Adolescent Rats Research Articles

Depressive-like behavior and impaired synaptic plasticity in the prefrontal cortex as later consequences of prenatal hypoxic-ischemic insult in rats

Perinatal hypoxia-ischemia (HI) is a leading cause of morbidity and mortality among newborns. Infants with HI encephalopathy may experience lasting consequences, such as depression, in adulthood. In this study, we examined depressive-like behavior, neuronal population, and markers of monoaminergic and synaptic plasticity in the prefrontal cortex (PFC) of adolescent rats subjected to a prenatal HI model. Pregnant rats underwent a surgery in which uterine and ovarian blood flow was blocked for 45 min at E18 (HI procedure). Sham-operated subjects were also generated (SH procedure). Behavioral tests were conducted on male and female pups from P41 to P43, and animals were histologically processed or dissected for western blotting at P45. We found that the HI groups consumed less sucrose in the sucrose preference test and remained immobile for longer periods in the forced swim test. Additionally, we observed a significant reduction in neuronal density and PSD95 levels in the HI group, as well as a smaller number of synaptophysin-positive cells. Our results underscore the importance of this model in investigating the effects of HI-induced injuries, as it reproduces an increase in depressive-like behavior and suggests that the HI insult affects circuits involved in mood modulation.

Effects of herbal mixture on burned rat skin infected with Pseudomonas aeruginosa

Purpose: The purpose of this study is to investigate the healing impact of an ointment derived from the Alkanna tinctoria plant upon Pseudomonas aeruginosa-induced infections. 
 Material and Methods: In this study, 18 male adolescent rats (mean age 6 weeks) weighed an average of 180 g were used. Animals were divided into 3 groups. Group 1: Control group (consisting of burns, no treatment was done), Group 2 (P. aeruginosa): Burn was created and infected with P. aeruginosa, Group 3 (Cream): P. aeruginosa was used to infect the burns area and the herbal mixture was administered twice a day, once in the morning and once in the afternoon. Under anesthesia, the backs of the rats were shaved, and a specially produced steel bar with a diameter of 1*1 cm was immersed in boiling water for 15 seconds before being applied to their backs for 20 seconds. The burned area was subsequently infected with the ATCC Pseudomonas aeruginosa strain, and samples were collected 24 hours later. To detect bacterial growth in this area, the samples were inoculated on blood and EMB (Eosin Methylene Blue) media in a microbiology laboratory. After inoculation, the animals were placed in separate sterile cages and randomly divided into three groups. Once the growth was observed, the tissue and blood samples were harvested from the rats on the 2nd, 7th, 14th, and 21st days.
 Results: Epithelial regeneration in this group was more prominent. Vascularization was remarkable on the 2nd day, especially in the group in where we induced a burn and applied the ointment. VEGF levels increased more in the ointment group than in that of others. On the 2nd day of the study, the average bacterial count was 105 in sample of both 2nd and 3rd groups. At the end of the study, while the average of bacterial count was increased in the 2nd group, the average of bacterial count was decreased in the 3rd group.
 Conclusion: It was concluded that the ointment obtained from A. tinctorial successfully repaired the epithelial tissue and contributed to the healing of wounds by modifying increasing VEGF in the blood. However, further research is needed before this ointment can be highly recommended for therapeutic usage

SALIFEN PREVENTS PERINATAL HYPOXIA-INDUCED COGNITIVE IMPAIRMENTS AND CHANGES IN GABA<sub>B</sub> RECEPTOR EXPRESSION IN THE RAT NEOCORTEX

We have studied the effects of acute normobaric hypoxia in the early postnatal period of the development (the 2nd postnatal day) on learning and memory abilities and the expression of GABAB receptors in the neocortex (medial prefrontal cortex) in adolescent rats (the 55–60th postnatal day), as well as the possibility of correction of the revealed impairments by GABA derivative salifen. It was shown that perinatal hypoxia disrupts task acquisition and consolidation in the novel object recognition test, impairs passive avoidance performance, and also reduces spatial learning abilities in the Morris water maze. Western blotting analysis revealed increased levels of GABAB receptor protein in the medial prefrontal cortex of the rats following the exposure to perinatal hypoxia. Post-hypoxic daily salifen injections over 14 days at a dose of 15 mg/kg improved cognitive abilities in rats, and also normalized GABAB receptor content in the rat medial prefrontal cortex. The results of the present research are of considerable significance for solution of applied problem of neonatology – the search for effective drug candidates for the pharmacological correction of the impacts of perinatal hypoxia.

