Agomelatine improves memory and learning impairments in a rat model of LPS-induced neurotoxicity by modulating the ERK/SorLA/BDNF/TrkB pathway.

The mutual interplay between neuroinflammation, synaptic plasticity, and autophagy has piqued researchers' interest, particularly when it comes to linking their impact and relationship to cognitive deficits. Being able to reduce inflammation and apoptosis, melatonin has shown to have positive neuroprotective effects; that is why we thought to check the possible role of agomelatine (AGO) as a promising candidate that could have a positive impact on cognitive deficits. In the current study, AGO (40 mg/kg/day, p.o., 7 days) successfully ameliorated the cognitive and learning disabilities caused by lipopolysaccharide (LPS) in rats (250 µg/kg/day, i.p., 7 days). This positive impact was supported by improved histopathological findings and improved spatial memory as assessed using Morris water maze. AGO showed a strong ability to control BACE1 activity and to rein in the hippocampal amyloid beta (Aß) deposition. Also, it improved neuronal survival, neuroplasticity, and neurogenesis by boosting BDNF levels and promoting its advantageous effects and by reinforcing the pTrkB expression. In addition, it upregulated the pre- and postsynaptic neuroplasticity biomarkers resembled in synapsin I, synaptophysin, and PSD-95. Furthermore, AGO showed a modulatory action on Sortilin-related receptor with A-type repeats (SorLA) pathway and adjusted autophagy. It is noteworthy that all of these actions were abolished by administering PD98059 a MEK/ERK pathway inhibitor (0.3 mg/kg/day, i.p., 7 days). In conclusion, AGO administration significantly improves memory and learning disabilities associated with LPS administration by modulating the ERK/SorLA/BDNF/TrkB signaling pathway parallel to its capacity to adjust the autophagic process.

Testosterone Influence on Microtubule-Associated Proteins and Spine Density in Hippocampus: Implications on Learning and Memory.

The thorny protrusions or spines increase the neuronal surface area, facilitate synaptic interconnections among neurons, and play an essential role in the hippocampus. Increasing evidence suggests that testosterone, the gonadal hormone, plays an important role in neurogenesis and synaptic plasticity. The role of testosterone on microtubule-associated proteins on dendritic neurite stability in the hippocampus and its impact on learning disability is not elucidated. Adult male Wistar albino rats were randomly selected for the control, castrated, castrated + testosterone, and control + testosterone groups. Bilateral orchidectomy was done, and the testosterone propionate was administered during the entire trial period, i.e., 14 days. The learning assessments were done using working/reference memory versions of the 8-arm radial maze and hippocampal tissues processed for histological and protein expressions. There were reduced expressions of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD95), and androgen receptor (AR) and increased expression of pTau in the castrated group. Conversely, the expression of MAP2, PSD95, and AR was increased, and the pTau expression was reduced in the hippocampus of the castrated rat administrated with testosterone. Androgen-depleted rats showed impaired synaptic plasticity in the hippocampus associated with contracted microtubule dynamics. Along with learning disability, there was an increased number of reference memory errors and working memory errors in castrated rats. Observations suggest that androgen regulates expression of neural tissue-specific MAPs and plays a vital role in hippocampus synaptic plasticity and that a similar mechanism may underlie neurological disorders in aging and hypogonadal men.

Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness.

AIMS: To characterize exercise fatigue, metabolic phenotype and cognitive and mood deficits correlated with brain neuroinflammatory and gut microbiome changes in a chronic Gulf War Illness (GWI) mouse model. The latter have been described in an accompanying paper [1]. MAIN METHODS: Adult male C57Bl/6N mice were exposed for 28 days (5 days/week) to pyridostigmine bromide: 6.5 mg/kg, b.i.d., P.O. (GW1) or 8.7 mg/kg, q.d., P.O. (GW2); topical permethrin (1.3 mg/kg in 100% DMSO) and N,N-diethyl-meta-toluamide (DEET 33% in 70% EtOH) and restraint stress (5 min). Exercise, metabolic and behavioral endpoints were compared to sham stress control (CON/S). KEY FINDINGS: Relative to CON/S, GW2 presented persistent exercise intolerance (through post-treatment (PT) day 161), deficient associative learning/memory, and transient insulin insensitivity. In contrast to GW2, GW1 showed deficient long-term object recognition memory, milder associative learning/memory deficit, and behavioral despair. SIGNIFICANCE: Our findings demonstrate that GW chemicals dose-dependently determine the presentation of exercise fatigue and severity/type of cognitive/mood-deficient phenotypes that show persistence. Our comprehensive mouse model of GWI recapitulates the major multiple symptom domains characterizing GWI, including fatigue and cognitive impairment that can be used to more efficiently develop diagnostic tests and curative treatments for ill Gulf War veterans.

Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin.

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin-a selective inhibitor of mTORC1, Torin-2-a non-selective mTORC1/mTORC2 inhibitor, and FK-506-a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4-9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.

Manganese exposure during early larval stages of C. elegans causes learning disability in the adult stage.

Manganese (Mn), even though an essential trace element, causes neurotoxicity in excess. In adults, over-exposure to Mn causes clinical manifestations, including dystonia, progressive bradykinesia, disturbance of gait, slurring, and stuttering of speech. These symptoms are mainly because of Mn-associated oxidative stress and degeneration of dopamine neurons in the central nervous system. Children with excessive Mn exposure often show learning disabilities but rarely show symptoms associated with dopaminergic neuron dysfunction. It is unclear why Mn exposure shows distinctive clinical outcomes in developing brains versus adult brains. Studies on nematode C. elegans have demonstrated that it is an excellent model to elucidate Mn-associated toxicity in the nervous system. In this study, we chronically exposed Mn to L1 larval stage of the worms to understand the effects on dopamine neurons and cognitive development. The worms showed modified behavior to exogenous dopamine compared to the control. The dopamine neurons showed resistance to neurodegeneration on repeated Mn exposure during the adult stage. As observed in mammalian systems, these worms showed significantly low olfactory adaptive learning and memory. This study shows that C. elegans alters adaptive developmental plasticity during Mn overexposure, modifying its sensitivity towards the metal ion and leads to remodeling in its innate learning behavior.

Repeated hypoxia exposure induces cognitive dysfunction, brain inflammation, and amyloidß/p-Tau accumulation through reduced brain O-GlcNAcylation in zebrafish.

Repetitive hypoxia (RH) exposure affects the initiation and progression of cognitive dysfunction, but little is known about the mechanisms of hypoxic brain damage. In this study, we show that sublethal RH increased anxiety, impaired learning and memory (L/M), and triggered downregulation of brain levels of glucose and several glucose metabolites in zebrafish, and that supplementation of glucose or glucosamine (GlcN) restored RH-induced L/M impairment. Fear conditioning (FC)-induced brain activation of and PKA/CREB signaling was abrogated by RH, and this effect was reversed by GlcN supplementation. RH was associated with decreased brain O-GlcNAcylation and an increased O-GlcNAcase (OGA) level. RH increased brain inflammation and p-Tau and amyloid ß accumulation, and these effects were suppressed by GlcN. Our observations collectively suggest that changes in O-GlcNAc flux during hypoxic exposure could be an important causal factor for neurodegeneration, and that supplementation of the HBP/O-GlcNAc flux may be a potential novel therapeutic or preventive target for addressing hypoxic brain damage.

p53 and clock genes play an important role in memory and learning ability depression due to long-term ultraviolet A eye irradiation.

BACKGROUND: Long-term ultraviolet A (UVA) eye irradiation decreases memory and learning ability in mice. However, the underlying mechanism is still unclear. OBJECTIVES: In this study, ICR mice were used to study the effects of long-term UVA eye irradiation. METHODS: The eyes of mice were exposed to UVA from an FL20SBLB-A lamp three times a week for 1 year. Then, we analyzed memory and learning ability in the mice using water maze and step-through passive avoidance tests, and measured the levels of p53, Period2 (Per2), Clock, brain and muscle Arnt-like protein-1 (Bmal1), nicotinamide mononucleotide adenylyltransferase (NMNAT) activity, nicotinamide phosphoribosyltransferase (NAMPT) activity, nicotinamide adenine dinucleotide (NAD+), and sirtuin 1 (Sirt1) in the brains of treated and control animals. RESULTS: The results showed that the p53 level increased significantly following long-term UVA eye irradiation, whereas the levels of Period2, Bmal1, Clock, NMNAT and NAMPT activities, NAD+, and Sirt1 decreased significantly. Furthermore, we found that p53 inhibition ameliorated the UVA eye irradiation-induced depression of memory and learning ability. CONCLUSION: These results indicate that long-term UVA eye irradiation stimulates p53, inhibits the clock gene, and reduces Sirt1 production in the NAD+ constructional system, resulting in reduced memory and learning ability.

