Neonatal resveratrol treatment in cerebral palsy model recovers neurodevelopment impairments by restoring the skeletal muscle morphology and decreases microglial activation in the cerebellum.

Cerebral Palsy (CP) is the main motor disorder in childhood resulting from damage to the developing brain. Treatment perspectives are required to reverse the primary damage caused by the early insult and consequently to recover motor skills. Resveratrol has been shown to act as neuroprotection with benefits to skeletal muscle. This study aimed to investigate the effects of neonatal resveratrol treatment on neurodevelopment, skeletal muscle morphology, and cerebellar damage in CP model. Wistar rat pups were allocated to four experimental groups (n = 15/group) according CP model and treatment: Control+Saline (CS), Control+Resveratrol (CR), CP + Saline (CPS), and CP + Resveratrol (CPR). CP model associated anoxia and sensorimotor restriction. CP group showed delay in the disappearance of the palmar grasp reflex (p < 0.0001) and delay in the appearance of reflexes of negative geotaxis (p = 0.01), and free-fall righting (p < 0.0001), reduced locomotor activity and motor coordination (p < 0.05) than CS group. These motor skills impairments were associated with a reduction in muscle weight (p < 0.001) and area and perimeter of soleus end extensor digitorum longus muscle fibers (p < 0.0001), changes in muscle fibers typing pattern (p < 0.05), and the cerebellum showed signs of neuroinflammation due to elevated density and percentage of activated microglia in the CPS group compared to CS group (p < 0.05). CP animals treated with resveratrol showed anticipation of the appearance of negative geotaxis and free-fall righting reflexes (p < 0.01), increased locomotor activity (p < 0.05), recovery muscle fiber types pattern (p < 0.05), and reversal of the increase in density and the percentage of activated microglia in the cerebellum (p < 0.01). Thus, we conclude that neonatal treatment with resveratrol can contribute to the recovery of the delay neurodevelopment resulting from experimental CP due to its action in restoring the skeletal muscle morphology and reducing neuroinflammation from cerebellum.

Creatine supplementation increases postnatal growth and strength and prevents overexpression of pro-inflammatory interleukin 6 in the hippocampus in an experimental model of cerebral palsy.

ABSTRACTObjectives: The aim of this study was thus to evaluate the effect of Cr supplementation on morphological changes and expression of pro-inflammatory cytokines in the hippocampus and on developmental parameters. Methods: Male Wistar rat pups were submitted to an experimental model of CP. Cr was administered via gavage from the 21st to the 28th postnatal day, and in water after the 28th, until the end of the experiment. Body weight (BW), food consumption (FC), muscle strength, and locomotion were evaluated. Expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 immunoreactivity was assessed by immunocytochemistry in the hippocampal hilus. Results: Experimental CP caused increased density and activation of microglial cells, and overexpression of IL-6. The rats with CP also presented abnormal BW development and impairment of strength and locomotion. Cr supplementation was able to reverse the overexpression of IL-6 in the hippocampus and mitigate the impairments observed in BW, strength, and locomotion. Discussion: Future studies should evaluate other neurobiological characteristics, including changes in neural precursor cells and other cytokines, both pro- and anti-inflammatory.

Neonatal kaempferol exposure attenuates impact of cerebral palsy model on neuromotor development, cell proliferation, microglia activation, and antioxidant enzyme expression in the hippocampus of rats.

OBJECTIVES: This study aims to assess the effect of neonatal treatment with kaempferol on neuromotor development, proliferation of neural precursor cells, the microglia profile, and antioxidant enzyme gene expression in the hippocampus. METHODS: A rat model of cerebral palsy was established using perinatal anoxia and sensorimotor restriction of hindlimbs during infancy. Kaempferol (1 mg/ kg) was intraperitoneally administered during the neonatal period. RESULTS: Neonatal treatment with kaempferol reduces the impact of the cerebral palsy model on reflex ontogeny and on the maturation of physical features. Impairment of locomotor activity development and motor coordination was found to be attenuated by kaempferol treatment during the neonatal period in rats exposed to cerebral palsy. Neonatal treatment of kaempferol in cerebral palsy rats prevents a substantial reduction in the number of neural precursor cells in the dentate gyrus of the hippocampus, an activated microglia profile, and increased proliferation of microglia in the sub-granular zone and in the granular cell layer. Neonatal treatment with kaempferol increases gene expression of superoxide dismutase and catalase in the hippocampus of rats submitted to the cerebral palsy model. DISCUSSION: Kaempferol attenuates the impact of cerebral palsy on neuromotor behavior development, preventing altered hippocampal microglia activation and mitigating impaired cell proliferation in a neurogenic niche in these rats. Neonatal treatment with kaempferol also increases antioxidant defense gene expression in the hippocampus of rats submitted to the cerebral palsy model.