Status of coagulation system in adolescent rats exposed to hypoxia during prenatal development

The goal of the research was to investigate the physiological indicators in the hemostasis of adult offspring developed under prenatal hypoxia conditions. Chronic hypoxia conditions were created during different periods of the pregnancy. Three-month-old white rats that had completed the period of puberty were used in the experiments. Clinical analyses of the main indicators of the coagulation system were performed to assess the state of the hemostasis system. The effect of intrauterine hypoxia on the "mother-fetus" relationship was manifested by prolonged pathological changes in the blood coagulation and expressed changes in the liver parenchyma at the later stages of development.

Chronic maternal morphine exposure and early-life adversity induce impairment in synaptic plasticity of adolescent male rats

Maternal morphine exposure has negative consequences for learning and memory in the offspring. Interaction between mothers and pups has a crucial effect on the mammal's development. Maternal Separation (MS) can cause behavioral and neuropsychiatric problems later in life. It seems that adolescents are more susceptible to the effects of early life stress; evidence for the combinatory effects of oral chronic maternal morphine exposure and MS in the CA1 area of the hippocampus in the male adolescent offspring is not found. Therefore, this study aimed to evaluate the effects of chronic maternal morphine consumption (21 days before and after mating, and gestation), and MS (180 min/day from postnatal day (PND) 1–21) on the synaptic plasticity of male offspring in mid-adolescence. Control, MS, Vehicle (V), Morphine, V + MS, and Morphine + MS groups were tested for in vivo field potential recording from the CA1 area of the hippocampus. The current results demonstrated that chronic maternal morphine exposure impaired the induction of early long-term potentiation (LTP). MS impaired average fEPSPs, induction of early-LTP and maintenance. Chronic maternal morphine exposure in combination with MS impaired the induction of early LTP but didn't deteriorate maintenance and the average field excitatory post-synaptic potentials (fEPSPs) measured in two hours. Prepulse facilitation ratios remained undisturbed and I/O curves showed decreased fEPSP slopes at high stimulus intensities in combinatory group. We concluded that chronic maternal morphine exposure in combination with MS negatively affects synaptic plasticity in the CA1 area in male adolescent offspring.

Effects of PM2.5 and high-fat diet interaction on blood glucose metabolism in adolescent male Wistar rats: A serum metabolomics analysis based on ultra-high performance liquid chromatography/mass spectrometry

Fine particulate matter (PM2.5) and high-fat diet (HFD) are known to contribute to blood glucose metabolic disorders. However, limited research has investigated the combined impact of PM2.5 and HFD on blood glucose metabolism. This study aimed to explore the joint effects of PM2.5 and HFD on blood glucose metabolism in rats using serum metabolomics and to identify involved metabolites and metabolic pathways. The 32 male Wistar rats were exposed to filtered air (FA) or PM2.5 (real-world inhaled, concentrated PM2.5, 8 times the ambient level, ranging from 131.42 to 773.44 μg/m3) and fed normal diet (ND) or HFD for 8 weeks. The rats were divided into four groups (n = 8/group): ND-FA, ND-PM2.5, HFD-FA and HFD-PM2.5 groups. Blood samples were collected to determine fasting glucose (FBG), plasma insulin and glucose tolerance test and HOMA Insulin Resistance (HOMA-IR) index was calculated. Finally, the serum metabolism of rats was analyzed by ultra-high performance liquid chromatography/mass spectrometry (UHPLC-MS). Then we constructed the partial least squares discriminant analysis (PLS-DA) model to screen the differential metabolites, and performed pathway analysis to screen the main metabolic pathways. Results showed that combined effect of PM2.5 and HFD caused changes in glucose tolerance, increased FBG levels and HOMA-IR in rats and there were interactions between PM2.5 and HFD in FBG and insulin. By metabonomic analysis, the serum differential metabolites pregnenolone and progesterone, which involved in steroid hormone biosynthesis, were two different metabolites in the ND groups. In the HFD groups, the serum differential metabolites were L-tyrosine and phosphorylcholine, which involved in glycerophospholipid metabolism, and phenylalanine, tyrosine, and tryptophan biosynthesis. When PM2.5 and HFD coexist, they may lead to more severe and complex effects on glucose metabolism by affecting lipid metabolism and amino acid metabolism. Therefore, reducing PM2.5 exposure and controlling dietary structure are important measures for preventing and reducing glucose metabolism disorders.

