PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation.

Eukaryotic elongation factor 2 (eEF2) mediates translocation of peptidyl-tRNA from the ribosomal A site to the P site to promote translational elongation. Its phosphorylation on Thr56 by its single known kinase eEF2K inactivates it and inhibits translational elongation. Extensive studies have revealed that different signal cascades modulate eEF2K activity, but whether additional factors regulate phosphorylation of eEF2 remains unclear. Here, we find that the X chromosome-linked intellectual disability protein polyglutamine-binding protein 1 (PQBP1) specifically binds to non-phosphorylated eEF2 and suppresses eEF2K-mediated phosphorylation at Thr56. Loss of PQBP1 significantly reduces general protein synthesis by suppressing translational elongation. Moreover, we show that PQBP1 regulates hippocampal metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) and mGluR-LTD-associated behaviors by suppressing eEF2K-mediated phosphorylation. Our results identify PQBP1 as a novel regulator in translational elongation and mGluR-LTD, and this newly revealed regulator in the eEF2K/eEF2 pathway is also an excellent therapeutic target for various disease conditions, such as neural diseases, virus infection, and cancer.

Two distinct ways to form long-term object recognition memory during sleep and wakefulness.

Memory consolidation is promoted by sleep. However, there is also evidence for consolidation into long-term memory during wakefulness via processes that preferentially affect nonhippocampal representations. We compared, in rats, the effects of 2-h postencoding periods of sleep and wakefulness on the formation of long-term memory for objects and their associated environmental contexts. We employed a novel-object recognition (NOR) task, using object exploration and exploratory rearing as behavioral indicators of these memories. Remote recall testing (after 1 wk) confirmed significant long-term NOR memory under both conditions, with NOR memory after sleep predicted by the occurrence of EEG spindle-slow oscillation coupling. Rats in the sleep group decreased their exploratory rearing at recall testing, revealing successful recall of the environmental context. By contrast, rats that stayed awake after encoding showed equally high levels of rearing upon remote testing as during encoding, indicating that context memory was lost. Disruption of hippocampal function during the postencoding interval (by muscimol administration) suppressed long-term NOR memory together with context memory formation when animals slept, but enhanced NOR memory when they were awake during this interval. Testing remote recall in a context different from that during encoding impaired NOR memory in the sleep condition, while exploratory rearing was increased. By contrast, NOR memory in the wake rats was preserved and actually superior to that after sleep. Our findings indicate two distinct modes of long-term memory formation: Sleep consolidation is hippocampus dependent and implicates event-context binding, whereas wake consolidation is impaired by hippocampal activation and strengthens context-independent representations.

The decanoate esters of nandrolone, testosterone, and trenbolone induce steroid specific memory impairment and somatic effects in the male rat.

Long-term use of anabolic androgenic steroids (AAS) in supratherapeutic doses is associated with severe adverse effects, including physical, mental, and behavioral alterations. When used for recreational purposes several AAS are often combined, and in scientific studies of the physiological impact of AAS either a single compound or a cocktail of several steroids is often used. Because of this, steroid-specific effects have been difficult to define and are not fully elucidated. The present study used male Wistar rats to evaluate potential somatic and behavioral effects of three different AAS; the decanoate esters of nandrolone, testosterone, and trenbolone. The rats were exposed to 15 mg/kg of nandrolone decanoate, testosterone decanoate, or trenbolone decanoate every third day for 24 days. Body weight gain and organ weights (thymus, liver, kidney, testis, and heart) were measured together with the corticosterone plasma levels. Behavioral effects were studied in the novel object recognition-test (NOR-test) and the multivariate concentric square field-test (MCSF-test). The results conclude that nandrolone decanoate, but neither testosterone decanoate nor trenbolone decanoate, caused impaired recognition memory in the NOR-test, indicating an altered cognitive function. The behavioral profile and stress hormone level of the rats were not affected by the AAS treatments. Furthermore, the study revealed diverse AAS-induced somatic effects i.e., reduced body weight development and changes in organ weights. Of the three AAS included in the study, nandrolone decanoate was identified to cause the most prominent impact on the male rat, as it affected body weight development, the weights of multiple organs, and caused an impaired memory function.

