Prefrontal Cortex Of Adult Rats Research Articles

Prenatal protein malnutrition decreases neuron numbers in the parahippocampal region but not prefrontal cortex in adult rats

ABSTRACT Objective Prenatal protein malnutrition produces anatomical and functional changes in the developing brain that persist despite immediate postnatal nutritional rehabilitation. Brain networks of prenatally malnourished animals show diminished activation of prefrontal areas and an increased activation of hippocampal regions during an attentional task [1]. While a reduction in cell number has been documented in hippocampal subfield CA1, nothing is known about changes in neuron numbers in the prefrontal or parahippocampal cortices. Methods In the present study, we used unbiased stereology to investigate the effect of prenatal protein malnutrition on the neuron numbers in the medial prefrontal cortex and the cortices of the parahippocampal region that comprise the larger functional network. Results Results show that prenatal protein malnutrition does not cause changes in the neuronal population in the medial prefrontal cortex of adult rats, indicating that the decrease in functional activation during attentional tasks is not due to a reduction in the number of neurons. Results also show that prenatal protein malnutrition is associated with a reduction in neuron numbers in specific parahippocampal subregions: the medial entorhinal cortex and presubiculum. Discussion The affected regions along with CA1 comprise a tightly interconnected circuit, suggesting that prenatal malnutrition confers a vulnerability to specific hippocampal circuits. These findings are consistent with the idea that prenatal protein malnutrition produces a reorganization of structural and functional networks, which may underlie observed alterations in attentional processes and capabilities.

Adolescent stress differentially modifies dopamine and norepinephrine release in the medial prefrontal cortex of adult rats

Adolescent stress (AS) has been associated with higher vulnerability to psychiatric disorders such as schizophrenia, depression, or drug dependence. Moreover, the alteration of brain catecholamine (CAT) transmission in the medial prefrontal cortex (mPFC) has been found to play a major role in the etiology of psychiatric disturbances. We investigated the effect of adolescent stress on CAT transmission in the mPFC of freely moving adult rats because of the importance of this area in the etiology of psychiatric disorders, and because CAT transmission is the target of a relevant group of drugs used in the therapy of depression and psychosis. We assessed basal dopamine (DA) and norepinephrine (NE) extracellular concentrations (output) by brain microdialysis in in the mPFC of adult rats that were exposed to chronic mild stress in adolescence. To ascertain the role of an altered release or reuptake, we stimulated DA and NE output by administering either different doses of amphetamine (0.5 and 1.0 mg / kg s.c.), which by a complex mechanism determines a dose dependent increase in the CAT output, or reboxetine (10 mg/kg i.p.), a selective NE reuptake inhibitor. The results showed the following: (i) basal DA output in AS rats was lower than in controls, while no difference in basal NE output was observed; (ii) amphetamine, dose dependently, stimulated DA and NE output to a greater extent in AS rats than in controls; (iii) reboxetine stimulated NE output to a greater extent in AS rats than in controls, while no difference in stimulated DA output was observed between the two groups. These results show that AS determines enduring effects on DA and NE transmission in the mPFC and might lead to the occurrence of psychiatric disorders or increase the vulnerability to drug addiction.

Protective effect of melatonin against methamphetamine-induced attention deficits through miR-181/SIRT1 axis in the prefrontal cortex.

Methamphetamine (METH) is an addictive psychostimulant with deleterious effects on the central nervous system. Chronic use of METH in high doses impairs cognition, attention and executive functions, but the underlying mechanisms are still unclear. Sirtuin 1 (SIRT1) is a post-translational regulator that is downregulated following METH neurotoxicity. Melatonin is a neuroprotective hormone that enhances mitochondrial metabolism. Here, we evaluated the effect of melatonin on METH-induced attention deficits disorder and the involvement of the miR-181/SIRT1 axis in melatonin neuroprotection. METH at a dose of 5mg/kg was injected for 21 consecutive days. The animals were assigned to receive either melatonin or the vehicle after METH injections. Attention levels were evaluated with abject-based attention test. In the prefrontal cortex, the expression levels of miR-181a-5p, SIRT1, p53 and CCAR2, as well as the mtDNA copy numbers were evaluated using qRT-PCR and western blotting. The outcomes revealed that melatonin treatment following METH injections improved METH-induced attention deficits. METH toxicity can be associated with changes in the miR-181/SIRT1 axis, elevated levels of p53 and COXII, and decreased levels of mtDNA in the prefrontal cortex of adult rats. Interestingly, administration of melatonin can improve the expression of these molecules and reduces the toxic effects of METH. Melatonin ameliorated the neurotoxicity of METH in the prefrontal cortex and the miR-181/SIRT1 axis is involve in the protective effects of melatonin. However, melatonin can be potentially administrated to improve attention impairment in METH use disorders.