Paternal morphine exposure in rats reduces social play in adolescent male progeny without affecting drug-taking behavior in juvenile males or female offspring

The ongoing opioid addiction crisis necessitates the identification of novel risk factors to improve prevention and treatment of opioid use disorder. Parental opioid exposure has recently emerged as a potential regulator of offspring vulnerability to opioid misuse, in addition to heritable genetic liability. An understudied aspect of this “missing heritability” is the developmental presentation of these cross-generational phenotypes. This is an especially relevant question in the context of inherited addiction-related phenotypes, given the prominent role of developmental processes in the etiology of psychiatric disorders. Paternal morphine self-administration was previously shown to alter the sensitivity to the reinforcing and antinociceptive properties of opioids in the next generation. Here, phenotyping was expanded to include the adolescent period, with a focus on endophenotypes related to opioid use disorders and pain. Paternal morphine exposure did not alter heroin or cocaine self-administration in male and female juvenile progeny. Further, baseline sensory reflexes related to pain were unaltered in morphine-sired adolescent rats of either sex. However, morphine-sired adolescent males exhibited a reduction in social play behavior. Our findings suggest that, in morphine-sired male offspring, paternal opioid exposure does not affect opioid intake during adolescence, suggesting that this phenotype does not emerge until later in life. Altered social behaviors in male morphine-sired adolescents indicate that the changes in drug-taking behavior in adults sired by morphine-exposed sires may be due to more complex factors not yet fully assessed.

Protective effects of empagliflozin on testicular injury induced by torsion/detorsion in adult male rats

Testicular torsion is a known urologic emergency condition and one of the common causes of infertility in males. Hence, prompt diagnosis and treatment play a crucial role in prevention of testicular injury. It has been observed that empagliflozin, a drug for management of hyperglycemia, has anti-oxidative properties against different pathologies, the most important of which are ischemia reperfusion related injuries. This study aims to evaluate the protective effects of empagliflozin on a testicular torsion injury in adolescent rats followed by ischemia/reperfusion (I/R) phenomena. Thirty-six rats were randomly assigned into three groups including sham-operated group received all surgical procedures except testicular torsion-detorsion, torsion/detorsion+dimethyl sulfoxide (DMSO) as vehicle, and torsion/detorsion+empagliflozin (10mg/kg). Testicular torsion was performed for 2h through rotating right testis 720° in the clockwise direction. Thirty minutes before detorsion, a single intraperitoneal dose of empagliflozin was injected to treatment group. Four hours later, orchiectomy was conducted for histopathological and biochemical examinations of testicular tissue specimens. The malondialdehyde (MDA) content in the torsion/detorsion animals was markedly greater than in the animals under sham operated procedure. Moreover, the testicular MDA levels in the torsion/detorsion+empagliflozin group were significantly lower than in the torsion/detorsion group. Also, significant decreases observed in catalase, superoxide dismutase, and glutathione peroxidase activities in the torsion/detorsion group in comparison with sham operated group. These values were significantly improved in the empagliflozin group. Furthermore, histopathological examinations also revealed severe testicular injury which were improved by empagliflozin administration. Empagliflozin prevented increases in oxidative stress markers and subsequently reduced the tissue injury induced by torsion/detorsion in the current study. It can be concluded that administration of empagliflozin before prevents I/R related cellular damage in testicular torsion, possibly via oxidative stress inhibition.

