Nociceptor neurons affect cancer immunosurveillance.

Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.

Impact of two different types of exercise training on AMPH addiction: Role of hippocampal neurotrophins.

INTRODUCTION: Amphetamine (AMPH) abuse results in neurobehavioral alterations related to the reward circuit. The hippocampus plays a role in cognition, reward, and drug addiction. There are no pharmacological approaches to prevent AMPH relapse. Physical exercise has been studied as a non-pharmacological promising influence to attenuate reward symptoms related to addictive drugs. OBJECTIVE: This study aimed to compare the effects of non-weight-loaded and weight-loaded physical exercise on behavioral (relapse, memory and anxiety) and hippocampal molecular parameters associated with AMPH addiction in Wistar rats. METHODS: Male rats were subjected to the AMPH-Conditioned Place Preference (CPP) paradigm. After 8-conditioning days, they were subjected to swimming physical exercise protocol (without or with weight-load). Behavioral evaluations were performed to assess the influence of both exercise protocols in addiction parameters, including relapse after AMPH reconditioning, working memory, locomotor activity, and anxiety-like symptoms. Subsequently, protein levels of Brain-Derived Neurotrophic Factor (BDNF) and pro-BDNF ex-vivo assays were carried out in samples of the hippocampus of the animals. RESULTS: AMPH relapse and anxiety-like behaviors were reduced only in rats subjected to non-weight-loaded exercise. Hippocampal BDNF and pro-BDNF immunoreactivity were increased in non-weight-loaded exercise rats. Behavioral and molecular analyses were not modified in rats subjected to weight-loaded exercise. CONCLUSION: These findings demonstrate that non-weight-loaded exercise was more effective against relapse and anxiety-like behavior induced by AMPH. Non-weight-loaded exercise upregulated the hippocampal immunocontent levels in rats.

Interesterified fat maternal consumption before conception programms memory and learning of adulthood offspring: How big is this deleterious repercussion?

In recent years, interesterified fat (IF) has largely replaced trans fat in industrialized food. Studies of our research group showed that IF consumption may not be safe for central nervous system (CNS) functions. Our current aim was to evaluate IF maternal consumption before conception on cognitive performance of adult rat offspring. Female Wistar rats were fed with standard chow plus 20% soybean and fish oil mix (control group) or plus 20% IF from weaning until adulthood (before mating), when the diets were replaced by standard chow only. Following the gestation and pups' development, locomotion and memory performance followed by neurotrophin immunocontent and fatty acids (FA) profile in the hippocampus of the adulthood male offspring were quantified. Maternal IF consumption before conception decreased hippocampal palmitoleic acid incorporation, proBDNF and BDNF levels, decreasing both exploratory activity and memory performance in adult offspring. Considering that, the adult male offspring did not consume IF directly, further studies are needed to understand the molecular mechanisms and if the IF maternal preconception consumption could induce the epigenetic changes observed here. Our outcomes reinforce an immediate necessity to monitor and / or question the replacement of trans fat by IF with further studies involving CNS functions.

Neuro-Immunity and Gut Dysbiosis Drive Parkinson's Disease-Induced Pain.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1-2% of the population aged 65 and over. Additionally, non-motor symptoms such as pain and gastrointestinal dysregulation are also common in PD. These impairments might stem from a dysregulation within the gut-brain axis that alters immunity and the inflammatory state and subsequently drives neurodegeneration. There is increasing evidence linking gut dysbiosis to the severity of PD's motor symptoms as well as to somatosensory hypersensitivities. Altogether, these interdependent features highlight the urgency of reviewing the links between the onset of PD's non-motor symptoms and gut immunity and whether such interplays drive the progression of PD. This review will shed light on maladaptive neuro-immune crosstalk in the context of gut dysbiosis and will posit that such deleterious interplays lead to PD-induced pain hypersensitivity.

Trans fat intake during pregnancy or lactation increases anxiety-like behavior and alters proinflammatory cytokines and glucocorticoid receptor levels in the hippocampus of adult offspring.