Resveratrol Reduces Neuroinflammation and Hippocampal Microglia Activation and Protects Against Impairment of Memory and Anxiety-Like Behavior in Experimental Cerebral Palsy.

Cerebral palsy (CP) is a neurodevelopmental disorder characterized by motor and postural impairments. However, early brain injury can promote deleterious effects on the hippocampus, impairing memory. This study aims to investigate the effects of resveratrol treatment on memory, anxiety-like behavior, and neuroinflammation markers in rats with CP. Male Wistar rats were subjected to perinatal anoxia (P0-P1) and sensory-motor restriction (P2-P28). They were treated with resveratrol (10 mg/kg, 0.1 ml/100 g) or saline from P3-P21, being divided into four experimental groups: CS (n = 15), CR (n = 15), CPS (n = 15), and CPR (n = 15). They were evaluated in the tests of novel object recognition (NORT), T-Maze, Light-Dark Box (LDB), and Elevated Plus Maze (EPM). Compared to the CS group, the CPS group has demonstrated a reduced discrimination index on the NORT (p < 0.0001) and alternation on the T-Maze (p < 0.01). In addition, the CPS group showed an increase in permanence time on the dark side in LDB (p < 0.0001) and on the close arms of the EPM (p < 0.001). The CPR group demonstrated an increase in the object discrimination index (p < 0.001), on the alternation (p < 0.001), on the permanence time on the light side (p < 0.0001), and on the open arms (p < 0.001). The CPR group showed a reduction in gene expression of IL-6 (p = 0.0175) and TNF-α (p = 0.0007) and an increase in Creb-1 levels (p = 0.0020). The CPS group showed an increase in the activated microglia and a reduction in cell proliferation in the hippocampus, while CPR animals showed a reduction of activated microglia and an increase in cell proliferation. These results demonstrate promising effects of resveratrol in cerebral palsy behavior impairment through reduced neuroinflammation in the hippocampus.

Polyphenols and Neurodegenerative Diseases: Potential Effects and Mechanisms of Neuroprotection.

The increase in people's longevity has, consequently, led to more brain involvement and neurodegenerative diseases, which can become complicated and lead to chronic degenerative diseases, thereby presenting greater public health problems. Medicinal plants have been used since ancient times and contain high concentrations of molecules, including polyphenols. It has been proven that polyphenols, which are present in various natural sources can provide curative effects against various diseases and brain disorders through neuroprotective effects. These neuroprotective effects are mainly attributed to their ability to cross the blood-brain barrier, eliminate reactive oxygen species, and cause the chelation of metal ions. Polyphenols increase the concentration of neurotrophic factors and bind directly to the membrane receptors of these neurotrophic factors, to modulate and activate the signaling cascades that allow the plasticity, survival, proliferation, and growth of neuronal cells, thereby allowing for better learning, memory, and cognition. Moreover, polyphenols have no serious adverse side effects resulting from their consumption.

Motor deficits are associated with increased glial cell activation in the hypothalamus and cerebellum of young rats subjected to cerebral palsy.