Mouth breathing induces condylar remodelling and chondrocyte apoptosis via both the extrinsic and mitochondrial pathways in male adolescent rats

The prevalence of mouth breathing is high in children and adolescents. It causes various changes to the respiratory tract and, consequently, craniofacial growth deformities. However, the underlying mechanisms contributing to these effects are obscure. Herein, we aimed to study the effects of mouth breathing on chondrocyte proliferation and death in the condylar cartilage and morphological changes in the mandible and condyle. Additionally, we aimed to elucidate the mechanisms underlying chondrocyte apoptosis and investigate any variations in the related pathways. Subchondral bone resorption and decreased condylar cartilage thickness were observed in mouth-breathing rats; further, mRNA expression levels of Collagen II, Aggrecan, and Sox 9 were lower in the mouth breathing group, while those of matrix metalloproteinase 9 increased. TdT-mediated dUTP nick end labelling staining and immunohistochemistry analyses showed that apoptosis occurred in the proliferative and hypertrophic layers of cartilage in the mouth breathing group. TNF, BAX, cytochrome c, and cleaved-caspase-3 were highly expressed in the condylar cartilage of the mouth-breathing rats. These results suggest that mouth breathing leads to subchondral bone resorption, cartilage layer thinning, and cartilage matrix destruction, inducing chondrocyte apoptosis via both the extrinsic and mitochondrial apoptosis pathways.

The effects of Spirulina platensis on behavior in adolescent rats fed a high-fat diet.

In recent years, childhood overweight and obesity have become a universal public health problem. Obesity may lead to cognitive disorders, depression and anxiety by affecting neuronal processes. Spirulina platensis (SP), a species of microalgae from the Chlorophyceae green algae class, has neuroprotective effects and may reduce body weight. In this study, we aimed to investigate the effects of SP on behavior alongside the role of leptin and Sirtuin-1 in fed with high-fat diet (HFD) adolescent rats. Four-week-old Sprague Dawley male rats were divided into four groups: control, HFD, HFD + SP150 (150 mg/kg/day SP, orally), HFD + SP450 (450 mg/kg/day SP, orally). Rats except for the control group exposed to 60% HFD along 12 weeks. Last 6 weeks SP or vehicle administered. After the behavioral tests, leptin and Sirtuin-1 levels in prefrontal cortex and hippocampus regions were evaluated. SP150 significantly reduced body weight compared with HFD group. The time spent in the center of open field increased significantly in SP150-treated rats compared with HFD. SP150 and SP450 significantly decreased immobility time in forced swim test compared with HFD. Leptin levels in HFD group were significantly lower in prefrontal cortex compared to control group. Leptin levels of the HFD + SP450 group were significantly higher than HFD group in the hippocampus. There was no significant difference between groups in Sirtuin-1 levels. In conclusion, SP supplementation in adolescence period might positively affect chronic high fat-induced anxiety-like and depressive-like behavior by partially affecting brain leptin levels and without affecting Sirtuin-1 levels.

Inheritance of wild and truncated DAT alleles from grand-parents: Opposite transgenerational consequences on the behavioral phenotype in adolescent DAT heterozygous rats