Changes in dietary habits, including the increased consumption of processed foods, rich in trans fatty acids (TFA), have profound effects on offspring health in later life. Thus, this study aimed to assess the influence of maternal trans fat intake during pregnancy or lactation on anxiety behavior, as well as markers of inflammation, oxidative stress, and expression of glucocorticoid receptors (GR) of adult male offspring. Female Wistar rats were supplemented daily with soybean oil/fish oil (SO/FO) or hydrogenated vegetable fat (HVF) by oral gavage (3.0 g/kg body weight) during pregnancy or lactation. After weaning, male offspring received only standard diet. On the postnatal day 60, anxiety-like symptoms were assessed, the plasma was collected for the quantification of cytokines levels and the hippocampus removed for biochemical and molecular analysis. Our findings have evidenced that offspring from HVF-supplemented dams during pregnancy or lactation showed significantly greater levels of anxiety behavior. HVF supplementation increased plasma levels of proinflammatory cytokines and these levels were higher in the lactation period. In contrast, HVF supplementation decreased plasma levels of IL-10 in relation to SO/FO in both periods. Biochemical evaluations showed higher reactive species generation, protein carbonyl levels and catalase activity in offspring from HVF-supplemented dams during lactation. In addition, offspring from HVF-supplemented dams showed decreased GR expression in both supplemented periods. Together, these data indicate that consumption of TFA in different periods of development may increase anxiety-like behavior at least in part via alterations in proinflammatory and anti-inflammatory cytokine levels and GR expression in limbic brain regions.

Interesterified fat consumption since gestation decreases striatal dopaminergic targets levels and gdnf impairing locomotion of adult offspring.

Interesterified fat (IF) currently substitutes the hydrogenated vegetable fat (HVF) in processed foods. However, the IF consumption impact on the central nervous system (CNS) has been poorly studied. The current study investigated connections between IF chronic consumption and locomotor impairments in early life period and adulthood of rats and access brain molecular targets related to behavior changes in adulthood offspring. During pregnancy and lactation, female rats received soybean oil (SO) or IF and their male pups received the same maternal supplementation from weaning until adulthood. Pups' motor ability and locomotor activity in adulthood were evaluated. In the adult offspring striatum, dopaminergic targets, glial cell line-derived neurotrophic factor (GDFN) and lipid profile were quantified. Pups from IF supplementation group presented impaired learning concerning complex motor skill and sensorimotor behavior. The same animals showed decreased locomotion in adulthood. Moreover, IF group showed decreased immunoreactivity of all dopaminergic targets evaluated and GDNF, along with important changes in FA composition in striatum. This study shows that the brain modifications induce by IF consumption resulted in impaired motor control in pups and decreased locomotion in adult animals. Other studies about health damages induced by IF consumption may have a contribution from our current outcomes.

Neonatal Tactile Stimulation Alters Behaviors in Heterozygous Serotonin Transporter Male Rats: Role of the Amygdala.

The serotonin transporter (SERT) gene, especially the short allele of the human serotonin transporter linked polymorphic region (5-HTTLPR), has been associated with the development of stress-related neuropsychiatric disorders. In line, exposure to early life stress in SERT knockout animals contributes to anxiety- and depression-like behavior. However, there is a lack of investigation of how early-life exposure to beneficial stimuli, such as tactile stimulation (TS), affects later life behavior in these animals. In this study, we investigated the effect of TS on social, anxiety, and anhedonic behavior in heterozygous SERT knockouts rats and wild-type controls and its impact on gene expression in the basolateral amygdala. Heterozygous SERT+/- rats were submitted to TS during postnatal days 8-14, for 10 min per day. In adulthood, rats were assessed for social and affective behavior. Besides, brain-derived neurotrophic factor (Bdnf) gene expression and its isoforms, components of glutamatergic and GABAergic systems as well as glucocorticoid-responsive genes were measured in the basolateral amygdala. We found that exposure to neonatal TS improved social and affective behavior in SERT+/- animals compared to naïve SERT+/- animals and was normalized to the level of naïve SERT+/+ animals. At the molecular level, we observed that TS per se affected Bdnf, the glucocorticoid-responsive genes Nr4a1, Gadd45ß, the co-chaperone Fkbp5 as well as glutamatergic and GABAergic gene expression markers including the enzyme Gad67, the vesicular GABA transporter, and the vesicular glutamate transporter genes. Our results suggest that exposure of SERT+/- rats to neonatal TS can normalize their phenotype in adulthood and that TS per se alters the expression of plasticity and stress-related genes in the basolateral amygdala. These findings demonstrate the potential effect of a supportive stimulus in SERT rodents, which are more susceptible to develop psychiatric disorders.