Prenatal MAM exposure raises kynurenic acid levels in the prefrontal cortex of adult rats.

Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. Pregnant Sprague-Dawley rats were treated with MAM (22mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.

Social interaction following prepubertal stress alters prefrontal gene expression associated with cell signalling and oligodendrocytes

Early-life adversity is associated with an increased risk of psychopathology, including mood disorders, later in life. Early-life stress affects several physiological systems, however, the exact mechanisms underlying pathological risk are not fully understood. This knowledge is crucial in developing appropriate therapeutic interventions. The prepubertal period is documented as a key developmental period for the maturation of the prefrontal cortex (PFC), a brain region involved in higher cognitive functions, including social function. In this study, we performed RNA sequencing on the PFC of adult rats who had experienced prepubertal stress (PPS) and controls to investigate the genome-wide consequences of this stress. PPS alters social behaviour in adulthood, therefore we also performed RNA sequencing on PPS and control rats following a social interaction test to determine social activity-dependent gene changes. At a baseline state (1 week following a social interaction test), no genes were differentially expressed in the PPS group. However, 1603 genes were differentially expressed in PPS rats compared to controls following a social interaction. These genes were enriched in biological pathways associated with cell signalling and axon myelination dynamics. Cell enrichment analysis showed these genes were associated with oligodendrocytes, and a comparison with an existing early-life stress sequencing dataset showed that pathways linked to oligodendrocyte morphology are impacted in a range of models of early-life stress in rodents. In conclusion, we identify pathways, including those involved in axon myelination, that are differentially activated in the adult in response to social stimulation following PPS. These differential responses may contribute to vulnerability to psychiatric pathology.

The impact of early life maternal deprivation on the perineuronal nets in the prefrontal cortex and hippocampus of young adult rats.

Early life stress negatively impacts brain development and affects structure and function of parvalbumin immunopositive (PV+) inhibitory neurons. Main regulators of PV+ interneurons activity and plasticity are perineuronal nets (PNNs), an extracellular matrix formation that enwraps PV+ interneurons mainly in the neocortex and hippocampus. To experimentally address the impact of early life stress on the PNNs and PV+ interneurons in the medial prefrontal cortex and dorsal hippocampus in rats, we employed a 24h maternal deprivation protocol. We show that maternal deprivation in the medial prefrontal cortex of adult rats caused a decrease in density of overall PNNs and PNNs that enwrap PV+ interneurons in the rostral cingulate cortex. Furthermore, a staining intensity decrease of overall PNNs and PNN+/PV+ cells was found in the prelimbic cortex. Finally, a decrease in both intensity and density of overall PNNs and PNNs surrounding PV+ cells was observed in the infralimbic cortex, together with increase in the intensity of VGAT inhibitory puncta. Surprisingly, maternal deprivation did not cause any changes in the density of PV+ interneurons in the mPFC, neither had it affected PNNs and PV+ interneurons in the hippocampus. Taken together, our findings indicate that PNNs, specifically the ones enwrapping PV+ interneurons in the medial prefrontal cortex, are affected by early life stress.