Cerebral palsy (CP) is a syndrome characterized by a wide range of sensory and motor damage, associated with behavioral and cognitive deficits. The aim of the present study was to investigate the potential of a model of CP using a combination of perinatal anoxia and sensorimotor restriction of hind paws to replicate motor, behavioral and neural deficits. A total of 30 of male Wistar rats were divided into Control (C, n = 15), and CP (CP, n = 15) groups. The potential of the CP model was assessed by evaluating food intake, the behavioral satiety sequence, performance on the CatWalk and parallel bars, muscle strength, and locomotor activity. The weight of the encephalon, soleus, and extensor digitorum longus (EDL) muscles, and the activation of glial cells (microglia and astrocytes) were also measured. The CP animals showed delayed satiety, impaired locomotion on the CatWalk and open field test, reduced muscle strength, and reduced motor coordination. CP also reduced the weight of the soleus and muscles, brain weight, liver weight, and quantity of fat in various parts of the body. There was also found to be an increase in astrocyte and microglia activation in the cerebellum and hypothalamus (arcuate nucleus, ARC) of animals subjected to CP.

Dietary flavonoid kaempferol reduces obesity-associated hypothalamic microglia activation and promotes body weight loss in mice with obesity.

BACKGROUND: Obesity results from an unbalance in the ingested and burned calories. Energy balance (EB) is critically regulated by the hypothalamic arcuate nucleus (ARC) by promoting appetite or anorectic actions. Hypothalamic inflammation, driven by high activation of the microglia, has been reported as a key mechanism involved in the development of diet-induced obesity. Kaempferol (KF), a flavonoid-type polyphenol present in a large number of fruits and vegetables, was shown to regulate both energy metabolism and inflammation. OBJECTIVES: In this work, we studied the effects of both the central and peripheral treatment with KF on hypothalamic inflammation and EB regulation in mice with obesity. METHODS: Obese adult mice were chronically (40 days) treated with KF (0.5 mg/kg/day, intraperitoneally). During the treatment, body weight, food intake (FI), feed efficiency (FE), glucose tolerance, and insulin sensitivity were determined. Analysis of microglia activation in the ARC of the hypothalamus at the end of the treatment was also performed. Body weight, FI, and FE changes were also evaluated in response to 5µg KF, centrally administrated. RESULTS: Chronic administration of KF decreased ∼43% of the density, and ∼30% of the ratio, of activated microglia in the arcuate nucleus. These changes were accompanied by body weight loss, decreased FE, reduced fasting blood glucose, and a tendency to improve insulin sensitivity. Finally, acute central administration of KF reproduced the effects on EB triggered by peripheral administration. CONCLUSION: These findings suggest that KF might fight obesity by regulating central processes related to EB regulation and hypothalamic inflammation.

Effects of the Treatment with Flavonoids on Metabolic Syndrome Components in Humans: A Systematic Review Focusing on Mechanisms of Action.

Diets high in bioactive compounds, such as polyphenols, have been used to mitigate metabolic syndrome (MetS). Polyphenols are a large group of naturally occurring bioactive compounds, classified into two main classes: non-flavonoids and flavonoids. Flavonoids are distributed in foods, such as fruits, vegetables, tea, red wine, and cocoa. Studies have already demonstrated the benefits of flavonoids on the cardiovascular and nervous systems, as well as cancer cells. The present review summarizes the results of clinical studies that evaluated the effects of flavonoids on the components of the MetS and associated complications when offered as supplements over the long term. The results show that flavonoids can significantly modulate several metabolic parameters, such as lipid profile, blood pressure, and blood glucose. Only theaflavin and catechin were unable to affect metabolic parameters. Moreover, only body weight and body mass index were unaltered. Thus, the evidence presented in this systematic review offers bases in support of a flavonoid supplementation, held for at least 3 weeks, as a strategy to improve several metabolic parameters and, consequently, reduce the risk of diseases associated with MetS. This fact becomes stronger due to the rare side effects reported with flavonoids.

The 5-HT1A receptor agonist, 8-OH-DPAT, attenuates long-lasting pain in imiquimod-induced psoriasis in mice.