Expression analysis of selected genes involved in tryptophan metabolic pathways in Egyptian children with Autism Spectrum Disorder and learning disabilities.

Autism Spectrum Disorder (ASD) and learning disabilities are neurodevelopmental disabilities characterized by dramatically increasing incidence rates, yet the exact etiology for these disabilities is not identified. Impairment in tryptophan metabolism has been suggested to participate in the pathogenesis of ASD, however, further validation of its involvement is required. Additionally, its role in learning disabilities is still uninvestigated. Our objective was to evaluate some aspects of tryptophan metabolism in ASD children (N = 45) compared to children with learning disabilities (N = 44) and healthy controls (N = 40) by measuring the expression levels of the MAOA, HAAO and AADAT genes using real-time RT-qPCR. We also aimed to correlate the expression patterns of these genes with parental ages at the time of childbirth, levels of serum iron, and vitamin D3 and zinc/copper ratio, as possible risk factors for ASD. Results demonstrated a significant decrease in the expression of the selected genes within ASD children (p < 0.001) relative to children with learning disabilities and healthy controls, which significantly associated with the levels of our targeted risk factors (p < 0.05) and negatively correlated to ASD scoring (p < 0.001). In conclusion, this study suggests that the expression of the MAOA, HAAO and AADAT genes may underpin the pathophysiology of ASD.

The ketogenic diet raises brain oxygen levels, attenuates postictal hypoxia, and protects against learning impairments.

OBJECTIVES: A prolonged vasoconstriction/hypoperfusion/hypoxic event follows self-terminating focal seizures. The ketogenic diet (KD) has demonstrated efficacy as a metabolic treatment for intractable epilepsy and other disorders but its effect on local brain oxygen levels is completely unknown. This study investigated the effects of the KD on tissue oxygenation in the hippocampus before and after electrically elicited (kindled) seizures and whether it could protect against a seizure-induced learning impairment. We also examined the effects of the ketone ß-hydroxybutyrate (BHB) as a potential underlying mechanism. METHODS: Male and female rats were given access to one of three diet protocols 2 weeks prior to the initiation of seizures: KD, caloric restricted standard chow, and ad libitum standard chow. Dorsal hippocampal oxygen levels were measured prior to initiation of diets as well as before and after a 10-day kindling paradigm. Male rats were then tested on a novel object recognition task to assess postictal learning impairments. In a separate cohort, BHB was administered 30 min prior to seizure elicitation to determine whether it influenced oxygen dynamics. RESULTS: The KD increased dorsal hippocampal oxygen levels, ameliorated postictal hypoxia, and prevented postictal learning impairments. Acute BHB administration did not alter oxygen levels before or after seizures. INTERPRETATION: The ketogenic diet raised brain oxygen levels and attenuated severe postictal hypoxia likely through a mechanism independent of ketosis and shows promise as a non-pharmacological treatment to prevent the postictal state.

Abrogation of atypical neurogenesis and vascular-derived EphA4 prevents repeated mild TBI-induced learning and memory impairments.

Brain injury resulting from repeated mild traumatic insult is associated with cognitive dysfunction and other chronic co-morbidities. The current study tested the effects of aberrant neurogenesis in a mouse model of repeated mild traumatic brain injury (rmTBI). Using Barnes Maze analysis, we found a significant reduction in spatial learning and memory at 24 days post-rmTBI compared to repeated sham (rSham) injury. Cell fate analysis showed a greater number of BrdU-labeled cells which co-expressed Prox-1 in the DG of rmTBI-injured mice which coincided with enhanced cFos expression for neuronal activity. We then selectively ablated dividing neural progenitor cells using a 7-day continuous infusion of Ara-C prior to rSham or rmTBI. This resulted in attenuation of cFos and BrdU-labeled cell changes and prevented associated learning and memory deficits. We further showed this phenotype was ameliorated in EphA4f./f/Tie2-Cre knockout compared to EphA4f./f wild type mice, which coincided with altered mRNA transcript levels of MCP-1, Cx43 and TGFß. These findings demonstrate that cognitive decline is associated with an increased presence of immature neurons and gene expression changes in the DG following rmTBI. Our data also suggests that vascular EphA4-mediated neurogenic remodeling adversely affects learning and memory behavior in response to repeated insult.

Flavonoids ameliorate aluminum chloride-induced learning and memory impairments via suppression of apoptosis and oxidative stress in rats.