Brief postnatal exposure to bisphenol A affects apoptosis and gene expression in the medial prefrontal cortex and social behavior in rats with sex specificity

Bisphenol A (BPA) is an endocrine disruptor found in polycarbonate plastics and exposure in humans is nearly ubiquitous and it has widespread effects on cognitive, emotional, and reproductive behaviors in both humans and animal models. In our laboratory we previously found that perinatal BPA exposure results in a higher number of neurons in the adult male rat prefrontal cortex (PFC) and less play in adolescents of both sexes. Here we examine changes in the rate of postnatal apoptosis in the rat prefrontal cortex and its timing with brief BPA exposure. Because an increased number of neurons in the PFC is a characteristic of a subtype of autism spectrum disorder, we tested social preference following brief BPA exposure and also expression of a small group of genes. Males and females were exposed to BPA from postnatal days (P) 6 through 8 or from P10 through 12. Both exposures significantly decreased indicators of cell death in the developing medial prefrontal cortex in male subjects only. Additionally, males exposed to BPA from P6 – 8 showed decreased social preference and decreased cortical expression of Shank3 and Homer1, two synaptic scaffolding genes that have been implicated in social deficits. There were no significant effects of BPA in the female subjects. These results draw attention to the negative consequences following brief exposure to BPA during early development.

Age-Specific Features of the Levels of Reference Proteins Actin, Tubulin, and GAPDH in Different Organs of Male Wistar Rats.

Western blot analysis is used for evaluation of the level of proteins production in organs and tissues, and housekeeping proteins GAPDH, actin, and tubulin are usually used as the reference proteins. The signal of the target protein is normalized to the corresponding signal of the reference protein. The data on the intensity of actin, tubulin, and GAPDH synthesis are fragmentary: their expression differs in different organs and can vary depending on age, which is often not taken into account in experimental studies. We studied the features of the production of reference proteins in the liver, heart, brain, and lungs of newborn, prepubertal, and adult male Wistar rats. Age-related differences in the expression of β-actin, β-tubulin, and GAPDH in the myocardium and dorsal prefrontal cortex were revealed. GAPDH expression in the dorsal prefrontal cortex in adult rats was significantly higher than in prepubertal rats; GAPDH expression in the myocardium of adult rats was significantly higher than in newborns. The level of actin in the dorsal prefrontal cortex in newborn rats was significantly higher than in prepubertal and adult rats. In the liver and lungs, the expression of actin, tubulin, and GAPDH did not differ in newborn, prepubertal, and adult rats. When choosing the reference protein for Western blotting, animals age and the studied organ should be taken into account.

Melatonin Attenuates Methotrexate-Induced Reduction of Antioxidant Activity Related to Decreases of Neurogenesis in Adult Rat Hippocampus and Prefrontal Cortex.

Previous studies have revealed that the side effects of anticancer drugs induce a decrease of neurogenesis. Methotrexate (MTX), one of anticancer drugs, can induce lipid peroxidation as an indicator of oxidative stress in the brain. Melatonin has been presented as an antioxidant that can prevent oxidative stress-induced neuronal damage via the activation of antioxidant enzymes associated with the increase of neurogenesis. The aims of the present study are to examine the neuroprotective effect of melatonin on the neurotoxicity of MTX on neurogenesis and the changes of protein expression and antioxidant enzyme levels in adult rat hippocampus and prefrontal cortex (PFC). Male Sprague-Dawley rats were assigned into four groups: vehicle, MTX, melatonin, and melatonin+MTX groups. The vehicle group received saline solution and 10% ethanol solution, whereas the experimental groups received MTX (75 mg/kg, i.v.) and melatonin (8 mg/kg, i.p.) treatments. After the animal examination, the brains were removed for p21 immunofluorescence staining. The hippocampus and PFC were harvested for Western blot analysis and biochemical assessments of malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD). The immunofluorescence result showed that coadministration with melatonin diminished p21-positive cells in the hippocampal dentate gyrus, indicating a decrease of cell cycle arrest. Melatonin reduced the levels of MDA and prevented the decline of antioxidant enzyme activities in rats receiving MTX. In the melatonin+MTX group, the protein expression results showed that melatonin treatment significantly upregulated synaptic plasticity and an immature neuron marker through enhancing brain derived neurotrophic factor (BDNF) and doublecortin (DCX), respectively. Moreover, melatonin ameliorated the antioxidant defense system by improving the nuclear factor erythroid 2-related factor 2 (Nrf2) in rats receiving MTX. These findings suggested that the effects of melatonin can ameliorate MTX toxicity by several mechanisms, including an increase of endogenous antioxidants and neurogenesis in adult rat hippocampus and PFC.