Psoriasis pain is a common symptom underestimated and rarely evaluated in psoriasis clinical trials. This work aimed to investigate whether the development of secondary chronic allodynia and hyperalgesia in the imiquimod (IMQ)-induced psoriasis mice model could be modulated by anti-inflammatory agents and compound 48/80 (C48/80) and to determine whether the activation of 5-HT1A receptor modulates these nociceptive behaviours. C57BL/6 male mice were treated with 5% IMQ for 7 days. The paw withdrawal responses to von Frey filaments (10 and 250 mN) were used to assess the allodynia and hyperalgesia. Nociceptive behaviours were also evaluated using ketorolac 15 mg/kg s.c., adalimumab 10 mg/kg s.c. and C48/80 10 mg/kg i.p. Then, the serum serotonin and the impact of 8-OH-DPAT (1 mg/kg s.c), a 5-HT1A receptor agonist, on long-lasting pain were examined. Mice receiving IMQ showed enhanced nociception, which decreased with all tested compounds. The serum serotonin in the IMQ group showed a significant decrease (947.042 ng/ml) regarding the control group (1143.68 ng/ml). The pretreatment with 8-OH-DPAT alleviated pain-related behaviours. These results suggest that the long-lasting pain resulting from psoriasis inflammation is also associated with the serotonergic system. The 5-HT1A receptor should be further explored as a potential therapeutic target for psoriasis pain modulation.

A systematic review of neurogenesis in animal models of early brain damage: Implications for cerebral palsy.

Brain damage during early life is the main factor in the development of cerebral palsy (CP), which is one of the leading neurodevelopmental disorders in childhood. Few studies, however, have focused on the mechanisms of cell proliferation, migration, and differentiation in the brain of individuals with CP. We thus conducted a systematic review of preclinical evidence of structural neurogenesis in early brain damage and the underlying mechanisms involved in the pathogenesis of CP. Studies were obtained from Embase, Pubmed, Scopus, and Web of Science. After screening 2329 studies, 29 studies, covering a total of 751 animals, were included. Prenatal models based on oxygen deprivation, inflammatory response and infection, postnatal models based on oxygen deprivation or hypoxic-ischemia, and intraventricular hemorrhage models showed varying neurogenesis responses according to the nature of the brain damage, the time period during which the brain injury occurred, proliferative capacity, pattern of migration, and differentiation profile in neurogenic niches. Results mainly from rodent studies suggest that prenatal brain damage impacts neurogenesis and curbs generation of neural stem cells, while postnatal models show increased proliferation of neural precursor cells, improper migration, and reduced survival of new neurons.

Melatonin Decreases Circulating Levels of Galectin-3 and Cytokines, Motor Activity, and Anxiety Following Acute Global Cerebral Ischemia in Male Rats.

BACKGROUND: Global cerebral ischemia (GCI) elicits damages to cerebral structures, learning dysfunction, memory impairments, hyperactivity, and anxiety. Circulating levels of galectin-3 (Gal-3) are associated with patient severity and outcome. AIM: To report circulating levels of Gal-3, and cytokines (TNF-α, IL-6, IL-10) in the initial hours (acute) following GCI in a four-vessel occlusion (4-VO) rat model and the effect of melatonin treatment. METHODS: 4-VO model was used to produce GCI using male Sprague-Dawley rats. Groups were: Sham-Veh, Sham-Mel, Isch-Veh and Isch-Mel. Melatonin was administered 30 min after carotid clamp removal. Gal-3 and cytokines levels were measured at 0, 30 min, 6 h and 24 h after the end of cerebral flow interruption using ELISA kits. Motor activity and anxiety were measured using open-field test. RESULTS: Acute GCI (AGCI) followed by reperfusion decreased serum concentrations of TNF-α and increased IL-6 levels 24 h after ischemia, whereas melatonin reduced significantly the concentrations of these cytokines. In all groups IL-10 was higher 30 min and negligible at other times. Circulating levels of Gal-3 were reduced 30 min after ischemia/reperfusion. In the Isch-Mel group the neuroprotective effect generated a reduction in circulating Gal-3 at 6 and 24 h after AGCI, compared with all the groups. Motor activity was increased due to ischemic reperfusion, but acute melatonin treatment reduced locomotion, similar to the control group. Anxiety was reduced in the melatonin group. CONCLUSIONS: Melatonin treatment following AGCI reduces pro-inflammatory factors, Gal-3, motility, and anxiety, therefore it should be considered as supplementary treatment following ischemic stroke.

Long-term activation of hippocampal glial cells and altered emotional behavior in male and female adult rats after different neonatal stressors.

