the central nervous system, namely lipid and protein oxidation and mitochondrial DNA deletions with subsequent impairment of the correspondent protein expression. Although these toxic effects were shown to be prevented by monoamine oxidase B inhibition, the role of monoamine oxidase A (MAO-A) in MDMA-mediated mitochondrial damage remains to be evaluated. Thus, the aim of the present study was to clarify the potential interference of a specific inhibition of MAO-A by clorgyline, on the deleterious effects produced by a binge administration of a neurotoxic dose of MDMA (10 mg MDMA/kg of body weight, intraperitoneally, every 2 hours in a total of four administrations) to an adolescent rat model. The parameters evaluated were mitochondrial lipid peroxidation, protein carbonylation and expression of the respiratory chain protein subunits II of reduced nicotinamide adenine dinucleotide dehydrogenase (NDII) and I of cytochrome oxidase (COXI). Considering that hyperthermia has been shown to contribute to the neurotoxic effects of MDMA, another objective of the present study was to evaluate the body temperature changes mediated by MDMA with a MAO-A selective inhibition by clorgyline. The obtained results demonstrated that the administration of a neurotoxic binge dose of MDMA to an adolescent rat model previously treated with the specific MAO-A inhibitor, clorgyline, resulted in synergistic effects on serotonin- (5-HT) mediated behaviour and body temperature, provoking high mortality. Inhibition of MAO-A by clorgyline administration had no protective effect on MDMA-induced alterations on brain mitochondria (increased lipid peroxidation, protein carbonylation and decrease in the expression of the respiratory chain subunits NDII and COXI), although it aggravated MDMA-induced decrease in the expression of COXI. These results reinforce the notion that the concomitant use of MAO-A inhibitors and MDMA is counter indicated because of the resulting severe synergic toxicity. [ABSTRACT FROM AUTHOR]

3,4-Methylenedioxymethamphetamine (MDMA)-induced neurotoxicity and the protective role of monoamine oxidase-B (MAO-B) inhibition were evaluated at the mitochondrial level in various regions of the adolescent rat brain. Four groups of adolescent male Wistar rats were used: (1) saline control, (2) exposed to MDMA (4x10 mg/kg, i.p.; two hourly), (3) treated with selegiline (2 mg/kg, i.p.) 30min before the same dosing of MDMA, and (4) treated with selegiline (2 mg/kg, i.p.). Body temperatures were monitored throughout the whole experiment. Animals were killed 2 weeks later, and mitochondria were isolated from several brain regions. Our results showed that "binge" MDMA administration causes, along with sustained hyperthermia, long-term alterations in brain mitochondria as evidenced by increased levels of lipid peroxides and protein carbonyls. Additionally, analysis of mitochondrial DNA (mtDNA) revealed that NDI (nicotinamide adenine dinucleotide phosphate dehydrogenase subunit I) and NDII (nicotinamide adenine dinucleotide phosphate dehydrogenase subunit II) subunits of mitochondrial complex I and cytochrome c oxidase subunit I of complex IV suffered deletions in MDMA-exposed animals. Inhibition of MAO-B by selegiline did not reduce hyperthermia but reversed MDMA-induced effects in the oxidative stress markers, mtDNA, and related protein expression. These results indicate that monoamine oxidation by MAO-B with subsequent mitochondrial damage may be an important contributing factor for MDMA-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

This study was undertaken to evaluate the effects of environmental enrichment (EE) in rats exposed to cocaine during the first month of postnatal life by examining several categories of social behaviour (play fighting, social investigation, comfort behaviours and invitation to play). Wistar rats were divided in four groups: pups exposed to cocaine hydrochloride (15 mg/kg body weight/day), sc, in two daily doses, from postnatal day (PND) 1 to 28 and reared in EE; exposed to cocaine as previously described and reared in standard environment (SE); saline-exposed and reared in EE; pups saline-exposed and reared in SE. On PND 21, 24 and 28, social interactions were examined for 10 min. Results show that cocaine animals reared in SE decreased the frequency of play solicitation. Control animals reared in EE exhibited decreased play fighting and social investigation behaviours compared to SE-reared rats. Animals postnatally exposed to cocaine when reared in EE displayed more comfort and invitation to play behaviours and decreased social investigation compared with SE-reared animals. The results suggest that in rats postnatally exposed to cocaine, EE rearing elicited differences in both processing of environmental stimuli and a response to social challenges. [ABSTRACT FROM AUTHOR]