Apical periodontitis induces changes on oxidative stress parameters and increases Na+/K+-ATPase activity in adult rats.

OBJECTIVES: Endodontic infection can cause systemic alterations. The involvement of oxidative stress (OS) and transmembrane enzymes compose the pathogenesis of various systemic diseases. However, the relation among apical periodontitis (AP), OS parameters, and Na+/K+-ATPase (NKA) pump was not reported in the literature. This study evaluated the AP influence on OS parameters and NKA activity in adult rats. METHODS: Adult male Wistar rats (sixteen weeks old) were randomly assigned to two experimental groups: control (CT group; n = 8) and AP (AP group; n = 9), which was induced in the first right mandibular molar tooth. After 21 days of AP induction, mandibles were dissected for radiographic analysis. In addition, the heart, liver, pancreas, and kidney were collected for analysis of endogenous OS parameters and NKA activity. Data were analyzed by Student's T-test. Values of p < 0.05 were considered statistically significant. RESULTS: AP presence increased reactive species (RS) generation only in the heart, while the other analyzed organs did not have this parameter modified. Heart and pancreas had a decreased endogenous antioxidant system (catalase activity and vitamin C levels), liver and kidney had an increased one. AP increased NKA activity in the heart, liver, and pancreas, but not in the kidney. CONCLUSION: The modulation of both endogenous antioxidant defense system and NKA activity in vital organs suggested that alterations in the antioxidant status and cellular electrochemical gradient may be involved in the AP pathophysiology.

Hypersensitivity to amphetamine's psychomotor and reinforcing effects in serotonin transporter knockout rats: Glutamate in the nucleus accumbens.

BACKGROUND AND PURPOSE: Amphetamine (AMPH) use disorder is a serious health concern, but, surprisingly, little is known about the vulnerability to the moderate and compulsive use of this psychostimulant and its underlying mechanisms. Previous research showed that inherited serotonin transporter (SERT) down-regulation increases the motor response to cocaine, as well as moderate (as measured during daily 1-h self-administration sessions) and compulsive (as measured during daily 6-h self-administration sessions) intake of this psychostimulant. Here, we sought to investigate whether these findings generalize to AMPH and the underlying mechanisms in the nucleus accumbens. EXPERIMENTAL APPROACH: In serotonin transporter knockout (SERT-/- ) and wild-type control (SERT+/+ ) rats, we assessed the locomotor response to acute AMPH and i.v. AMPH self-administration under short access (ShA: 1-h daily sessions) and long access (LgA: 6-h daily sessions) conditions. Twenty-four hours after AMPH self-administration, we analysed the expression of glutamate system components in the nucleus accumbens shell and core. KEY RESULTS: We found that SERT-/- animals displayed an increased AMPH-induced locomotor response and increased AMPH self-administration under LgA but not ShA conditions. Further, we observed changes in the vesicular and glial glutamate transporters, NMDA and AMPA receptor subunits, and their respective postsynaptic scaffolding proteins as function of SERT genotype and AMPH exposure (baseline, ShA, and LgA), specifically in the nucleus accumbens shell. CONCLUSION AND IMPLICATIONS: We demonstrate that SERT gene deletion increases the psychomotor and reinforcing effects of AMPH and that the latter is potentially mediated, at least in part, by homeostatic changes in the glutamatergic synapse of the nucleus accumbens shell and/or core.

Glucocorticoid and brain-derived neurotrophic factor relationship: a brief investigation into the model of depression by chronic administration of corticosterone.