Bidirectional Effect of Repeated Exposure to Extremely Low-Frequency Electromagnetic Field (50 Hz) of 1 and 7 mT on Oxidative/Antioxidative Status in Rat's Brain: The Prediction for the Vulnerability to Diseases.

Studies reported evidence for opposite effects of extremely low-frequency electromagnetic field (EMF): harmful, including the oxidative stress induction, and beneficial, such as the activation of antioxidant defense. People's exposure to EMF is often repeated or prolonged, and it is important to consider the cumulative effect of such kind of exposure on the organism. If changes evoked by repeated exposure to EMF are permanent, responsiveness to other stress factors can be modified. The aims of our study were (1) to evaluate changes in the levels of oxidative stress and antioxidant defense markers in the prefrontal cortex of adult rats after repeated exposure to 1 and 7 mT EMF and (2) to assess whether repeated EMF exposure can modify oxidative/antioxidative status in response to other stress factors. Rats were exposed to EMF 1 h/day for 7 days, one, twice, or three times. After each exposure, 8-isoprostanes, protein carbonyl groups, and the total antioxidant capacity were assessed. Part of the animals, after EMF treatment, was exposed to another stress factor—open field. Results showed that repeated exposure changed the oxidative/antioxidative status depending on the intensity of the EMF and the number of exposures. 1 mT EMF created weak changes in the oxidative status in the brain; however, 7 mT EMF moved the balance to a clearly higher level. The changes in the oxidative status after 1 mT EMF were enough to reduce, and after 7 mT EMF to intensify oxidative processes in response to the next stress. We concluded that the organism might adapt to “weak” EMF, while “strong” EMF exceeds the adaptive capacity of the organism and sensitizes it to subsequent stress, and thus may modulate vulnerability to diseases. Our results also provide new insights into the possible therapeutic properties of the magnetic field, as 1 mT EMF appears to have a potentially protective impact on the brain.

Single Prolonged Stress Reduces Intrinsic Excitability and Excitatory Synaptic Drive Onto Pyramidal Neurons in the Infralimbic Prefrontal Cortex of Adult Male Rats.

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and intrinsic excitability of pyramidal neurons in the rodent homolog of the vmPFC, the infralimbic cortex (IL), following exposure to single prolonged stress (SPS), a paradigm that mimics core symptoms of PTSD in rats. Rats were exposed to SPS and allowed 1 week of recovery, following which brain slices containing the PFC were prepared for whole-cell patch clamp recordings from layer V pyramidal neurons in the IL. Our results indicate that SPS reduces spontaneous excitatory synaptic drive to pyramidal neurons. In addition, SPS decreases the intrinsic membrane excitability of IL PFC pyramidal cells, as indicated by an increase in rheobase, decrease in input resistance, hyperpolarization of resting membrane potential, and a reduction in repetitive firing rate. Our results suggest that SPS causes a lasting reduction in PFC activity, supporting a body of evidence linking traumatic stress with prefrontal hypoactivity.

CE-123, a novel dopamine transporter inhibitor, attenuates locomotor hyperactivity and improves cognitive functions in rat model of fetal alcohol spectrum disorders