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model.

The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.

Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease.

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder characterized by cognitive decline, memory loss, behavioral changes, and other neurological symptoms. Considering the urgent need for new AD therapeutics, in the present study we designed, synthesized, and evaluated multitarget compounds structurally inspired by sulfonylureas and pitolisant with the aim of obtaining multitarget ligands for AD treatment. Due to the diversity of chemical scaffolds, a novel strategy has been adopted by merging into one structure moieties displaying H3R antagonism and acetylcholinesterase inhibition. Eight compounds, selected by their binding activity on H3R, showed a moderate ability to inhibit acetylcholinesterase activity in vitro, and two of the compounds (derivatives 2 and 7) were also capable of increasing acetylcholine release in vitro. Among the tested compounds, derivative 2 was identified and selected for further in vivo studies. Compound 2 was able to reverse scopolamine-induced cognitive deficits with results comparable to those of galantamine, a drug used in clinics for treating AD. In addition to its efficacy, this compound showed moderate BBB permeation in vitro. Altogether, these results point out that the fragment-like character of compound 2 leads to an optimal starting point for a plausible medicinal chemistry approach for this novel strategy.

The Impact of LY487379 or CDPPB on eNOS Expression in the Mouse Brain and the Effect of Joint Administration of Compounds with NO• Releasers on MK-801- or Scopolamine-Driven Cognitive Dysfunction in Mice.

The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer's disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO• donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD.

Oral self-administration of pregabalin in a mouse model and the resulting drug addiction features.

Prescription drug abuse is an issue that is rapidly growing globally. Pregabalin, an anticonvulsant, analgesic, and anxiolytic medication, is effective in the management of multiple neurological disorders; however, there is increasing concern regarding its widespread illicit use. It has been previously reported in mice that pregabalin can induce conditioned place preference. In this current investigation, the potential of pregabalin to elicit free-choice drinking in a mouse model of drug addiction, and its effect on recognition and withdrawal behaviors after forced abstinence, were studied. Twenty-two male BALB/c mice were randomly divided into three groups (n = 7-8/group); control, pregabalin-30, and pregabalin-60. The study had three phases: habituation (days 1-5) with free water access, free-choice drinking (days 6-13) with pregabalin groups receiving one water and one pregabalin bottle, and forced abstinence (days 14-21) with free water access. On day 13, the first open field test was conducted, followed by the Novel Object Recognition Test. On day 21, the second open field test was performed, followed by the Tail Suspension Test and Forced Swimming Test. Pregabalin elicited voluntary drinking in the higher-dose group, concurrently causing a decline in recognition memory performance in the novel object recognition test. Moreover, pregabalin induced withdrawal behavior after a period of forced abstinence in the forced swimming and tail suspension tests. This is the first report to establish an animal model of free-choice pregabalin drinking that may be used for further molecular studies and targeted therapy for pregabalin addiction.

Loss of oxytocin receptors in hilar mossy cells impairs social discrimination.

Hippocampal oxytocin receptor (OXTR) signaling is crucial for discrimination of social stimuli to guide social recognition, but circuit mechanisms and cell types involved remain incompletely understood. Here, we report a role for OXTR-expressing hilar mossy cells (MCs) of the dentate gyrus in social stimulus discrimination by regulating granule cell (GC) activity. Using a Cre-loxP recombination approach, we found that ablation of Oxtr from MCs impairs discrimination of social, but not object, stimuli in adult male mice. Ablation of MC Oxtr increases spontaneous firing rate of GCs, synaptic excitation to inhibition ratio of MC-to-GC circuit, and GC firing when temporally associated with the lateral perforant path inputs. Using mouse hippocampal slices, we found that bath application of OXTR agonist [Thr4,Gly7]-oxytocin causes membrane depolarization and increases MC firing activity. Optogenetic activation of MC-to-GC circuit ameliorates social discrimination deficit in MC OXTR deficient mice. Together, our results uncover a previously unknown role of MC OXTR signaling for discrimination of social stimuli and delineate a MC-to-GC circuit responsible for social information processing.