Dopamine plays important roles in implicit memory and motivation of behavior. Environmental inputs can produce transgenerational epigenetic changes. This concept also includes the uterus: experimentally, we sought to create hyper-dopaminergic uterine conditions through ineffective dopamine-transporter (DAT) protein, obtained by inserting a stop-codon into the SLC6A3 gene. By crossing WT-dam with KO-sire (or vice-versa), we obtained a 100% DAT-heterozygous (HET) offspring with known derivation of the wild allele: MAT rats are offspring of WT-female and KO-male; PAT rats are offspring of KO-female and WT-male. We reconstructed inheritance of alleles, by crossing PAT-male with MAT-female or vice-versa, obtaining GIX (PAT-male with MAT-female) and DIX (MAT-male with PAT-female) rats (such offspring present specular paths in allele inheritance from grandparents). We conducted three experiments: first, we assessed maternal behaviour (four epigenotypes: WT, MAT, PAT and WHZ=HET-pups fostered-to-a WT-dam); in the second, we analysed sleep-wake cycles of GIX and DIX epigenotypes with their WIT siblings as controls; in the third, we explored the impact of WT or MAT mother on WT or HET pups. MAT-dams (with GIX-pups) express excessive licking/grooming. However, in the mere presence of “sick” epigenotype, PAT-dams (with DIX-pups) and also WHZ (i.e., WT-dams but with HET-pups) expressed greater nest-building care towards the offspring, compared to “true-wild” litters (WT-dams with WT-pups). In Exp. 2 at adolescence, GIX epigenotype showed locomotor hyperactivity during late waking-phase, while DIX epigenotype exhibited pronounced hypoactivity compared to controls. In Exp. 3, we confirmed that HET adolescent pups receiving cares from a MAT-dam may develop additional hyperactivity when awake, but additional hypoactivity during rest-hours. Thus, behavioral changes observed in DAT-heterozygous offspring have opposite courses based on of DAT-allele inheritance from a grandparent through the sire or the dam. In conclusion, behavioural changes in the offspring have antithetic courses with respect to inheritance of DAT-allele via sperm or egg.

Perinatal opioid exposure leads to decreased social play in adolescent male and female rats: Potential role of oxytocin signaling in brain regions associated with social reward

Over the last two decades, the number of infants exposed to opioids in utero has quadrupled in the United States, with some states reporting rates as high as 55 infants per 1000 births. Clinical studies report that children previously exposed to opioids during gestation show significant deficits in social behavior, including an inability to form friendships or other social relationships. To date, the neural mechanisms whereby developmental opioid exposure disrupts social behavior remain unknown. Using a novel paradigm of perinatal opioid administration, we tested the hypothesis that chronic opioid exposure during critical developmental periods would disrupt juvenile play. As oxytocin is a major regulator of sociability, the impact of perinatal morphine exposure on oxytocin peptide expression was also examined. Juvenile play was assessed in vehicle- or morphine-exposed male and female rats at P25, P35, and P45. Classical features of juvenile play were measured, including time spent engaged in social play, time not in contact, number of pins, and number of nape attacks. We report that morphine-exposed males and females spend less time engaged in play behavior than control males and females, with a corresponding increase in time spent alone. Morphine-exposed males and females also initiated fewer pins and nape attacks. Together, these data suggest that male and female rats exposed to morphine during critical developmental periods are less motivated to participate in social play, potentially due to alterations in oxytocin-mediated reward signaling.

Acute alcohol induces greater dose-dependent increase in the lateral cortical network functional connectivity in adult than adolescent rats

Alcohol misuse and, particularly adolescent drinking, is a major public health concern. While evidence suggests that adolescent alcohol use affects frontal brain regions that are important for cognitive control over behavior, little is known about how acute alcohol exposure alters large-scale brain networks and how sex and age may moderate such effects. Here, we employ a recently developed functional magnetic resonance imaging (fMRI) protocol to acquire rat brain functional connectivity data and use an established analytical pipeline to examine the effect of sex, age, and alcohol dose on connectivity within and between three major rodent brain networks: default mode, salience, and lateral cortical network. We identify the intra- and inter-network connectivity differences and establish moderation models to reveal significant influences of age on acute alcohol-induced lateral cortical network connectivity. Through this work, we make brain-wide isotropic fMRI data with acute alcohol challenge publicly available, with the hope to facilitate future discovery of brain regions/circuits that are causally relevant to the impact of acute alcohol use.