Depression is considered a common mental disorder that affects more than 300 million people worldwide. Despite this high incidence, its etiology is not completely elucidated instigating further studies. For this purpose, different animal models are used to study routes and molecular changes involved in depression, among them the chronic administration of corticosterone. However, the knowledge about neurochemical changes after this protocol is still controversial. In this work, we evaluated serum corticosterone levels, adrenal/body weight ratio, as well as glucocorticoid receptor and brain-derived neurotrophic factor protein expression and its receptor, tropomyosin-receptor kinase B. These analyzes were performed on prefrontal cortex, hippocampus, and striatum samples taken of mice after 21 days of administration of corticosterone. Exposure to corticosterone reduced the serum corticosterone levels and the adrenal/body weight ratio. Moreover, the glucocorticoid receptor and tyrosine-receptor kinase B expression were increased in the hippocampus while the brain-derived neurotrophic factor expression was reduced in the prefrontal cortex. We also found a positive correlation between the expression of glucocorticoid receptor and tyrosine-receptor kinase B and our results suggest a possible relationship between the glucocorticoid/glucocorticoid receptor and brain-derived neurotrophic factor/tropomyosin-receptor kinase B routes after chronic corticosterone administration. To our knowledge, this is the first study that evaluate these parameters concomitantly in important mood-related structures. In addition, these results may be useful to other research groups seeking to explore new pathways and substances with therapeutic potential to treat this silent epidemic.

Influence of magnesium supplementation and L-type calcium channel blocker on haloperidol-induced movement disturbances.

Haloperidol (Hal) is an antipsychotic related to movement disorders. Magnesium (Mg) showed benefits on orofacial dyskinesia (OD), suggesting its involvement with N-methyl-D-aspartate receptors (NMDAR) since it acts blocking calcium channels. Comparisons between nifedipine (NIF; a calcium channel blocker) and Mg were performed to establish the Mg mechanism. Male rats concomitantly received Hal and Mg or NIF for 28 days, and OD behaviors were weekly assessed. Both Mg and NIF decreased Hal-induced OD. Hal increased Ca2+-ATPase activity in the striatum, and Mg reversed it. In the cortex, both Mg and NIF decreased such activity. Dopaminergic and glutamatergic immunoreactivity were modified by Hal and treatments: i) in the cortex: Hal reduced D1R and D2R, increasing NMDAR immunoreactivity. Mg and NIF reversed this Hal influence on D1R and NMDAR, while only Mg reversed Hal effects on D2R levels; ii) in the striatum: Hal decreased D2R and increased NMDAR while Mg and NIF decreased D1R and reversed the Hal-induced decreasing D2R levels. Only Mg reversed the Hal-induced increasing NMDAR levels; iii) in the substantia nigra (SN): while Hal increased D1R, D2R, and NMDAR, both Mg and NIF reversed this influence on D2R, but only Mg reversed the Hal-influence on D1R levels. Only NIF reversed the Hal effects on NMDAR immunoreactivity. These findings allow us to propose that Mg may be useful to minimize Hal-induced movement disturbances. Mg molecular mechanism seems to be involved with a calcium channel blocker because the NIF group showed less expressive effects than the Mg group.

Chitosan hydrogels containing nanoencapsulated phenytoin for cutaneous use: Skin permeation/penetration and efficacy in wound healing.

Although phenytoin is an antiepileptic drug used in the oral treatment of epilepsy, its off-label use as a cutaneous healing agent has been studied in recent years due to the frequent reports of gingival hyperplasia after oral administration. However, the cutaneous topical application of phenytoin should prevent percutaneous skin permeation. Therefore, the aim of this study was to evaluate the in vitro skin permeation/retention and in vivo effects of nanocapsules and nanoemulsions loaded with phenytoin and formulated as chitosan hydrogels on the healing process of cutaneous wounds in rats. The hydrogels had adequate pH values (4.9-5.6) for skin application, drug content of 0.025% (w/w), and non-Newtonian pseudoplastic rheological behaviour. Hydrogels containing nanocapsules and nanoemulsions enabled improved controlled release of phenytoin and adhesion to skin, compared with hydrogels containing non-encapsulated phenytoin. In vitro skin permeation studies showed that phenytoin permeation to the receptor compartment, and consequently the risk of systemic absorption, may be reduced by nanoencapsulation without any change in the in vivo performance of phenytoin in the wound healing process in rats.