Independent and combined effects of astaxanthin and omega-3 on behavioral deficits and molecular changes in a prenatal valproic acid model of autism in rats.

Objectives: Autism is a devastating neurodevelopmental disorder and recent studies showed that omega-3 or astaxanthin might reduce autistic symptoms due to their anti-inflammatory properties. Therefore, we investigated the effects of omega-3 and astaxanthin on the VPA-induced autism model of rats.Material and Methods: Female Wistar albino pups (n = 40) were grouped as control, autistic, astaxanthin (2 mg/kg), omega-3 (200 mg/kg), and astaxanthin (2 mg/kg)+omega-3 (200 mg/kg). All groups except the control were prenatally exposed to VPA. Astaxanthin and omega-3 were orally administered from the postnatal day 41 to 68 and behavioral tests were performed between day 69 and 73. The rats were decapitated 24 h after the behavioral tests and hippocampal and prefrontal cytokines and 5-HT levels were analyzed by ELISA.Results: VPA rats have increased grooming behavior while decreased sociability (SI), social preference index (SPI), discrimination index (DI), and prepulse inhibition (PPI) compared to control. Additionally, IL-1ß, IL-6, TNF-α, and IFN-γ levels increased while IL-10 and 5-HT levels decreased in both brain regions. Astaxanthin treatment raised SI, SPI, DI, PPI, and prefrontal IL-10 levels. It also raised 5-HT levels and decreased IL-6 levels in both brain regions. Omega-3 and astaxanthin + omega-3 increased the SI, SPI, DI, and PPI and decreased grooming behavior. Moreover, they increased IL-10 and 5-HT levels whereas decreased IL-1ß, IL-6, TNF-α, IFN-γ levels in both brain regions.Conclusions: Our results showed that VPA administration mimicked the behavioral and molecular changes of autism in rats. Single and combined administration of astaxanthin and omega-3 improved the autistic-like behavioral and molecular changes in the VPA model of rats.

Effect of D-pinitol on MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.

Effect of Combined Levothyroxine (L-T4) and 3-Iodothyronamine (T1AM) Supplementation on Memory and Adult Hippocampal Neurogenesis in a Mouse Model of Hypothyroidism.

Mood alterations, anxiety, and cognitive impairments associated with adult-onset hypothyroidism often persist despite replacement treatment. In rodent models of hypothyroidism, replacement does not bring 3-iodothyronamine (T1AM) brain levels back to normal. T1AM is a thyroid hormone derivative with cognitive effects. Using a pharmacological hypothyroid mouse model, we investigated whether augmenting levothyroxine (L-T4) with T1AM improves behavioural correlates of depression, anxiety, and memory and has an effect on hippocampal neurogenesis. Hypothyroid mice showed impaired performance in the novel object recognition test as compared to euthyroid mice (discrimination index (DI): 0.02 ± 0.09 vs. 0.29 ± 0.06; t = 2.515, p = 0.02). L-T4 and L-T4+T1AM rescued memory (DI: 0.27 ± 0.08 and 0.34 ± 0.08, respectively), while T1AM had no effect (DI: -0.01 ± 0.10). Hypothyroidism reduced the number of neuroprogenitors in hippocampal neurogenic niches by 20%. L-T4 rescued the number of neuroprogenitors (mean diff = 106.9 ± 21.40, t = 4.99, pcorr = 0.003), while L-T4+T1AM produced a 30.61% rebound relative to euthyroid state (mean diff = 141.6 ± 31.91, t = 4.44, pcorr = 0.004). We performed qPCR analysis of 88 genes involved in neurotrophic signalling pathways and found an effect of treatment on the expression of Ngf, Kdr, Kit, L1cam, Ntf3, Mapk3, and Neurog2. Our data confirm that L-T4 is necessary and sufficient for recovering memory and hippocampal neurogenesis deficits associated with hypothyroidism, while we found no evidence to support the role of non-canonical TH signalling.