Early life stress increases the risk of developing psychiatric diseases in adulthood. Severe neonatal infections can also contribute to the development of affective illnesses. Stress and infections both trigger the immediate activation of the neuroimmune system. We compared the long-term effects of neonatal single or combined stress-immune challenges on emotional behavior and glial cell responses in the hippocampus. Male and female Sprague Dawley rats were randomly allocated across four conditions: (1) control + vehicle; (2) maternal separation (MS, 3 h/day on postnatal days [PN] 1-14) + vehicle; (3) control + lipopolysaccharide (LPS, 0.5. mg/kg, PN14); (4) MS + LPS. The rats' behaviors were analyzed from PN120 in males and from PN150 in diestrous females. LPS, but not MS, increased anxiety-like behavior in male rats; however, in females, it increased with both challenges. Depressive-like behavior increased after MS-but not LPS-in males and females. Combined stressors increased depressive-like behavior in both sexes. All stressors promoted microglial activation in CA3 and hilus in males and females. MS and LPS increased the astrocytic density within the male hilus, but LPS only increased it in CA3. MS prevented the rise in astrocytic density with LPS. In females, MS reduced the astrocytic population of the hilus and CA3 areas. Taken together, the behavioral and glial cell responses to early life challenges are sex-dependent and cell-type specific. This suggests a sexual dimorphism in the nature of the adverse event faced. These results have implications for understanding the emergence of psychiatric illnesses.

Prenatal immobilization stress and postnatal maternal separation cause differential neuroendocrine responses to fasting stress in adult male rats.

Prenatal immobilization stress (PNS) and postnatal maternal separation (MS180) are two widely used rodent models of early-life stress (ELS) that affect the hypothalamus-pituitary-adrenal (HPA) axis, cause behavioral alterations, and affect glucose tolerance in adults. We compared anxiety-like behavior, coping strategies, and HPA axis activity in PNS and MS180 adult (4-month-old) male rats and assessed their glucose tolerance and HPA axis response after mild fasting stress. Both PNS and MS180 induced a passive coping strategy in the forced swimming test, without affecting anxiety-like behavior in the elevated plus-maze. Moreover, both PNS and MS180 increased the hypothalamic corticotropin-releasing hormone expression; however, only MS180 increased the circulating corticosterone levels. Both early life stressors increased fasting glucose levels and this effect was significantly higher in PNS rats. MS180 rats showed impaired glucose tolerance 120 min after intravenous glucose administration, whereas PNS rats displayed an efficient homeostatic response. Moreover, MS180 rats showed higher circulating corticosteroid levels in response to fasting stress (overnight fasting, 12 hr), which were restored after glucose administration. In conclusion, early exposure to postnatal MS180, unlike PNS, increases the HPA axis response to moderate fasting stress, indicating a differential perception of fasting as a stressor in these two ELS models.

Early-life stress increases granule cell density in the cerebellum of male rats.

In rodents, daily maternal separation for 180 min (MS180) during the first weeks of life affects hippocampal granule cell neurogenesis. Development of the cerebellum granule cell layer also occurs during the first weeks of life. However, whether MS180 affects this neurogenic niche remains unknown. To study this, we evaluated the immediate and long term effect of MS180 on granule cell survival within the cerebellum. Pups were injected twice at an 8-hour interval at PND (postnatal day) 5 with bromodeoxyuridine (BrdU, 50 mg/kg) and were sacrificed ten days later (PND15) or allowed to survive into adulthood (PND60). We observed a higher density of BrdU-positive cells in the cerebellar foliae (p < 0.05) of MS180 pups at PND15. This increase was also observed in both, cerebellar foliae and fissures (p < 0.05) at PND60. Triple immunofluorescence staining against BrdU, NeuN (a marker of mature neurons), and GFAP (a marker of mature glia), revealed that BrdU + cells labeled at PND5 co-localized with NeuN but not with GFAP, indicating that they were mature neurons. MS180 did not affect baseline corticosterone levels at PND15 but significantly increased adult corticosterone levels (p < 0.05). In conclusion, MS180 increased cell survival in the granular layer of cerebellar foliae and fissures and resulted in further integration of the cells into adult circuits. These effects occurred without early alterations of basal corticosterone by MS180. Our results indicate that early-life stress induces a permanent increase in cerebellar neurogenesis.