Perinatal alcohol exposure can lead to fetal alcohol spectrum disorders (FASD), usually first diagnosed in childhood, that are characterized by hyperactivity, impulsivity and learning and memory disability, among others. To test the hypothesis that dopamine signaling is one of the main factors underlying these impairments, a new atypical dopamine transporter (DAT) inhibitor, CE-123 (1, 3 or 10 mg/kg) was assessed for its potential to overcome the ethanol-induced behavioral effects in a rat model of FASD. In the present study, neonatal rats were exposed to alcohol intubations across the neonatal period (postnatal day (PND)4‐9, the third trimester equivalent of human gestation) and, after weaning, the animals (male rats) were assigned randomly to three groups. The first group was tested at PND21 (hyperactivity test). A second group was tested at PND45 (anxiety test), at PND47 (locomotor activity test), at PND49 (spatial cognitive test in the Barnes maze) and PND50 (reversal learning in the Barnes maze). The third group was tested at PND50 (dopamine receptor mRNA expression). Our results support the hypothesis that dopamine signaling is associated with FASD because the dopamine (D1, D2 and D5) receptor mRNA expression was altered in the striatum, hippocampus and prefrontal cortex in adult rats exposed to ethanol during neonatal period. CE-123 (3 and 10 mg/kg) inhibited the hyperactivity and ameliorated (10 mg/kg) the impairment of reversal learning in alcohol-exposed rats. Thus, these findings provide support that CE-123 may be a useful intervention for same of the deficits associated with neonatal ethanol exposure.

Chronic Treatment with a Phytosomal Preparation Containing Centella asiatica L. and Curcuma longa L. Affects Local Protein Synthesis by Modulating the BDNF-mTOR-S6 Pathway.

Brain derived neurotrophic factor (Bdnf) is the most diffuse neurotrophin in the central nervous system and it is crucial for the proper brain development and maintenance. Indeed, through the binding to its high affinity receptor TRKB and the activation of different intracellular cascades, it boosts cell survival, neurite growth and spine maturations mechanisms. Here, we evaluated if the chronic oral treatment for 10 days with a phytosomal preparation containing Centella asiatica L. and Curcuma longa L. could improve Bdnf levels in the prefrontal cortex of adult rats. Interestingly we found an increased expression of Bdnf with main effect of the treatment on the mTOR-S6 downstream signaling pathway. Accordingly, we found an increase in the expression of eukaryotic elongation factor (eEF2) with a shift towards the phosphorylated form thus increasing the transcription of Oligophrenin-1, a protein carrying the upstream Open Reading Frame (uORF) which reduction is paralleled by memory dysfunctions. These results show the ability of the phytosome to enhance mTOR-S6 regulated transcription and suggest the possibility to use this preparation in subjects with impairments in neuroplastic mechanisms, memory and cognitive abilities.

Prenatal THC exposure raises kynurenic acid levels in the prefrontal cortex of adult rats

Cannabis remains one of the most widely used illicit drugs during pregnancy. The main psychoactive component of marijuana (Δ9-tetrahydrocannabinol, THC) is correlated with untoward physiological effects in the offspring. Neurobehavioral and cognitive impairments have been reported in longitudinal studies on children and adolescents prenatally exposed to marijuana, and a link to psychiatric disorders has been proposed. Interestingly, the deleterious effects of prenatal cannabis use are similar to those observed in adult rats prenatally exposed to (L)-kynurenine, the direct bioprecursor of the neuroactive metabolite kynurenic acid (KYNA). We therefore investigated whether alterations in KYNA levels in the rat brain might play a role in the long-term consequences of prenatal cannabinoid exposure. Pregnant Wistar rats were treated daily with THC [5 mg/kg, p.o.] from gestational day (GD)5 through GD20. Using in vivo microdialysis in the medial prefrontal cortex, adult animals were then used to determine the extracellular levels of KYNA and glutamate. Compared to controls, extracellular basal KYNA levels were higher, and basal glutamate levels were lower, in prenatally THC-exposed rats. These rats also showed abnormal short-term memory. Following an additional acute challenge with a low dose of kynurenine (5 mg/kg i.p.) in adulthood, the increase in extracellular KYNA levels in the mPFC was more pronounced in in prenatally THC-exposed rats. These effects could be causally related to the cognitive dysfunction seen in prenatally THC-exposed rats. In the translational realm, these experiments raise the prospect of prevention of KYNA neosynthesis as a promising novel approach to combat some of the detrimental long-term effects of prenatal cannabis use.

Prenatal Protein Malnutrition Leads to Hemispheric Differences in the Extracellular Concentrations of Norepinephrine, Dopamine and Serotonin in the Medial Prefrontal Cortex of Adult Rats.