Effect Sizes of Cognitive and Locomotive Behavior Tests in the 5XFAD-J Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid ß (Aß) plaques in the brain, leading to cognitive impairment and other clinical symptoms. The 5XFAD mouse model is commonly used in AD research because it expresses five human transgenes that result in the accumulation of Aß plaques and cognitive decline at a relatively early age. Behavioral experiments are frequently conducted using this model; however, the effect size has not yet been reported. In this study, we examined basic cognition and locomotion in 5XFAD mice with a C57BL6/J background (5XFAD-J) at 6 months of age, a period in which impairments of cognitive function and locomotion are commonly observed. We analyzed the effect sizes of cognitive and locomotive experiments in the 5XFAD mice compared with those in the wild-type mice. Our results suggest that for long-term memory analysis, the novel object recognition test (p = 0.013, effect size 1.24) required a sample size of at least 12 to obtain meaningful results. Moreover, analysis of general locomotion over total distance with the Laboratory Animal Behavior Observation, Registration and Analysis System (LABORAS) test during the dark phase (p = 0.007, effect size -1.37) needed a sample size of 10 for a statistical power (1-ß) of 0.8. In conclusion, we can conduct more ethical and scientifically rigorous animal experiments using 5XFAD mice based on the effect and sample sizes suggested in this study.

The Potent and Selective Histamine H3 Receptor Antagonist E169 Counteracts Cognitive Deficits and Mitigates Disturbances in the PI3K/AKT/GSK-3ß Signaling Pathway in MK801-Induced Amnesia in Mice.

The role of histamine H3 receptors (H3Rs) in memory and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer's disease (AD), is well-accepted. Therefore, the procognitive effects of acute systemic administration of H3R antagonist E169 (2.5-10 mg/kg, i.p.) on MK801-induced amnesia in C57BL/6J mice using the novel object recognition test (NORT) were evaluated. E169 (5 mg) provided a significant memory-improving effect on MK801-induced short- and long-term memory impairments in NORT. The E169 (5 mg)-provided effects were comparable to those observed with the reference phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and were abrogated with the H3R agonist (R)-α-methylhistamine (RAMH). Additionally, our results demonstrate that E169 ameliorated MK801-induced memory deficits by antagonism of H3Rs and by modulation of the level of disturbance in the expression of PI3K, Akt, and GSK-3ß proteins, signifying that E169 mitigated the Akt-mTOR signaling pathway in the hippocampus of tested mice. Moreover, the results observed revealed that E169 (2.5-10 mg/kg, i.p.) did not alter anxiety levels and locomotor activity of animals in open field tests, demonstrating that performances improved following acute systemic administration with E169 in NORT are unrelated to changes in emotional response or in spontaneous locomotor activity. In summary, these obtained results suggest the potential of H3R antagonists such as E169, with good in silico physicochemical properties and stable retained key interactions in docking studies at H3R, in simultaneously modulating disturbed brain neurotransmitters and the imbalanced Akt-mTOR signaling pathway related to neurodegenerative disorders, e.g., AD.

Role of Cannabinoid CB1 Receptor in Object Recognition Memory Impairment in Chronically Rapid Eye Movement Sleep-deprived Rats.