Tau Phosphorylation in Female Neurodegeneration: Role of Estrogens, Progesterone, and Prolactin.

Sex differences are important to consider when studying different psychiatric, neurodevelopmental, and neurodegenerative disorders, including Alzheimer's disease (AD). These disorders can be affected by dimorphic changes in the central nervous system and be influenced by sex-specific hormones and neuroactive steroids. In fact, AD is more prevalent in women than in men. One of the main characteristics of AD is the formation of neurofibrillary tangles, composed of the phosphoprotein Tau, and neuronal loss in specific brain regions. The scope of this work is to review the existing evidence on how a set of hormones (estrogen, progesterone, and prolactin) affect tau phosphorylation in the brain of females under both physiological and pathological conditions.

Global Effects of Early Life Stress on Neurons and Glial Cells.

Early life stress is considered a risk factor for the development of many diseases in both adolescence and adulthood. It has been reported that chronic stress (for instance, due to maternal separation during breast feeding), causes damage to the central nervous system at the level of neurons and glial cells, which are reflected in behavioral disturbances and susceptibility to the development of primarily emotional psychopathology. The aim of this review is to identify the overall state of the scientific literature that relates the information about the consequences of early life stress, contextualizing the mechanisms that may be altered, the behavioral consequences that have been studied and the possible dimorphic effects and its causes. At the end a short overview of pharmacological treatments that have been proposed to reduce the behavioral and neuroendocrine consequences caused by early life stress is presented. This review pretends to integrate general but relevant information based primarily on studies in animal models, which allow the experimental approach and the study of the mechanisms involved. A series of questions remains for reflection and surely will be answered in the near future.

Forced swimming-induced oxytocin release into blood and brain: Effects of adrenalectomy and corticosterone treatment.

The oxytocin (OXT) system is functionally linked to the HPA axis in a reciprocal and complex manner. Certain stressors are known to cause the simultaneous release of OXT and adrenocorticotrophic hormone (ACTH) followed by corticosterone (CORT). Furthermore, brain OXT attenuates ACTH and CORT responses. Although there are some indications of CORT influencing OXT neurotransmission, specific effects of CORT on neurohypophyseal or intra-hypothalamic release of OXT have not been studied in detail. In the present set of experiments, adult male rats were adrenalectomized (ADX) or sham-operated and fitted with a jugular vein catheter and/or microdialysis probe targeting the hypothalamic paraventricular nucleus (PVN). Blood samples and dialysates were collected before and after forced swimming (FS) and analyzed for CORT, ACTH and AVP concentrations (in plasma) and OXT concentrations (in plasma and dialysates). Experimental treatments included acute infusion of CORT (70 or 175µg/kg i.v.) 5min prior to FS, or subcutaneous placement of 40% CORT pellets resulting in stable CORT levels in the normal basal range. Although ADX did not alter basal OXT concentrations either in plasma or in microdialysates from the PVN, it did cause an exaggerated peripheral secretion of OXT and a blunted intra-PVN release of OXT in response to FS. CORT pellets did not influence either of these ADX-induced effects, while acute infusion of 175µg/kg CORT rescued the stress-induced rise in OXT release within the PVN and modestly increased peripheral OXT secretion. In conclusion, these results indicate that CORT regulates both peripheral and intracerebral OXT release, but in an independent manner. Whereas the peripheral secretion of OXT occurs simultaneously to HPA axis activation in response to FS and is modestly influenced by CORT, HPA axis activation and circulating CORT strongly contribute to the stress-induced stimulation of OXT release within the PVN.

Early Life Stress Activates Glial Cells in the Hippocampus but Attenuates Cytokine Secretion in Response to an Immune Challenge in Rat Pups.