Exposure to prenatal protein malnutrition (PPM) leads to a reprogramming of the brain, altering executive functions involving the prefrontal cortex (PFC). In this study we used in vivo microdialysis to assess the effects of PPM on extracellular concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) bilaterally in the ventral portion of the medial prefrontal cortex (vmPFC; ventral prelimbic and infralimbic cortices) of adult Long-Evans rats. Female Long-Evans rats were fed either a low protein (6%) or adequate protein diet (25%) prior to mating and throughout pregnancy. At birth, all litters were culled and fostered to dams fed a 25% (adequate) protein diet. At 120 days of age, 2 mm microdialysis probes were placed into left and right vmPFC. Basal extracellular concentrations of NE, DA, and 5-HT were determined over a 1-h period using HPLC. In rats exposed to PPM there was a decrease in extracellular concentrations of NE and DA in the right vmPFC and an increase in the extracellular concentration of 5-HT in the left vmPFC compared to controls (prenatally malnourished: N = 10, well-nourished: N = 20). Assessment of the cerebral laterality of extracellular neurotransmitters in the vmPFC showed that prenatally malnourished animals had a significant shift in laterality from the right to the left hemisphere for NE and DA but not for serotonin. In a related study, these animals showed cognitive inflexibility in an attentional task. In animals in the current study, NE levels in the right vmPFC of well-nourished animals correlated positively with performance in an attention task, while 5-HT in the left vmPFC of well-nourished rats correlated negatively with performance. These data, in addition to previously published studies, suggest a long-term reprogramming of the vmPFC in rats exposed to PPM which may contribute to attention deficits observed in adult animals exposed to PPM.

Repeated fluoxetine treatment induces long-lasting neurotrophic changes in the medial prefrontal cortex of adult rats.

Fluoxetine (Flx), a selective serotonin reuptake inhibitor, is extensively used to treat mood and anxiety disorders. Previous animal studies have shown that early-life exposure to Flx results in long-lasting behavioral alterations and neuroplasticity in the hippocampus and cortex, which may persist into adulthood. It remains unclear whether repeated Flx treatment in normal adult animals can induce lasting neuroplasticity and behavioral alterations persisting long beyond the treatment period. In this study, young adult rats (about 9 weeks old) were treated with Flx (10 mg/kg body weight, twice daily) for 15 consecutive days, and the effects of Flx on medial prefrontal cortex (mPFC) neuroplasticity and mPFC-related behaviors were assessed 20 days after the last injection. It was observed that the mPFC of Flx-treated rats had significant increases in the number of 5-bromodeoxyuridine-positive (BrdU+) cells, dendritic complexity/spine density in layer II/III pyramidal neurons, and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) expression levels, as well as a significant decrease in the number of parvalbumin-positive (PV+) interneurons. The Flx-treated rats exhibited higher motivation to explore new environments, evidenced by a significantly increased number of entries into the novel arm in the Y-maze test. However, they did not show any significant changes in the anhedonia and anxiety levels measured by sucrose preference and elevated plus maze tests respectively. In conclusion, repeated Flx treatment, with the paradigm used, induces long-lasting neuroplastic changes in the mPFC of normal adult rats; such changes and related behavioral manifestations may persist up to 20 days after the last dose.

Short- and long-term alterations of FKBP5-GR and specific microRNAs in the prefrontal cortex and hippocampus of male rats induced by adolescent stress contribute to depression susceptibility