Repeated dextromethorphan administration in adolescent rats produces long-lasting behavioral alterations

Initiation of non-medical dextromethorphan (DXM) use often occurs in adolescence, yet little is known about the consequences when use begins during this developmental period. The current experiments examined the acute response and the effects of repeated exposure to DXM in adolescence on behavior in adulthood. We examined locomotor activity, locomotor sensitization, and cognitive function, in rats that received repeated administration of DXM. Groups of adolescent (PND 30) and adult (PND 60) male rats were treated with DXM (60 mg/kg) once daily for 10 days. Locomotor activity in response to DXM was assessed following the first injection, on the 10th day of injection (adolescent – PND 39; adult – PND 69), and following 20 days of abstinence (adolescent – PND 59; adult – PND 89). Acute locomotor effects and locomotor sensitization were compared in adolescents and adults; cross-sensitization to ketamine, another dissociative with abuse potential, was also examined. In a separate group of rodents cognitive deficits were assessed following a 20 day abstinence period (adolescent – PND 59; adult – PND 89) in spatial learning and novel object recognition tasks. The locomotor stimulant effect of DXM was much greater in adolescents than adults. Also, only adolescent rats that were repeatedly administered DXM demonstrated locomotor sensitization at the end of 10 days of injection. However, sensitization occurred after the abstinence period in all rats regardless of age. Nonetheless, cross-sensitization to ketamine was only evident in adolescent-treated rats. DXM also led to an increase in perseverative errors in reversal learning only in the adolescent-treated group. We conclude that repeated use of DXM produces long-lasting neuroadaptations that may contribute to addiction. Deficits in cognitive flexibility occur in adolescents, although further work is necessary to confirm these findings. The results extend the understanding of potential long-term consequences of DXM use in adolescents and adults.

A maturational shift in the frontal cortex synaptic transcriptional landscape underlies schizophrenia-relevant behavioural traits: A congenital rat model

Disruption of brain development early in life may underlie the neurobiology behind schizophrenia. We have reported more immature synaptic spines in the frontal cortex (FC) of adult Roman High-Avoidance (RHA-I) rats, a behavioural model displaying schizophrenia-like traits. Here, we performed a whole transcriptome analysis in the FC of 4 months old male RHA-I (n=8) and its counterpart, the Roman Low-Avoidance (RLA-I) (n=8). We identified 203 significant genes with overrepresentation of genes involved in synaptic function. Next, we performed a gene set enrichment analysis (GSEA) for genes co-expressed during neurodevelopment. Gene networks were obtained by weighted gene co-expression network analysis (WGCNA) of a transcriptomic dataset containing human FC during lifespan (n=269). Out of thirty-one functional gene networks, six were significantly enriched in the RHA-I. These were differentially regulated during infancy and enriched in biological ontologies related to myelination, synaptic function, and immune response. We validated differential gene expression in a new cohort of adolescent (<=2 months old) and young-adult (>=3 months old) RHA-I and RLA-I rats. The results confirmed overexpression of Gsn, Nt5cd1, Ppp1r1b, and Slc9a3r1 in young-adult RHA-I, while Cables1, a regulator of Cdk5 phosphorylation in actin regulation and involved in synaptic plasticity and maturation, was significantly downregulated in adolescent RHA-I. This age-related expression change was also observed for presynaptic components Snap25 and Snap29. Our results show a different maturational expression profile of synaptic components in the RHA-I strain, supporting a shift in FC maturation underlying schizophrenia-like behavioural traits and adding construct validity to this strain as a neurodevelopmental model.

Microbiota-Liver-Bile Salts Axis, a Novel Mechanism Involved in the Contrasting Effects of Sodium Selenite and Selenium-Nanoparticle Supplementation on Adipose Tissue Development in Adolescent Rats.

