Dissociation of rugose‐dependent short‐term memory component from memory consolidation in Drosophila

Extensive investigations show several molecular and neuroanatomical mechanisms underlying short‐lived and long‐lasting memory in Drosophila. At the molecular level, the genetic pathway of memory formation, which was obtained through mutant research, seems to occur sequentially. So far, studies of Drosophila mutants appear to support the idea that mutants defective in short‐term memory (STM) are always associated with long‐term memory (LTM) impairment. At the neuroanatomical level, distinct memory traces are partially independently distributed. However, whether memory phase dissociation also exists at the molecular level remains unclear. Here, we report on molecular separation of STM and consolidated memory through genetic dissection of rugose mutants. Mutants in the rugose gene, which encodes an evolutionarily conserved A‐kinase anchor protein, show immediate memory defects as assayed through aversive olfactory conditioning. Intriguingly, two well‐defined consolidated memory components, anesthesia‐resistant memory and protein synthesis‐dependent LTM, are both normal in spite of the defective immediate memory after 10‐session massed and spaced training. Moreover, rugose genetically interacts with cyclic AMP‐protein kinase A signaling during STM formation. Considering our previous study that AKAP Yu specifically participates in LTM formation, these results suggest that there exists a molecular level of memory phase dissociation with distinct AKAPs in Drosophila.     

α8‐Integrins are required for hippocampal long‐term potentiation but not for hippocampal‐dependent learning

Integrins are heterodimeric transmembrane cell adhesion receptors that are essential for a wide range of biological functions via cell–matrix and cell–cell interactions. Recent studies have provided evidence that some of the subunits in the integrin family are involved in synaptic and behavioral plasticity. To further understand the role of integrins in the mammalian central nervous system, we generated a postnatal forebrain and excitatory neuron‐specific knockout of α8‐integrin in the mouse. Behavioral studies showed that the mutant mice are normal in multiple hippocampal‐dependent learning tasks, including a T‐maze, non‐match‐to‐place working memory task for which other integrin subunits like α3‐ and β1‐integrin are required. In contrast, mice mutant for α8‐integrin exhibited a specific impairment of long‐term potentiation (LTP) at Schaffer collateral–CA1 synapses, whereas basal synaptic transmission, paired‐pulse facilitation and long‐term depression (LTD) remained unaffected. Because LTP is also impaired in the absence of α3‐integrin, our results indicate that multiple integrin molecules are required for the normal expression of LTP, and different integrins display distinct roles in behavioral and neurophysiological processes like synaptic plasticity.     

Melatonin and its metabolite N(1)‐acetyl‐N(1)‐formyl‐5‐methoxykynuramine improve learning and memory impairment related to Alzheimer's disease in rats

The aim of this study was to investigate the effect of melatonin (MT) and its metabolite N(1)‐acetyl‐N(2)‐formyl‐5‐methoxykynuramine (AFMK) on Alzheimer‐like learning and memory impairment in rats intracerebroventricularly injected with streptozotocin (STZ). The results showed that the escape latency of the STZ group was longer than that of the control (CON), MT, and AFMK groups. Increased levels of hyperphosphorylated tau, neurofilament proteins, and malondialdehyde and decreased superoxide dismutase levels were observed in the brains of the rats from the STZ group compared with the brains of the rats from the CON, MT, AFMK high and low group. These results suggest that exogenous MT and AFMK can improve memory impairment and downregulate AD‐like hyperphosphorylation induced by STZ, most likely through their antioxidation function. Meanwhile, we found that an equal dose of AFMK had a stronger effect than that of MT. Our results indicate that MT and its metabolite AFMK represent novel treatment strategies for Alzheimer's disease.     

Early‐life exposure to high‐fat diet influences brain health in aging mice

Epidemiological studies have suggested a link between exposure to environmental factors early in life and susceptibility to neurodegenerative diseases in adulthood. In the short term, maternal diet is important for the growth and development of the fetus; however, it may also have long‐term effects on the health status of the offspring. Here, we investigate the effect that maternal high‐fat diet during gestation has on brain health of the offspring later in life. B6129SF2/J dams were fed a high‐fat diet during the 3 weeks’ gestation, then switched to standard chow diet after delivery. Offspring were always fed regular diet for the entire study and assessed in learning, memory, and brain pathology when 18 months old. Compared with offspring from control mothers, the ones from mothers exposed to high‐fat diet had significant better performance in learning and memory tests, which associated with an amelioration of synaptic integrity. Additionally, they had a significant reduction in total tau, a decrease in its pathological conformational changes and lower levels of caspase‐3‐cleaved isoforms. Our findings demonstrate that in utero exposure to high‐fat diet plays a protective role for offspring brain health later in life. They support the novel hypothesis that targeted dietary intervention specifically restricted to the gestation period could be implemented as preventative strategy for the age‐dependent decline in brain health.     