The study was to investigate the effects of flavonoids (rutin, puerarin, and silymarin) on learning and memory function in rats exposed to aluminum chloride (AlCl3). Wistar rats were administered flavonoids at a dose of 100 mg/(kg·bw)/day or 200 mg/(kg·bw)/day after exposed to 281.40 mg/(kg·bw)/day AlCl3·6H2O. The results of Morris water maze suggested that rutin and puerarin increased the frequency of crossing the platform and swimming time spent in the target quadrant of AlCl3-induced rats significantly. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay indicated that three flavonoids could alleviate apoptosis of hippocampal neurons induced by AlCl3. Real time-PCR and western blot suggested that rutin, puerarin and 100 mg/(kg·bw)/day silymarin could decrease the AlCl3-induced high expression of Bcl-2 associated X protein (Bax) mRNA and protein in hippocampus, but the expression of B cell lymphoma/leukemia-2 (Bcl-2) mRNA and protein was not significantly different among groups. Flavonoids could up regulate the low expression of autophagy related proteins (Beclin 1 (Bcl-2-interacting protein with a coiled-coil domain 1) and LC3 (microtubule-associated protein 1 light chain 3)) caused by AlCl3 exposure. Flavonoids could also adjust the change in adenosine triphosphatase, superoxide dismutase, glutathione peroxidase and malondialdehyde induced by intake of AlCl3. The results of inductively coupled plasma atomic emission spectroscopy (ICP-AES) suggested that flavonoids could effectively reduce the high Al level in brain and serum of AlCl3 exposed rats. In conclusion, three flavonoids may improve learning and memory function by inhibiting excessive apoptosis and oxidative stress in AlCl3 exposed rats.

Association of deficits in short-term learning and Aß and hippocampal volume in cognitively normal adults.

OBJECTIVE: To determine the extent to which deficits in learning over 6 days are associated with ß-amyloid-positive (Aß+) and hippocampal volume in cognitively normal (CN) adults. METHODS: Eighty CN older adults who had undergone PET neuroimaging to determine Aß status (n = 42 Aß- and 38 Aß+), MRI to determine hippocampal and ventricular volume, and repeated assessment of memory were recruited from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Participants completed the Online Repeatable Cognitive Assessment-Language Learning Test (ORCA-LLT), which required they learn associations between 50 Chinese characters and their English language equivalents over 6 days. ORCA-LLT assessments were supervised on the first day and were completed remotely online for all remaining days. RESULTS: Learning curves in the Aß+ CN participants were significantly worse than those in matched Aß- CN participants, with the magnitude of this difference very large (d [95% confidence interval (CI)] 2.22 [1.64-2.75], p < 0.001), and greater than differences between these groups for memory decline since their enrollment in AIBL (d [95% CI] 0.52 [0.07-0.96], p = 0.021), or memory impairment at their most recent visit. In Aß+ CN adults, slower rates of learning were associated with smaller hippocampal and larger ventricular volumes. CONCLUSIONS: These results suggest that in CN participants, Aß+ is associated more strongly with a deficit in learning than any aspect of memory dysfunction. Slower rates of learning in Aß+ CN participants were associated with hippocampal volume loss. Considered together, these data suggest that the primary cognitive consequence of Aß+ is a failure to benefit from experience when exposed to novel stimuli, even over very short periods.

Prenatal urban traffic noise exposure impairs spatial learning and memory and reduces glucocorticoid receptor expression in the hippocampus of male rat offspring.

INTRODUCTION: Exposure to noise stress during early life may permanently affect the structure and function of the central nervous system. The aim of this study was to evaluate the effects of prenatal exposure to urban traffic noise on the spatial learning and memory of the rats' offspring and the expression of glucocorticoid receptors (GRs) in their hippocampi. METHODS: Three g\roups of pregnant rats were exposed to recorded urban traffic noise for 1, 2 or 4 h/day during the last week of pregnancy. At the age of 45 days, their male offspring were introduced to the Morris water maze (MWM) for assessment of spatial learning and memory. The corticosterone levels were measured in the offspring's sera by radioimmunoassay, and the relative expression of glucocorticoid and mineralocorticoid receptors (MRs) in their hippocampi was evaluated via RT-PCR. RESULTS: Facing urban traffic noise for 2 and 4 h/day during the third trimester of pregnancy caused the offspring to spend more time and to travel a larger distance than the controls to find the target platform. Analogously, these two groups were inferior to their control counterparts in the probe test. Also, prenatal noise stress elevated the corticosterone concentration in the sera of the rats' offspring and dose-dependently decreased the relative expression of the mRNA of both GRs and MRs in their hippocampi. CONCLUSIONS: Urban traffic noise exposure during the last trimester of pregnancy impairs spatial learning and memory of rat offspring and reduces GRs and MRs gene expression in the hippocampus.