Can the dietary fat type facilitate memory impairments in adulthood? A comparative study between Mediterranean and Western-based diet in rats.

A balanced intake of fatty acids (FA) of both omega-6 (n-6) and -3 (n-3) series is essential for memory. The Mediterranean diet (MD), rich in n-3 polyunsaturated FA (PUFA) and low n-6/n-3 PUFA ratio, has shown beneficial influences on health. Inversely, the Western diet contains saturated fats, including hydrogenated vegetable fat (HVF, rich in trans fat) and interesterified fat (IF), making the n-6/n-3 PUFA ratio high. Due to the health impairments caused by HVF, it has been replaced by IF in processed foods. We compared an MD (balanced n-6/n-3 PUFA ratio) with Western diets 1 (WD1, rich in trans fat) and 2 (WD2, rich in IF) on memory process per se and following scopolamine (SCO) administration, which induces amnesia in rats. While MD exerted protective effects, WD1 and WD2 showed declined memory per se, showing higher susceptibility to SCO-induced memory deficits. In addition, WD1 and WD2 showed increased proinflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-1ß, IL-6] and decreased anti-inflammatory cytokines (IL-10) in plasma. IL-1ß was higher in the hippocampus of WD1, which was reflected on histological assessments. Significant correlations between cognitive decline and inflammatory markers reinforce our hypothesis: MD-like fats may act preventively on cognitive loss, while WD-like fats may facilitate this.

Toxicological aspects of the interesterified-fat from processed foods: Influences on opioid system and its reward effects in rats.

Considering the high consumption of processed foods, interesterified fat (IF) has been used to replace trans fat, since it may harm nervous system functions. Opioids are intensely used to alleviate pain, and have a highly addictive potential. Therefore, their improper use is related to addiction, tolerance, and withdrawal syndrome. Wistar rats received soybean oil (SO) or IF during gestation, lactation and post-weaning until pups' adolescence. On post-natal day 39, animals received morphine (4 mg/kg i.p.) in the conditioned place preference (CPP) paradigm. SO group showed morphine preference during drug withdrawal, while IF group showed no preference or withdrawal symptoms, but higher sensitivity to thermal stimuli than SO group. Morphine contidioning increased dopamine 1 receptor (D1R) and NMDAR: N-methyl-d-aspartate receptor (NMDAR) immunoreactivity in the hippocampus of SO, whereas these molecular changes were not observed in IF group. Regardless of morphine conditioning, IF group showed increased Kappa opioid receptor (KOR) immunoreactivity in the spinal cord, evidencing a negative correlation with thermal sensitivity. The chronic consumption of IF-rich foods during earlier periods of life may affect opioid neurotransmission, resulting in loss of rewarding effects related to this system.

Toxicological aspects of interesterified fat: Brain damages in rats.

In recent years, interesterified fat (IF) has been used to replace hydrogenated vegetable fat (HVF), rich in trans isomers, being found in processed foods. Studies involving IF have shown deleterious influences on the metabolic system, similarly to HVF, whereas no studies regarding its influence on the central nervous system (CNS) were performed. Rats from first generation born and maintained under supplementation (3g/Kg, p.o.) of soybean-oil or IF until adulthood were assessed on memory, biochemical and molecular markers in the hippocampus. IF group showed higher saturated fatty acids and linoleic acid and lower docosahexaenoic acid incorporation in the hippocampus. In addition, IF supplementation impaired short and long-term memory, which were related to increased reactive species generation and protein carbonyl levels, decreased catalase activity, BDNF and TrkB levels in the hippocampus. To the best of our knowledge, this is the first study to show that lifelong IF consumption may be related to brain oxidative damage, memory impairments and neurotrophins modifications, which collectively may be present indifferent neurological disorders. In fact, the use of IF in foods was intended to avoid damage from HVF consumption; however this substitute should be urgently reviewed, since this fat can be as harmful as trans fat.

