Immune Synaptopathy and Sex Differences in Recognition Memory from Neonatal Staphylococcus epidermidis Infection

Our aim was to develop a quantitative model for immediately estimating the risk of death and/or brain injury in late-onset sepsis (LOS) in preterm infants, based on objective and measurable data available at the time sepsis is first suspected (i.e., time of blood culture collection). Retrospective study on neonates ≤36 weeks' gestation with a positive blood and/or cerebrospinal fluid culture after 72 hours from birth. Among 3217 preterm live births, 94 cases were included (median gestational age 26.5 weeks' IQR 25.0;28.0), of whom 26 (27.7%) had poor outcomes (17 death; 9 brain injuries). Infants with poor outcomes showed lower postnatal age (11.5 vs 12.5 days, p < 0.001), lower mean blood pressure (30.5 vs 43 mmHg, p < 0.001) and higher lactate levels (4.4 vs 1.5 mmol/l, p < 0.001). Our multivariable model showed good discrimination and calibration (c statistic=0.8618, Hosmer-Lemeshow p = 0.8532), stratifying the population into 3 groups: low-risk (sensitivity 97%, specificity 52%), middle-risk, and high-risk (sensitivity 77%, specificity 80%). This predictive model performs well as a practical and easy-to-use tool to help clinicians early identify the sickest neonates who may benefit from timely and aggressive support (e.g., central line, haemodynamic assessment) and close monitoring (e.g., 1:1 nursing assignment, frequent reassessments). We lack data to early identify the severity of neonatal late-onset sepsis in preterm infants. Delay in treatment contributes to poor prognosis. We developed a model for early prediction of poor outcomes (mortality and brain injuries). The model utilizes immediately available and measurable data at the time sepsis is first suspected. This can help clinicians in tailoring management based on individual risks.

Chapter 22 - Mild Traumatic Brain Injuries and Object Recognition

miRNAs may regulate GABAergic transmission associated genes in aged rats with anesthetics-induced recognition and working memory dysfunction

Risk factors and prevention of late-onset sepsis in premature infants

ABSTRACTOBJECTIVE: The aims of this study were to investigate the protective effect of quercetin on changes in recognition memory as assessed by the novel object recognition (NOR) test, as well as on changes in the oxidative stress levels in the hippocampus and prefrontal cortex, produced in a model of memory impairment in schizophrenia induced by administration of a subanesthetic dose of ketamine.METHODS: A total of 40 Balb-C mice were randomly divided into five groups (Corn oil + Saline, Quercetin 50 + Saline, Corn oil + Ketamine, Quercetin 25 + Ketamine, Quercetin 50 + Ketamine). Corn oil and Quercetin (25 or 50 mg/kg/day) was given by orogastric gavage once daily for 21 days. Corn oil was chosen as the vehicle and administered at the same volume as quercetin. Ketamine was injected at a dose of 25 mg/kg intraperitoneally (i.p.) for a period of 7 days starting from the 15th day. Behavioural responses were evaluated with the NOR test. The activity levels of antioxidant enzymes and levels of malondialdehyde (MDA) were assayed in the prefrontal cortex and hippocampus.RESULTS: The time of exploration of the novel object was longer than TF (time to explore the familiar object) in the Corn oil + Saline and Quercetin 50 + Saline groups in NOR Test-1 (p < .05). The discrimination ratios of the Quercetin 50 + Ketamine and Corn oil + Ketamine groups were significantly lower than that of the Quercetin 50 + Saline group (p < .05). The discrimination ratios of the Quercetin 50 + Ketamine and Corn oil + Saline groups were significantly lower than that of the Quercetin 50 + Saline group (p < .05). The time of exploration of the novel object was longer than TF in the Corn oil + Saline and Quercetin 50 + Ketamine groups in NOR Test-2 (p < .05). The discrimination ratios of the Corn oil + Ketamine and Quercetin 25 + Ketamine groups were significantly lower than those of the Quercetin 50 + Ketamine group (p < .05). Quercetin at 50 mg/kg reduced the MDA levels and elevated the SOD and GPx activity compared to the Corn oil + Ketamine group.CONCLUSION: These results show that quercetin has the potential to improve cognitive deficits in mice and that quercetin may be useful for treating the symptoms of schizophrenia, partially due to its ability to scavenge free radicals and its high antioxidant capacity.