Inhibition of cellular inflammatory mediator production and amelioration of learning deficit in flies by deep sea Aspergillus-derived cyclopenin.

In the course of screening lipopolysaccharide (LPS)-induced nitric oxide (NO) production inhibitors, two related benzodiazepine derivatives, cyclopenol and cyclopenin, were isolated from the extract of a deep marine-derived fungal strain, Aspergillus sp. SCSIOW2. Cyclopenol and cyclopenin inhibited the LPS-induced formation of NO and secretion of IL-6 in RAW264.7 cells at nontoxic concentrations. In terms of the mechanism underlying these effects, cyclopenol and cyclopenin were found to inhibit the upstream signal of NF-κB activation. These compounds also inhibited the expression of IL-1ß, IL-6, and inducible nitric oxide synthase (iNOS) in mouse microglia cells, macrophages in the brain. In relation to the cause of Alzheimer's disease, amyloid-ß-peptide is known to induce inflammation in the brain. Therefore, the present study investigated the ameliorative effects of these inhibitors on an in vivo Alzheimer's model using flies. Learning deficits were induced by the overexpression of amyloid-ß42 in flies, and cyclopenin but not cyclopenol was found to rescue learning impairment. Therefore, novel anti-inflammatory activities of cyclopenin were identified, which may be useful as a candidate of anti-inflammatory agents for neurodegenerative diseases.

Kcnn2 blockade reverses learning deficits in a mouse model of fetal alcohol spectrum disorders.

Learning disabilities are hallmarks of congenital conditions caused by prenatal exposure to harmful agents. These include fetal alcohol spectrum disorders (FASDs) with a wide range of cognitive deficiencies, including impaired motor skill development. Although these effects have been well characterized, the molecular effects that bring about these behavioral consequences remain to be determined. We previously found that the acute molecular responses to alcohol in the embryonic brain are stochastic, varying among neural progenitor cells. However, the pathophysiological consequences stemming from these heterogeneous responses remain unknown. Here we show that acute responses to alcohol in progenitor cells altered gene expression in their descendant neurons. Among the altered genes, an increase of the calcium-activated potassium channel Kcnn2 in the motor cortex correlated with motor learning deficits in a mouse model of FASD. Pharmacologic blockade of Kcnn2 improves these learning deficits, suggesting Kcnn2 blockers as a new intervention for learning disabilities in FASD.

HFD refeeding in mice after fasting impairs learning by activating caspase-1 in the brain.

BACKGROUND: Diets that include some aspect of fasting have dramatically increased in popularity. In addition, fasting reduces inflammasome activity in the brain while improving learning. Here, we examine the impact of refeeding a low-fat diet (LFD) or high-fat diet (HFD) after fasting. METHODS: Male wildtype (WT), caspase-1 knockout (KO) and/or IL-1 receptor 1 (IL-1R1) KO mice were fasted for 24 h or allowed ad libitum access to food (chow). Immediately after fasting, mice were allowed to refeed for 2 h in the presence of LFD, HFD or chow. Mouse learning was examined using novel object recognition (NOR) and novel location recognition (NLR). Caspase-1 activity was quantified in the brain using histochemistry (HC) and image analysis. RESULTS: Refeeding with a HFD but not a LFD or chow fully impaired both NOR and NLR. Likewise, HFD when compared to LFD refeeding increased caspase-1 activity in the whole amygdala and, particularly, in the posterior basolateral nuclei (BLp) by 2.5-fold and 4.6-fold, respectively. When caspase-1 KO or IL-1R1 KO mice were examined, learning impairment secondary to HFD refeeding did not occur. Equally, administration of n-acetylcysteine to fasted WT mice prevented HFD-dependent learning impairment and caspase-1 activation in the BLp. Finally, the free-fatty acid receptor 1 (FFAR1) antagonist, DC260126, mitigated learning impairment associated with HFD refeeding while blocking caspase-1 activation in the BLp. CONCLUSIONS: Consumption of a HFD after fasting impairs learning by a mechanism that is dependent on caspase-1 and the IL-1R1 receptor. These consequences of a HFD refeeding on the BLP of the amygdala appear linked to oxidative stress and FFAR1.