OBJECTIVE: Early life stress (ELS) increases the vulnerability to developing psychopathological disorders in adulthood that are accompanied by brain inflammatory processes. However, it is not known how a combined double hit (stress and immune) at an early age affects the response of the neuroimmune system. Here we investigated the effect of periodic maternal separation (MS) followed by administration of lipopolysaccharide (LPS) on glial cells in the CA3 region and hilus of the hippocampus and on cytokine release on postnatal day (PN) 15. METHODS: Male rat pups were subjected to MS (3 h/day, PN1-14). MS and control pups received a single LPS injection (1 mg/kg of body weight) on PN14. They were subjected to an open field test 1 h later. The pups were sacrificed 90 min after LPS injection (PN14) or on PN15 for cytokine or immunohistological analyses, respectively. RESULTS: LPS reduced the locomotion and induced high corticosterone levels in treated pups. MS or LPS reduced microglial density and activated microglial cells in the hippocampal CA3 and hilus regions. Microglial activation was highest in MS-LPS pups. The astrocyte density was mildly reduced by MS or LPS in the CA3 region and hilus, but the reduction was maximal in MS-LPS pups. LPS increased the secretion of plasmatic interleukin (IL)-1ß, tumor necrosis factor-α, and IL-6, and of hippocampal IL-1ß protein, but these were attenuated in MS-LPS pups. CONCLUSION: Although MS and LPS activate neuroimmune cells, stress attenuates the hippocampal and peripheral cytokine response to LPS through an as-yet unidentified adaptive mechanism. These results provide information regarding the neurobiology of stress and inflammation.

Actions of Prolactin in the Brain: From Physiological Adaptations to Stress and Neurogenesis to Psychopathology.

Prolactin (PRL) is one of the most versatile hormones known. It is considered an adaptive hormone due to the key roles it plays in the modulation of the stress response and during pregnancy and lactation. Within the brain, PRL acts as a neuropeptide to promote physiological responses related to reproduction, stress adaptation, neurogenesis, and neuroprotection. The action of PRL on the nervous system contributes to the wide array of changes that occur in the female brain during pregnancy and result in the attenuation of the hypothalamic-pituitary-adrenal axis. Together, all these changes promote behavioral and physiological adaptations of the new mother to enable reproductive success. Brain adaptations driven by PRL are also important for the regulation of maternal emotionality and well-being. PRL also affects the male brain during the stress response, but its effects have been less studied. PRL regulates neurogenesis both in the subventricular zone and in the hippocampus. Therefore, alterations in the PRL system due to stress or exposure to substances that reduce neurogenesis or other conditions, could contribute to maladaptive responses and pathological behavioral outcomes. Here, we review the PRL system and the role it plays in the modulation of stress response and emotion regulation. We discuss the effects of PRL on neurogenesis and neuroprotection, the putative neuronal mechanisms underlying these effects, and their contribution to the onset of psychopathological states such as depression.

Maternal separation activates microglial cells and induces an inflammatory response in the hippocampus of male rat pups, independently of hypothalamic and peripheral cytokine levels.

Adult animals subjected to chronic stress show an inflammatory response in the hippocampus which has been related to cognitive dysfunction and psychopathology. However the immediate consequences of early life stress on hippocampal glial cells have not been studied. Here we analyzed the effects of maternal separation (MS) on astrocyte and microglial cell morphology in the hippocampal hilus, compared the expression of cytokines in the hippocampus and hypothalamus, and the peripheral response of cytokines, on postnatal day (PD) 15. Male rat pups of MS (3h/day, PD1-PD14) and Control (CONT) pups showed similar microglial cell densities in the hilus, but MS pups presented more activated microglia. MS decreased astrocyte density and the number of processes in the hilus. Cytokine mRNA expression (qPCR) was analyzed in MS and CONT groups, sacrificed (i) under basal (B) conditions or (ii) after a single stress event (SS) at PN15. In hippocampal extracts, MS increased IL-1ß mRNA, under B and SS conditions while IL-6 and TNF-α did not change. In hypothalamic tissue, MS increased TNF-α and IL-6 mRNA, but not IL-1b, after SS. Peripheral concentrations of IL-1ß were decreased under B and SS conditions in MS; IL-6 concentration increased after SS in MS pups, and TNF-α concentration was unchanged. In conclusion, MS activates microglial cells and decreases astrocyte density in the hippocampus. A differential cytokine expression is observed in the hippocampus and the hypothalamus after MS, and after SS. Also, MS triggers an independent response of peripheral cytokines. These specific responses together could contribute to decrease hippocampal neurogenesis and alter the neuroendocrine axis.