Influence of magnesium supplementation on movement side effects related to typical antipsychotic treatment in rats.

Chronic use of typical antipsychotic haloperidolis related to movement disturbances such as parkinsonism, akathisia and tardive dyskinesia which have been related to excitotoxicity in extrapyramidal brain areas, requiring their prevention and treatment. In the current study we evaluated the influence of the magnesium on prevention (for 28days before-), reversion (for 12days after-) and concomitant supplementation on haloperidol-induced movement disorders in rats. Sub-chronic haloperidol was related to orofacial dyskinesia (OD) and catalepsy development, increased generation of reactive species (RS) and levels of protein carbonyl (PC) in cortex, striatum and substantia nigra (SN) in all experimental protocols. When provided preventatively, Mg reduced the increase of OD and catalepsy time 14 and 7days after haloperidol administration, respectively. When supplemented after haloperidol-induced OD establishment, Mg reversed this behavior after 12days, while catalepsy was reversed after 6days of Mg supplementation.When Mg was concomitantly supplemented with haloperidol administration, OD and catalepsy were prevented. Moreover, Mg supplementation was able to prevent the RS generation in both cortex and SN, reducing PC levels in all brain areas evaluated. When supplemented after haloperidol, Mg reversed RS generation in cortex and striatum, decreasing PC levels in SN and striatum.The co-administration of haloperidol and Mg supplementation prevented RS generation in cortex, striatum and SN, and PC levels in the SN.These outcomes indicate that Mg supplementation may be a useful alternative to prevent movement disturbances resulting of classic antipsychotic pharmacotherapy as haloperidol.

Maternal trans fat intake during pregnancy or lactation impairs memory and alters BDNF and TrkB levels in the hippocampus of adult offspring exposed to chronic mild stress.

This study aimed to assess the influence of maternal dietary fat intake during pregnancy or lactation on memory of adult offspring after chronic mild stress (CMS) exposure. Female Wistar rats were supplemented daily with soybean oil/fish oil (SO/FO) or hydrogenated vegetable fat (HVF) by oral gavage (3.0g/kg body weight) during pregnancy or lactation. On post-natal day (PND) 60, half of the animals were exposed to CMS following behavioral assessments. While the adult offspring born under influence of SO/FO and HVF supplementations during pregnancy showed higher levels of n-3 and n-6 fatty acids (FA) series DHA and ARA metabolites, respectively, in the hippocampus, adult offspring born from supplemented dams during lactation showed higher levels of their precursors: ALA and LA. However, only HVF supplementation allowed TFA incorporation of adult offspring, and levels were higher in lactation period. Adult offspring born from dams supplemented with trans fat in both pregnancy and lactation showed short and long-term memory impairments before and after CMS. Furthermore, our study also showed higher memory impairment in offspring born from HVF-supplemented dams during lactation in comparison to pregnancy. BDNF expression was increased by stress exposure in offspring from both SO/FO- and HVF-supplemented dams during pregnancy. In addition, offspring from HVF-supplemented dams showed decreased TrkB expression in both supplemented periods, regardless of stress exposure. In conclusion, these findings show for the first time that the type of dietary FA as well as the period of brain development is able to change FA incorporation in brain neural membranes.

Tactile stimulation during different developmental periods modifies hippocampal BDNF and GR, affecting memory and behavior in adult rats.