Autophagy May Be Involved in Fluoride-Induced Learning Impairment in Rats.

Fluoride can induce neurotoxicity, but the mechanism is not clear. In this study, we explored the role of autophagy in F--induced neurotoxicity of Wistar rats. Eighty Wistar rats were randomly divided into four groups: the control group (distilled water containing less than 0.1 mg/L F-) and three NaF-treated groups (F- was respectively administered at 25, 50, and 100 mg/L orally via drinking water). The water maze experiment showed that NaF exposure impaired the learning capabilities of the rats. When compared with the control group, the mean escape latency of the rats in the 100 mg/L F- group was much longer (P < 0.05). Immunohistochemical analysis showed that NaF exposure induced autophagy, as shown by the significant increase of Beclin-1 expression in the hippocampal CA1 region and DG region. Transmission electron microscopy was used to observe the ultrastructural changes of hippocampal neurons. With the increase of F- concentration, the ultrastructural abnormalities of hippocampal neurons increased. These results indicate that fluoride can impair the learning ability of rats, which may be related to the induction of autophagy in rat hippocampal neurons.

Emerging roles for long noncoding RNAs in learning, memory and associated disorders.

While protein-coding genes have been widely studied in learning and memory, the role of the non-coding genome has only recently been investigated. With advances in high throughput sequencing technologies and functional profiling methods, multiple long noncoding RNAs (lncRNAs) have been functionally and mechanistically linked with neurobiological processes related with learning and memory, as well disorders that lead to memory impairment. However, these macromolecules are still a subject of controversy and intense scrutiny regarding the proper criteria for determining their functionality and their evolution in the central nervous system. Recent studies have implicated multiple lncRNAs as critical regulators of gene expression in the central nervous system and mediate learning processes. In this review, we explore possible explanations for how lncRNAs are evolved in our central nervous system, discuss our current understanding of their involvement in learning and memory related disorders, and describe emerging tools for studying lncRNAs.

Neurocognitive Disorders in Heart Failure: Novel Pathophysiological Mechanisms Underpinning Memory Loss and Learning Impairment.

Heart failure (HF) is a major public health issue affecting more than 26 million people worldwide. HF is the most common cardiovascular disease in elder population; and it is associated with neurocognitive function decline, which represent underlying brain pathology diminishing learning and memory faculties. Both HF and neurocognitive impairment are associated with recurrent hospitalization episodes and increased mortality rate in older people, but particularly when they occur simultaneously. Overall, the published studies seem to confirm that HF patients display functional impairments relating to attention, memory, concentration, learning, and executive functioning compared with age-matched controls. However, little is known about the molecular mechanisms underpinning neurocognitive decline in HF. The present review round step recent evidence related to the possible molecular mechanism involved in the establishment of neurocognitive disorders during HF. We will make a special focus on cerebral ischemia, neuroinflammation and oxidative stress, Wnt signaling, and mitochondrial DNA alterations as possible mechanisms associated with cognitive decline in HF. Also, we provide an integrative mechanism linking pathophysiological hallmarks of altered cardiorespiratory control and the development of cognitive dysfunction in HF patients. Graphical Abstract Main molecular mechanisms involved in the establishment of cognitive impairment during heart failure. Heart failure is characterized by chronic activation of brain areas responsible for increasing cardiac sympathetic load. In addition, HF patients also show neurocognitive impairment, suggesting that the overall mechanisms that underpin cardiac sympathoexcitation may be related to the development of cognitive disorders in HF. In low cardiac output, HF cerebral infarction due to cardiac mural emboli and cerebral ischemia due to chronic or intermittent cerebral hypoperfusion has been described as a major mechanism related to the development of CI. In addition, while acute norepinephrine (NE) release may be relevant to induce neural plasticity in the hippocampus, chronic or tonic release of NE may exert the opposite effects due to desensitization of the adrenergic signaling pathway due to receptor internalization. Enhanced chemoreflex drive is a major source of sympathoexcitation in HF, and this phenomenon elevates brain ROS levels and induces neuroinflammation through breathing instability. Importantly, both oxidative stress and neuroinflammation can induce mitochondrial dysfunction and vice versa. Then, this ROS inflammatory pathway may propagate within the brain and potentially contribute to the development of cognitive impairment in HF through the activation/inhibition of key molecular pathways involved in neurocognitive decline such as the Wnt signaling pathway.