Maladaptation of the hypothalamic-pituitary-adrenal (HPA) axis is involved in susceptibility to depression. Glucocorticoid receptors (GRs) and the co-chaperone protein, FK506 binding protein 51 (FKBP5), play crucial roles in dysfunction of the HPA axis. Further, certain microRNAs (miRNAs), such as miR-124a and miR-18a, which could reduce GR protein expression, contribute to affective disorders, while miR-511 as a regulator of FKBP5 is involved in an increased risk of depression. However, the short-term and persistent impacts of adolescent stress on miR-124a, miR-18a, and miR-511 expressions in the brain are unknown. Using depression models of chronic unpredictable mild stress (CUMS) or dexamethasone administration of adolescent rats, the authors of the present study probed the depressive-like behaviors, GR and FKBP5 expressions, and miR-124a, miR-18a, and miR-511 expressions in the prefrontal cortex and hippocampus. The GR antagonist RU486 was used as intervention. The results revealed that both CUMS and dexamethasone administration in the adolescent period resulted in anhedonia, altered locomotor behaviors, anxiety, and cognitive impairment. A remarkable decrease in GR expression, and increase in FKBP5, miR-124a, and miR-18a expressions were detected in the prefrontal cortex and hippocampus of adolescent rats. Furthermore, the similar long-term changes on behaviors and expressions of GR, FKBP5 and GR-related microRNAs were found in the adult rats following CUMS and dexamethasone treatment in adolescence. However, reduced miR-511 expression was observed only in the prefrontal cortex of adult rats exposed to adolescent CUMS or dexamethasone administration. These data suggested that the downregulation of GR, upregulation of FKBP5, miR-124a, and miR-18a in the prefrontal cortex and hippocampus, and downregulation of miR-511 in the prefrontal cortex were relevant to depressive-like behaviors.

Redirection of neuroblast migration from the rostral migratory stream into a lesion in the prefrontal cortex of adult rats.

Clinical treatment of structural brain damage today is largely limited to symptomatic approaches and the avoidance of secondary injury. However, neuronal precursor cells are constantly produced within specified regions of the mammalian brain throughout life. Here we evaluate the potential of the known chemoattractive properties of the glycoprotein laminin on neuroblasts to relocate the cells into damaged brain areas. Injection of a thin laminin tract, leading from the rostral migratory stream to an excitotoxic lesion within the medial prefrontal cortex of rats, enabled neuroblasts to migrate away from their physiological route towards the olfactory bulb into the lesion site. Once they reached the damaged tissue, they migrated further in a non-uniform orientation within the lesion. Furthermore, our data indicate that the process of diverted migration is still active 6 weeks after the treatment and that at least some of the neuroblasts are capable of maturing into adult neurons.

Maternal Separation Induces Different Autophagic Responses in the Hippocampus and Prefrontal Cortex of Adult Rats

Our previous study has reported that maternal separation (MS) results in abnormal behaviors such as depressive-like and anxious-like behaviors in adult rats. However, the underlying mechanism remains unclear. In this study, we focused on the relationship between MS and autophagy in an effort to explain potential mechanisms. Pups experienced MS from postnatal days 7 to 21 and were randomly divided into the control (CON) group and MS group. Data showed that MS induced depressive-like and anxious-like behaviors in adult rats. Compared with the CON group, the glutamate level was obviously increased in the hippocampus (HP) and prefrontal cortex (PFC) of rats in the MS group. Interestingly, both beclin-1 expression and ratio of LC3II/LC3I were decreased in the HP, but they were increased in the PFC. Furthermore, N-methyl-d-aspartate receptor subunit 2B (NR2B) expression was significantly increased in the HP and PFC. Additionally, postsynaptic density-95 was increased in the HP; however, it was unchanged in the PFC. Moreover, the expression of synaptophysin was obviously decreased in both the HP and PFC. In conclusion, these findings suggest that MS induces different autophagic responses in the HP and PFC (i.e., the inhibition of autophagy in the HP and the activation of autophagy in the PFC), which can be related to the NR2B signaling pathway.

α5 nAChR modulation of the prefrontal cortex makes attention resilient

A loss-of-function polymorphism in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene has been linked to both drug abuse and schizophrenia. The α5 nAChR subunit is strategically positioned in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. However, the specific contribution of α5 to PFC-dependent cognitive functions has yet to be illustrated. In the present studies, we used RNA interference to knockdown the α5 nAChR subunit in the PFC of adult rats. We provide evidence that through its contribution to cholinergic modulation of cholinergic modulation of neurons in the PFC, the α5 nAChR plays a specific role in the recovery of attention task performance following distraction. Our combined data reveal the potent ability of this subunit to modulate the PFC and cognitive functions controlled by this brain region that are impaired in disease.