Objective We aimed to investigate whether antagonism of the cannabinoid CB1 receptor (CB1R) could affect novel object recognition (NOR) memory in chronically rapid eye movement sleep-deprived (RSD) rats.Methods The animals were examined for recognition memory following a 7-day chronic partial RSD paradigm using the multiple platform technique. The CB1R antagonist rimonabant (1 or 3 mg/kg, i.p.) was administered either at one hour prior to the sample phase for acquisition, or immediately after the sample phase for consolidation, or at one hour before the test phase for retrieval of NOR memory. For the reconsolidation task, rimonabant was administered immediately after the second sample phase.Results The RSD episode impaired acquisition, consolidation, and retrieval, but it did not affect the reconsolidation of NOR memory. Rimonabant administration did not affect acquisition, consolidation, and reconsolidation; however, it attenuated impairment of the retrieval of NOR memory induced by chronic RSD.Conclusions These findings, along with our previous report, would seem to suggest that RSD may affect different phases of recognition memory based on its duration. Importantly, it seems that the CB1R may, at least in part, be involved in the adverse effects of chronic RSD on the retrieval, but not in the acquisition, consolidation, and reconsolidation, of NOR memory.

Oligodendrogenesis is a key process for cognitive performance improvement induced by voluntary physical activity.

Physical activity (PA) promotes the proliferation of neural stem cells and enhances neurogenesis in the dentate gyrus resulting in hippocampal circuit remodeling and cognitive enhancement. Nonetheless, knowledge of other neural progenitors affected by PA and the mechanisms through which they could contribute to circuit plasticity and cognitive enhancement are still poorly understood. In this work we demonstrated that NG2-glia, also known as oligodendrocyte progenitor cells, show enhanced proliferation and differentiation in response to voluntary PA in a brain region-dependent manner in adult mice. Surprisingly, preventing NG2-glia differentiation during enhanced PA abolishes the exercise-associated cognitive improvement without affecting neurogenesis or baseline learning capacity. Thus, here we provided new evidence highlighting the requirement of oligodendrogenesis for exercise induced-cognition enhancement.

Novelty promotes recognition memory persistence by D1 dopamine receptor and protein kinase A signalling in rat hippocampus.

Strategies for improving memory are increasingly studied, and exposure to a novel experience can be an efficient neuromodulator. Novelty effects on memory depend on D1-family dopamine receptors (D1Rs) activation. Here, we evaluated the novelty effect on memory persistence of Wistar rats and investigated the contribution of D1Rs and their signalling pathways by protein kinase A (PKA) and C (PKC). Animals with infusion cannulae inserted into the CA1 hippocampus area were trained on the novel object recognition (NOR) task, which involved exploring two different objects. After training, some rats received intrahippocampal infusions of vehicle or D1Rs agonist; others explored a novel environment for 5 min and were infused with a variety of drugs targeting D1Rs and their signalling pathways. We demonstrated that pharmacological stimulation of D1Rs or novelty exposure promoted NOR memory persistence for 14 days and that the novelty effect depended on D1Rs activation. To determine if the D1 and D5 receptor subtypes were necessary for the impact of novelty exposure on memory, we blocked or stimulated PKA or PKC-protein kinases activated mainly by D1 and D5, respectively. Only PKA inhibition impaired the effect of novelty on memory persistence. After novelty and D1Rs blocking, PKA but not PKC stimulation maintained the memory persistence effect. Thus, we concluded that novelty promoted memory persistence by a mechanism-dependent on activating hippocampal D1Rs and PKA pathway.

Reduced Reelin Expression Induces Memory Deficits through Dab-1/ NMDAR Signaling Pathway: Cronobacter sakazakii Infection in a Rat Model of Experimental Meningitis.