Recent studies have shown that tactile stimulation (TS) in pups is able to prevent and/or minimize fear, anxiety behaviors, and addiction to psychostimulant drugs in adult rats. In these studies, animals have been exposed to handling from postnatal day (PND) 1-21. This study was designed to precisely establish which period of preweaning development has a greater influence of TS on neuronal development. After birth, male pups were exposed to TS from PND1-7, PND8-14, and PND15-21. In adulthood, the different periods of postnatal TS were assessed through behavioral, biochemical, and molecular assessments. Animals that received TS from PND8-14 showed lower anxiety-like symptoms, as observed by decreased anxiety index in elevated plus maze. This same TS period was able to improve rats' working memory by increasing the percentage of alternation rate in Y-maze, and induce better ability to cope with stressful situations, as showed in the defensive burying test by a reduced time of burying behavior. On the other hand, animals receiving TS in the first week of life showed longest cumulative burying time, which is directly related to increased anxiety-like behavior. Moreover, TS from PND8-14 showed lower corticosterone levels and better oxidative status, as observed by decreased lipid peroxidation and increased catalase activity in the hippocampus. Brain-derived neurotrophic factor (BDNF) immunocontent was increased in the hippocampus of animals receiving TS from PND8-14, while glucocorticoid receptors immunocontent was decreased in both TS1-7 and TS15-21 , but not TS8-14 . To the best of our knowledge, this study is the first to show TS can be more efficient if applied over a focused period of neonatal development (PND8-14) and this beneficial influence can be reflected on reduced emotionality and increased ability to address stressful situations in adulthood. © 2016 Wiley Periodicals, Inc.

Trans fat intake across gestation and lactation increases morphine preference in females but not in male rats: Behavioral and biochemical parameters.

The abuse of morphine has risen considerably in recent years, mainly due to the increase of its prescription in clinical medicine. Also, increased consumption of processed foods, rich in trans fatty acids (TFA), has caused concerns about human health. Thus, the aim of our study was to determine whether trans fat consumption in the perinatal period may affect preference for morphine in adolescent female and male rats. Dams were orally supplemented with water (C-control) or hydrogenated vegetable fat (HVF-rich in TFA) during gestation and lactation periods. On post-natal day 43, pups were exposed to morphine (4mg/kg i.p., for 4 days) and assessed in the conditioned place preference paradigm. Anxiety-like symptoms were assessed, and oxidative status of the brain was estimated by reactive species (RS) generation. Female rats with HVF supplementation showed increased morphine preference and less anxiety-like symptoms. Additionally, both male and female rats from HVF-supplementation showed increased RS generation in the ventral tegmental area, whose level was similar in morphine-conditioned female rats. RS generation was increased in the hippocampus of morphine-conditioned female rats, regardless of the supplementation of their dams. We may infer that gender is a predictive factor to opioid preference, since adolescent female rats showed more susceptibility to addiction than males. Furthermore, trans fat consumption across the perinatal period is able to modify parameters of opioid preference in female rats, possibly due to TFA incorporation in phospholipid membranes, modifying the endogenous opioid system and the oxidative status in brain areas related to drug addiction.

Lifelong consumption of trans fatty acids promotes striatal impairments on Na(+)/K(+) ATPase activity and BDNF mRNA expression in an animal model of mania.

PURPOSE: To evaluate the toxicity of chronic consumption of processed foods that are rich in trans fat on the lipid composition of brain membranes, as well as its functional repercussions. METHODS: A second generation of male rats born from mothers and grandmothers supplemented with soybean oil (SOC, an isocaloric control group) or hydrogenated vegetable fat (HVF, rich in TFA) (3g/kg; p.o.) were kept under oral treatment until 90 days of age, when they were exposed to an AMPH-induced model of mania. RESULTS: The HVF group presented 0.38% of TFA incorporation in the striatum, affecting Na(+)/K(+) ATPase activity, which was decreased per se and following AMPH-exposure. The HVF group also showed increased protein carbonyl (PC) and brain-derived neurotrophic factor (BDNF) mRNA levels after AMPH administration, while these oxidative and molecular changes were not observed in the other experimental groups. Additionally, a negative correlation between striatal Na(+)/K(+) ATPase activity and PC levels (r(2)=0.49) was observed. CONCLUSION: The prolonged consumption of trans fat allows TFA incorporation and increases striatal oxidative status, thus impairing the functionality of Na(+)/K(+)-ATPase and affecting molecular targets as BDNF mRNA. We hypothesized that the chronic intake of processed foods (rich in TFA) facilitates the development of neuropsychiatric diseases, particularly bipolar disorder.