Adolescence is a period during which body composition changes deeply. Selenium (Se) is an excellent antioxidant trace element related to cell growth and endocrine function. In adolescent rats, low Se supplementation affects adipocyte development differently depending on its form of administration (selenite or Se nanoparticles (SeNPs). Despite this effect being related to oxidative, insulin-signaling and autophagy processes, the whole mechanism is not elucidated. The microbiota-liver-bile salts secretion axis is related to lipid homeostasis and adipose tissue development. Therefore, the colonic microbiota and total bile salts homeostasis were explored in four experimental groups of male adolescent rats: control, low-sodium selenite supplementation, low SeNP supplementation and moderate SeNPs supplementation. SeNPs were obtained by reducing Se tetrachloride in the presence of ascorbic acid. Supplementation was received orally through water intake; low-Se rats received twice more Se than control animals and moderate-Se rats tenfold more. Supplementation with low doses of Se clearly affected anaerobic colonic microbiota profile and bile salts homeostasis. However, these effects were different depending on the Se administration form. Selenite supplementation primarily affected liver by decreasing farnesoid X receptor hepatic function, leading to the accumulation of hepatic bile salts together to increase in the ratio Firmicutes/Bacteroidetes and glucagon-like peptide-1 (GLP-1) secretion. In contrast, low SeNP levels mainly affected microbiota, moving them towards a more prominent Gram-negative profile in which the relative abundance of Akkermansia and Muribaculaceae was clearly enhanced and the Firmicutes/Bacteroidetes ratio decreased. This bacterial profile is directly related to lower adipose tissue mass. Moreover, low SeNP administration did not modify bile salts pool in serum circulation. In addition, specific gut microbiota was regulated upon administration of low levels of Se in the forms of selenite or SeNPs, which are properly discussed. On its side, moderate-SeNPs administration led to great dysbiosis and enhanced the abundance of pathogenic bacteria, being considered toxic. These results strongly correlate with the deep change in adipose mass previously found in these animals, indicating that the microbiota-liver-bile salts axis is also mechanistically involved in these changes.

Selective chemogenetic inactivation of corticoaccumbal projections disrupts trait choice impulsivity.

Impulsive choice has enduring trait-like characteristics and is defined by preference for small immediate rewards over larger delayed ones. Importantly, it is a determining factor in the development and persistence of substance use disorder (SUD). Emerging evidence from human and animal studies suggests frontal cortical regions exert influence over striatal reward processing areas during decision-making in impulsive choice or delay discounting (DD) tasks. The goal of this study was to examine how these circuits are involved in decision-making in animals with defined trait impulsivity. To this end, we trained adolescent male rats to stable behavior on a DD procedure and then re-trained themin adulthood to assess trait-like, conserved impulsive choice across development. We then used chemogenetic tools to selectively and reversibly target corticostriatal projections during performance of the DD task. The prelimbic region of the medial prefrontal cortex (mPFC) was injected with a viral vector expressing inhibitory designer receptors exclusively activated by designer drugs (Gi-DREADD), and then mPFC projections to the nucleus accumbens core (NAc) were selectively suppressed by intra-NAc administration of the Gi-DREADD actuator clozapine-n-oxide (CNO). Inactivation of the mPFC-NAc projection elicited a robust increase in impulsive choice in rats with lower vs. higher baseline impulsivity. This demonstrates a fundamental role for mPFC afferents to the NAc during choice impulsivity and suggests that maladaptive hypofrontality may underlie decreased executive control in animals with higher levels of choice impulsivity. Results such as these may have important implications for the pathophysiology and treatment of impulse control, SUDs, and related psychiatric disorders.

Transcriptome-wide identification of altered RNA m6A profiles in cardiac tissue of rats with LPS-induced myocardial injury.

Myocardial injury is a common complication in patients with endotoxaemia/sepsis, especially in children. Moreover, it develops through an unclear pathophysiological mechanism, and effective therapies are lacking. Recently, RNA modification, particularly N 6-methyladenosine (m6A) modification, has been found to be involved in various physiological processes and to play important roles in many diseases. However, the role of m6A modification in endotoxaemia/sepsis-induced myocardial injury is still in its infancy. Therefore, we attempted to construct the m6A modification map of myocardial injury in a rat model treated by lipopolysaccharide (LPS) and explore the role of m6A modification in LPS-induced myocardial injury. Myocardial injury adolescent rat model was constructed by intraperitoneal injection of LPS. m6A RNA Methylation Quantification Kit was used to detect overall level of m6A modification in rat cardiac tissue. m6A-specific methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were conducted to identify the altered m6A-modified genes and differentially expressed genes in cardiac tissue of rats treated by LPS and control rats (6 versus. 6). Bioinformatics was used to analyze the functions of differentially m6A modified genes, differentially expressed genes, and genes with both differential m6A modification and differential expression. qPCR was used to detect expression of m6A modification related enzymes. We found that the overall level of m6A modification in cardiac tissue of the LPS group was up-regulated compared with that of the control group. MeRIP-seq and RNA-seq results showed that genes with differential m6A modification, genes with differential expression and genes with both differential m6A modification and differential expression were closely associated with inflammatory responses and apoptosis. In addition, we found that m6A-related enzymes (Mettl16, Rbm15, Fto, Ythdc2 and Hnrnpg) were differentially expressed in the LPS group versus. the control group. m6A modification is involved in the pathogenesis process of LPS-induced myocardial injury, possibly through the regulation of inflammatory response and apoptosis-related pathways. These results provide valuable information regarding the potential pathogenic mechanisms underlying LPS-induced myocardial injury.