The purpose of this study was to examine whether the Cronobacter sakazakii infection-induced inflammation alters the Reelin signaling pathway that is involved in learning and memory. To test this, postnatal day (PND)-15 rat pups were either treated with Luria Bertani broth/Escherichia coli OP50/C. sakazakii through oral gavage or maintained as control and allowed to stay with their mothers until PND-24. Experimental groups' rats were subjected to long-term novel object recognition test during their adolescent age PND-30-32. Observed behavioral data showed that C. sakazakii infection causes a deficit in recognition of novel objects from known objects. Further, our analysis showed that C. sakazakii infection-mediated inflammation decreases the Reelin expression by proteolytic cleavage and alters its receptor apolipoprotein E-receptor (ApoER)-2 splice variants ApoER2 (ex19) and ApoER2 (Δ). Subsequently, downregulated Reelin alters the phosphorylation of disabled adapter protein (Dab)-1 and leads to differential expression of N-methyl-D-aspartate (NMDA) receptor subunits 2A and 2B. Further, the NMDA receptor influences the expression of postsynaptic density (PSD)-95 protein and brain-derived neurotrophic factor (BDNF). Observed results suggest a deficit in recognition of novel objects possibly due to the alternation in Reelin signaling pathway.

Neonatal administration of erythropoietin attenuates cognitive deficits in adult rats following placental insufficiency.

Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.

Task-specific effects of biological sex and sex hormones on object recognition memories in a 6-hydroxydopamine-lesion model of Parkinson's disease in adult male and female rats.

Many patients with Parkinson's disease (PD) experience cognitive or memory impairments with few therapeutic options available to mitigate them. This has fueled interest in determining how factors including sex and sex hormones modulate higher order function in this disease. The objective of this study was to use the Novel Object Recognition (NOR) and Object-in-Place (OiP) paradigms to compare the effects of a bilateral neostriatal 6-hydroxydopamine (6-OHDA) lesion model of PD in gonadally intact male and female rats, in orchidectomized male rats and in orchidectomized males supplemented with 17ß-estradiol or testosterone propionate on measures of recognition memory similar to those at risk in PD. These studies showed that 6-ODHA lesions impaired discrimination in both tasks in males but not females. Further, 6-OHDA lesions disrupted NOR performance similarly in all males regardless of whether they were gonadally intact, orchidectomized or hormone-supplemented. In contrast, OiP performance was disrupted in males that were orchidectomized or 6-OHDA-lesioned but was spared in orchidectomized and orchidectomized, 6-OHDA lesioned males supplemented with 17ß-estradiol. The distinct effects that sex and/or sex hormones have on 6-OHDA lesion-induced NOR vs. OiP deficits identified here also differ from corresponding impacts recently described for 6-OHDA lesion-induced deficits in spatial working memory and episodic memory. Together, the collective data provide strong evidence for effects of sex and sex hormones on cognition and memory in PD as being behavioral task and behavioral domain specific. This specificity could explain why a cohesive clinical picture of endocrine impacts on higher order function in PD has remained elusive.

Preventing adolescent stress-induced cognitive and microbiome changes by diet.

Psychological stress during adolescence may cause enduring cognitive deficits and anxiety in both humans and animals, accompanied by rearrangement of numerous brain structures and functions. A healthy diet is essential for proper brain development and maintenance of optimal cognitive functions during adulthood. Furthermore, nutritional components profoundly affect the intestinal community of microbes that may affect gut-brain communication. We adopted a relatively mild stress protocol, social instability stress, which when repeatedly administered to juvenile rats modifies cognitive behaviors and plasticity markers in the brain. We then tested the preventive effect of a prolonged diet enriched with the ω-3 polyunsaturated fatty acids eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid and vitamin A. Our findings highlight the beneficial effects of this enriched diet on cognitive memory impairment induced by social instability stress, as stressed rats fed the enriched diet exhibited performance undistinguishable from that of nonstressed rats on both emotional and reference memory tests. Furthermore, in stressed rats, the decline in brain-derived neurotrophic factor expression in the hippocampus and shifts in the microbiota composition were normalized by the enriched diet. The detrimental behavioral and neurochemical effects of adolescent stress, as well as the protective effect of the enriched diet, were maintained throughout adulthood, long after the exposure to the stressful environment was terminated. Taken together, our results strongly suggest a beneficial role of nutritional components in ameliorating stress-related behaviors and associated neurochemical and microbiota changes, opening possible new venues in the field of nutritional neuropsychopharmacology.