Status epilepticus (SE) can significantly increase the risk of temporal lobe epilepsy (TLE) and cognitive comorbidities. A potential candidate mechanism underlying memory defects in epilepsy may be the immune complement system. The complement cascade, part of the innate immune system, modulates inflammatory and phagocytosis signaling, and has been shown to contribute to learning and memory dysfunctions in neurodegenerative disorders. We previously reported that complement C3 is elevated in brain biopsies from human drug-resistant epilepsy and in experimental rodent models. We also found that SE-induced increases in hippocampal C3 levels paralleled the development of hippocampal-dependent spatial learning and memory deficits in rats. Thus, we hypothesized that SE-induced C3 activation contributes to this pathophysiology in a mouse model of SE and acquired TLE. In this study C3 knockout (KO) and wild type (WT) mice were subjected to one hour of pilocarpine-induced SE or sham conditions (control; C). Following a latent period of two weeks, recognition memory was assessed utilizing the novel object recognition (NOR) test. Western blotting was utilized to determine the protein levels of C3 in hippocampal lysates. In addition, we assessed the protein levels and distribution of the astrocyte marker glial fibrillary acidic protein (GFAP). In the NOR test, control WT + C or C3 KO + C mice spent significantly more time exploring the novel object compared to the familiar object. In contrast, WT+SE mice did not show preference for either object, indicating a memory defect. This deficit was prevented in C3 KO + SE mice, which performed similarly to controls. In addition, we found that SE triggered significant increases in the protein levels of GFAP in hippocampi of WT mice but not in C3 KO mice. These findings suggest that ablation of C3 prevents SE-induced recognition memory deficits and that a C3-astrocyte interplay may play a role. Therefore, it is possible that enhanced C3 signaling contributes to SE-associated cognitive decline during epileptogenesis and may serve as a potential therapeutic target for treating cognitive comorbidities in acquired TLE.

The perirhinal cortex (PRh) is a critical mediator of recognition memory, and a wealth of evidence points to impairment in PRh function with age. Despite this evidence, age-related deficits in recognition memory are not consistently observed. This may be partially due to the fact that older animals also have well-established deficits in hippocampal function, and many protocols that assess perirhinal function are also sensitive to hippocampal damage. When using one of these protocols, spontaneous object recognition in an open field, we are able to replicate published age-related deficits using pairs of complex objects. However, when using zero-delay object recognition, a task that is more resistant to the influence of changes in hippocampal function, we find no significant age-related differences in recognition memory in the same animals. These data highlight the importance of the protocol used for testing recognition memory, and may place constraints on the role of the PRh in age-related recognition memory impairment as it is typically tested in much of the literature.

Recognition memory for conspecific and heterospecific song in juvenile zebra finches, Taeniopygia guttata

Prior research suggests that older adults are less likely than young adults to use effective learning strategies during intentional encoding. This functional magnetic resonance imaging (fMRI) study investigated whether training older adults to use semantic encoding strategies can increase their self-initiated use of these strategies and improve their recognition memory. The effects of training on older adults' brain activity during intentional encoding were also examined. Training increased older adults' self-initiated semantic encoding strategy use and eliminated pretraining age differences in recognition memory following intentional encoding. Training also increased older adults' brain activity in the medial superior frontal gyrus, right precentral gyrus, and left caudate during intentional encoding. In addition, older adults' training-related changes in recognition memory were strongly correlated with training-related changes in brain activity in prefrontal and left lateral temporal regions associated with semantic processing and self-initiated verbal encoding strategy use in young adults. These neuroimaging results demonstrate that semantic encoding strategy training can alter older adults' brain activity patterns during intentional encoding and suggest that young and older adults may use the same network of brain regions to support self-initiated use of verbal encoding strategies.