Efeitos dos exercícios físicos sobre a neurogênese do cérebro de ratos adolescentes

Introduction. The neurogenesis of the brain of young rats can be affected by several factors in their development, with the practice of physical exercises being an important factor in the neurogenesis of nervous tissue. Objective. To investigate the effects of different physical exercise protocols of medium and high intensity on neurogenesis in the brain of adolescent rats. Method. The experimental study, where three groups of animals were used: a control group (RC), a group that performed medium-intensity physical exercise (R1) and a group that performed high-intensity physical exercise (R2). Each group with 8 animals, totaling 24 animals. The progressive resisted physical exercise program on the vertical ladder was carried out for 4 weeks, 5 days a week with a duration varying between 30 and 45 minutes. After the end of the experiments, the animals were euthanized for removal of the brain and subsequent processing, staining using the Nissl method and histomorphometric analysis by counting neurons in the dentate gyrus of the hippocampus and subventricular zone. Results. The data demonstrated that there was no significant difference in the area and height of the apex of the hippocampal dentate gyrus between the groups (p=0.2474 and p=0.3337; respectively). The results of the length of the apex of the hippocampal dentate gyrus showed significant differences (p=0.0172). Conclusion. The practice of medium and high intensity progressive resisted physical exercises did not modify the morphology and neuronal density in the hippocampal dentate gyrus and subventricular zone of young rats.

The relative reinforcing efficacy of nicotine in an adolescent rat model of attention-deficit hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is an independent risk factor for tobacco use disorder. Individuals with ADHD are more likely to begin smoking at a younger age, become a daily smoker sooner, smoke more cigarettes per day, and exhibit greater nicotine dependence than individuals without ADHD. It is unclear whether these findings are due to the reinforcing efficacy of nicotine per se being greater among individuals with ADHD. The purpose of the present study was to examine this issue using an animal model of ADHD, the spontaneously hypertensive rat (SHR) strain. Adolescent SHR and Wistar (control) rats were given access to a typically reinforcing nicotine unit dose (30 μg/kg), a threshold reinforcing nicotine dose (4 μg/kg), or saline under an FR 1 (week 1) and FR 2 (week 2) schedule during 23 h sessions to examine acquisition of self-administration. Behavioral economic demand elasticity was then evaluated at the 30 μg/kg dose through an FR escalation procedure. At the 30 μg/kg dose, SHR rats exhibited a lower average response rate, lower mean active to inactive lever discrimination ratio, and lower proportion of rats acquiring self-administration compared to control rats. During demand assessment, SHR rats showed no significant difference from Wistars in demand intensity (Q0) or elasticity (α; i.e., reinforcing efficacy). In addition, no strain difference in acquisition measures were observed at the 4 μg/kg dose. These findings suggest that the increased risk of tobacco use disorder in adolescents with ADHD may not be attributable to a greater reinforcing efficacy of nicotine, and that other aspects of tobacco smoking (e.g., non-nicotine constituents, sensory factors) may play a more important role. A policy implication of these findings is that a nicotine standard to reduce initiation of tobacco use among adolescents in the general population may also be effective among those with ADHD.