Nervous tissue homeostasis requires the regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation, producing a neurological phenotype (including synapse and neuron loss, impairment of long-term potentiation [LTP], formation of β-amyloid plaques, and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated tumor necrosis factor (TNF) production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also find that the Rhoa/Src signaling pathway is disrupted in microglia of the APP/PS1 mouse model of Alzheimer disease and that low doses of Aβ oligomers trigger microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing Rho GTPase signaling in microglia can directly cause neurodegeneration. • Microglia lacking Rhoa become neurotoxic • Rhoa ablation in microglia leads to amyloidosis, synapse loss, and memory deficits • Rhoa ablation in microglia is sufficient to produce an AD-like pathology • Rhoa activation is decreased in microglia from AD mice Socodato et al. show that ablating Rhoa in microglia of young adult mice is sufficient to produce major hallmarks of AD (including amyloid pathology, impairment of long-term synaptic plasticity, synapse loss, and memory deficits), suggesting that disrupting Rho GTPase signaling in microglia might underlie the neurodegenerative process in AD. [ABSTRACT FROM AUTHOR]

Group B streptococcal (GBS) meningitis remains a devastating disease. The absence of an animal model reproducing the natural infectious process has limited our understanding of the disease and, consequently, delayed the development of effective treatments. We describe here a mouse model in which bacteria are transmitted to the offspring from vaginally colonised pregnant females, the natural route of infection. We show that GBS strain BM110, belonging to the CC17 clonal complex, is more virulent in this vertical transmission model than the isogenic mutant BM110∆cylE, which is deprived of hemolysin/cytolysin. Pups exposed to the more virulent strain exhibit higher mortality rates and lung inflammation than those exposed to the attenuated strain. Moreover, pups that survive to BM110 infection present neurological developmental disability, revealed by impaired learning performance and memory in adulthood. The use of this new mouse model, that reproduces key steps of GBS infection in newborns, will promote a better understanding of the physiopathology of GBS-induced meningitis. Animal models of group-B streptococcal infections are needed to develop effective therapies. Here, Andrade et al. present a mouse model in which the bacteria are transmitted from vaginally colonised pregnant females to their offspring, causing neonatal meningitis and neurological developmental disabilities. [ABSTRACT FROM AUTHOR]

Prosocial behavior in rats is known to occur in response to a familiar rat's distress, but the motivations underlying prosocial behavior remain elusive. In this study, we adapted the experimental setting of Ben-Ami Bartal, Decety, and Mason (2011) to explore different motivations behind helping behavior in adolescent rats. In the original setting, a free rat is placed in an arena where a cagemate is trapped inside a restrainer that can only be opened from the outside by the free rat. Here we added a dark compartment to the experimental setting that allowed the free rat to escape the arena and the distress evoked by the trapped cagemate, based on rodents' aversion to bright areas. As a control, we tested rats in the same arena but with the door to the dark area closed. Our results showed that all free rats, except one in the escape condition, learned to open the restrainer's door. However, in the escape condition, rats took significantly longer to open the restrainer to the cagemates when compared with rats that could not escape. To further explore the motivations underlying these group differences in door-opening latencies, we measured both rats' behavior. We found that struggling behavior (i.e., distress) in the trapped rat did not affect door-opening, whereas exploratory behavior (i.e., proactive/positive behavior) in both rats contributed to shorter times. Our results highlight that adolescent rats show prosocial behavior even when they can escape without helping and contribute to demonstrate the role of positive emotional states in prosocial behavior. [ABSTRACT FROM AUTHOR]

Addiction to psychoactive substances is a maladaptive learned behaviour. Contexts surrounding drug use integrate this aberrant mnemonic process and hold strong relapse-triggering ability. Here, we asked where context and salience might be concurrently represented in the brain during retrieval of drug-context paired associations. For this, we developed a morphine-conditioned place preference protocol that allows contextual stimuli presentation inside a magnetic resonance imaging scanner and investigated differences in activity and connectivity at context recall. We found context-specific responses to stimulus onset in multiple brain regions, namely, limbic, sensory and striatal. Differences in functional interconnectivity were found among amygdala, lateral habenula, and lateral septum. We also investigated alterations to resting-state functional connectivity and found increased centrality of the lateral septum in a proposed limbic network, as well as increased functional connectivity of the lateral habenula and hippocampal 'cornu ammonis' 1 region, after a protocol of associative drug-context. Finally, we found that pre- conditioned place preference resting-state connectivity of the lateral habenula and amygdala was predictive of inter-individual conditioned place preference score differences. Overall, our findings show that drug and saline-paired contexts establish distinct memory traces in overlapping functional brain microcircuits and that intrinsic connectivity of the habenula, septum, and amygdala likely underlies the individual maladaptive contextual learning to opioid exposure. We have identified functional maps of acquisition and retrieval of drug-related memory that may support the relapse-triggering ability of opioid-associated sensory and contextual cues. These findings may clarify the inter-individual sensitivity and vulnerability seen in addiction to opioids found in humans., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)