β-caryophyllene (BCP), a natural sesquiterpene present in plants, is a selective agonist of cannabinoid receptor type-2 (CB2) of the endocannabinoid system. In this study, we have prepared an extract from Piper nigrum (black pepper) seeds using supercritical fluid extraction, standardized to contain 30% BCP (ViphyllinTM ). The beneficial effects of prophylactic treatment with Viphyllin on cognitive functions were demonstrated in Scopolamine-induced dementia model mice. Male Swiss albino mice (25-30g) were administered with Viphyllin (50mg and 100mg/kg body weight p.o.) or donepezil (1.60mg/kg) for 14days. Subsequently, cognitive deficits were induced by treating the animals intraperitoneally with Scopolamine (0.75mg/kg). The cognitive behavior of mice was evaluated using a novel object recognition test (NORT) and Morris water maze (MWM) test. The brain homogenates were studied for biochemical parameters including cholinesterase activities and antioxidant status. Western blot analysis was performed to investigate the mechanism of action. Viphyllin dose dependently improved the recognition and spatial memory and cholinergic functions in Scop-treated mice. The extract was found protective against Scop-induced oxidative damage and histopathologic changes in the brain. At 100mg/kg Viphyllin markedly reduced the proBDNF/mBDNF ratio (p<.05) and augmented the TrkB expression (p<.01). Viphyllin (100mg/kg) was found to be neuroprotective by reducing the Scop-induced upregulation of p-JNK and p-p38 MAPK proteins, Bax/Bcl-2 ratio, and caspase activation in the brain. Viphyllin also exerted anti-inflammatory effects by downregulating Cox-2, TNF-α, and NOS-2 in Scop-induced mice (p<.05). To summarize, our data encourage Viphyllin as a functional ingredient/dietary supplement for brain health and cognition. PRACTICAL APPLICATIONS: Black pepper is a culinary spice having several medicinal attributes. Essential oils in the seeds of the plant give aroma and flavor to it. Here we have prepared an extract from the seeds of black pepper using supercritical fluid extraction, characterized for the presence of β-caryophyllene (not <30%). This research work further validates the neuroprotective mechanism of the extract in Scopolamine-induced cognitive impairment model mice. The findings from this study strongly suggest the beneficial neuroactive properties of black pepper seed extract having the presence of BCP, a CB2 receptor agonist. It can thus be used potentially as a functional food ingredient for cognition and brain function.

Objective: This study aimed to investigate the potential therapeutic effects of agmatine (AGM), a neuromodulatory compound, on social interaction impairments and repetitive behaviors in a valproic acid (VPA)-induced animal model of Autism Spectrum Disorder (ASD). Methods: Pregnant Sprague-Dawley rats were administered VPA (400 mg/kg, s.c.) on embryonic day 12.5, while the control group received saline (0.1ml/100g body weight). The pups were weaned on postnatal day 21 and divided into control, ASD, and ASD+AGM groups. AGM was administered intraperitoneally at a dose of 50 mg/kg between postnatal days 30 and 45. On postnatal days 46 and 52, the open field test (OFT) was performed to assess locomotor activity and repetitive behaviors, the social interaction test was performed to assess social approach and communication, and the novel object recognition test (NORT) was performed to assess learning and memory performance. Results: Compared with the control group, the ASD group exhibited increased locomotor activity and repetitive grooming in the OFT, decreased learning performance in the NORT, and impaired social interaction in the social interaction test. AGM treatment significantly reversed these behavioral abnormalities, restoring repetitive behaviors, learning and memory performance, and social interaction to levels comparable to controls. Conclusion: These findings suggest that exogenous administration of AGM, an endogenous neuromodulator, can effectively modulate the behavioral deficits observed in ASD. Therefore, targeting molecules involved in AGM synthesis and metabolism may offer promising prospects for the development of novel therapeutic strategies for ASD.

Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA methylation profiles in the mouse medial prefrontal cortex

Prolonged interaction with challenging life situations is a well-recognised risk factor for depression, anxiety, and cognitive decline, particularly among menopausal women. This research aimed to assess the effects of metformin (MF) on anxiety-like behavioural changes, cognitive impairment, brain neuroplasticity, and apoptosis induced by chronic unpredictable mild stress (CUMS) in menopausal rats. To achieve this, we conducted the open field test (OFT) to measure anxiety- like behaviours and locomotor activity, the elevated plus- maze (EPM) to assess anxiety-like behaviour, and the novel object recognition test (NORT) to evaluate recognition memory. Additionally, we measured the levels of BDNF, SIRT 1, synaptophysin, and caspase-9 by ELISA in the hippocampus, prefrontal cortex (PFC), and amygdala. Our experimental groups were categorised into five groups, with six rats in each group, as follows: Control, ovariectomized (OVX), OVX+CUMS, OVX+MF, and OVX+CUMS+MF. Four weeks after the OVX, the CUMS protocol was implemented, and MF treatment commenced following CUMS and continued for 14 days. Chronic administration of MF improved recognition memory and anxiety levels in rats subjected to CUMS, as assessed by the NORT, OFT, and EPM. MF increased brain-derived neurotrophic factor, synaptophysin, and sirtuin1, key markers of neuroplasticity in specific brain regions. We also found that MF treatment reduced pro-apoptotic caspase-9 levels. Histopathological analysis of the hippocampal DG and prefrontal cortex indicated neurodegenerative changes such as pyknotic nuclei, cytoplasmic sparseness, widespread vacuolization, and perivascular and pericellular oedema in the OVX and OVX+CUMS groups. However, these pathological features were significantly diminished in the MF groups, resulting in better preservation of neuronal integrity, fewer pyknotic cells, and reduced vacuolization. In conclusion, metformin appears to be a beneficial therapeutic agent that enhances neural plasticity, decreases apoptosis, and improves recognition memory and anxiety- like behaviours induced by OVX+CUMS

BackgroundMemory impairment is frequent among alcohol use disorder (AUD) patients, and we lack specific biomarkers to detect it. Certain apolipoproteins were linked to cognition, and carrying the APOE4 gene is a vulnerability factor to memory impairment in AUD patients. We explored memory deficits in alcohol‐dependent male mice and humans versus controls, and their relationship to Apolipoprotein AI (APOAI), apolipoprotein B (APOB), and apolipoprotein E (APOE) plasma levels.MethodsMale C57BL/6J mice underwent voluntary alcohol drinking (two‐bottle choice, 2BC) and chronic intermittent ethanol vapor exposure (CIE) as a model of alcohol dependence; memory was assessed by the Object Location Test (OLT) and Novel Object Recognition Test (NORT). Additionally, male AUD‐diagnosed patients were recruited in Spain during an alcohol dishabituation program and assessed by the Wechsler Memory Scale‐IV (WMS‐IV). Plasma APOAI, APOB, and APOE levels were checked in mice and humans by ELISA kits and Luminex immunoassay technology. APOAI immunolabeling was quantified in mouse brain in early withdrawal and following alcohol consumption.ResultsCIE‐2BC mice (n = 8) escalated alcohol consumption compared to Air‐2BC controls (n = 11) and showed deficits in spatial memory (OLT) and recognition memory (NORT) while AUD patients (n = 12) showed deficits in verbal and visual memory (WMS‐IV) versus controls (n = 16). Higher plasma levels of APOAI were detected in CIE‐2BC mice and AUD patients, with no differences in APOB and APOE in animals and humans. Significant negative correlations were found between levels of APOAI, APOB, and APOE and memory function tests/scales in the entire sample, with APOAI showing consistent results in both animals and humans. APOAI immunoreactivity was detected in the mice subfornical organ, but the signal did not differ between experimental groups.ConclusionsBoth CIE‐2BC mice and AUD patients exhibited elevated plasma levels of APOAI during early abstinence. APOAI correlated with poorer memory performance in both species, suggesting a potential role for this apolipoprotein in the context of alcohol‐induced cognitive impairment.

Chapter 18 - Immediate-Early Gene Expression in Neural Circuits Related to Object Recognition Memory