Aging‐associated formaldehyde‐induced norepinephrine deficiency contributes to age‐related memory decline

A norepinephrine (NE) deficiency has been observed in aged rats and in patients with Alzheimer's disease and is thought to cause cognitive disorder. Which endogenous factor induces NE depletion, however, is largely unknown. In this study, we investigated the effects of aging‐associated formaldehyde (FA) on the inactivation of NE in vitro and in vivo, and on memory behaviors in rodents. The results showed that age‐related DNA demethylation led to hippocampal FA accumulation, and when this occurred, the hippocampal NE content was reduced in healthy male rats of different ages. Furthermore, biochemical analysis revealed that FA rapidly inactivated NE in vitro and that an intrahippocampal injection of FA markedly reduced hippocampal NE levels in healthy adult rats. Unexpectedly, an injection of FA (at a pathological level) or 6‐hydroxydopamine (6‐OHDA, a NE depletor) can mimic age‐related NE deficiency, long‐term potentiation (LTP) impairments, and spatial memory deficits in healthy adult rats. Conversely, an injection of NE reversed age‐related deficits in both LTP and memory in aged rats. In agreement with the above results, the senescence‐accelerated prone 8 (SAMP8) mice also exhibited a severe deficit in LTP and memory associated with a more severe NE deficiency and FA accumulation, when compared with the age‐matched, senescence‐resistant 1 (SAMR1) mice. Injection of resveratrol (a natural FA scavenger) or NE into SAMP8 mice reversed FA accumulation and NE deficiency and restored the magnitude of LTP and memory. Collectively, these findings suggest that accumulated FA is a critical endogenous factor for aging‐associated NE depletion and cognitive decline.     

Protection against β‐amyloid neurotoxicity by a non‐toxic endogenous N‐terminal β‐amyloid fragment and its active hexapeptide core sequence

High levels (μM) of beta amyloid (Aβ) oligomers are known to trigger neurotoxic effects, leading to synaptic impairment, behavioral deficits, and apoptotic cell death. The hydrophobic C‐terminal domain of Aβ, together with sequences critical for oligomer formation, is essential for this neurotoxicity. However, Aβ at low levels (pM‐nM) has been shown to function as a positive neuromodulator and this activity resides in the hydrophilic N‐terminal domain of Aβ. An N‐terminal Aβ fragment (1–15/16), found in cerebrospinal fluid, was also shown to be a highly active neuromodulator and to reverse Aβ‐induced impairments of long‐term potentiation. Here, we show the impact of this N‐terminal Aβ fragment and a shorter hexapeptide core sequence in the Aβ fragment (Aβcore: 10–15) to protect or reverse Aβ‐induced neuronal toxicity, fear memory deficits and apoptotic death. The neuroprotective effects of the N‐terminal Aβ fragment and Aβcore on Aβ‐induced changes in mitochondrial function, oxidative stress, and apoptotic neuronal death were demonstrated via mitochondrial membrane potential, live reactive oxygen species, DNA fragmentation and cell survival assays using a model neuroblastoma cell line (differentiated NG108‐15) and mouse hippocampal neuron cultures. The protective action of the N‐terminal Aβ fragment and Aβcore against spatial memory processing deficits in amyloid precursor protein/PSEN1 (5XFAD) mice was demonstrated in contextual fear conditioning. Stabilized derivatives of the N‐terminal Aβcore were also shown to be fully protective against Aβ‐triggered oxidative stress. Together, these findings indicate an endogenous neuroprotective role for the N‐terminal Aβ fragment, while active stabilized N‐terminal Aβcore derivatives offer the potential for therapeutic application.

     

Overexpression of the NR2A subunit in the forebrain impairs long‐term social recognition and non‐social olfactory memory

Animals must recognize and remember conspecifics and potential mates, and distinguish these animals from potential heterospecific competitors and predators. Despite its necessity, aged animals are known to exhibit impaired social recognition memory. As the brain ages, the ratio of NR2A:NR2B in the brain increases over time and has been postulated to underlie the cognitive decline observed during the aging process. Here, we test the hypothesis that an increased NR2A:NR2B subunit ratio underlies long‐term social recognition memory. Using transgenic overexpression of NR2A in the forebrain regions, we investigated the ability of these mice to learn and remember male and female conspecifics, mice of another strain and animals of another rodent species, the rat. Furthermore, due to the importance of olfaction in social recognition, we tested the olfactory memory in the NR2A transgenic mice. Our series of behavioral experiments revealed significant impairments in the NR2A transgenic mice in long‐term social memory of both male and female conspecifics. Additionally, the NR2A transgenic mice are unable to recognize mice of another strain or rats. The NR2A transgenic mice also exhibited long‐term memory impairments in the olfactory recognition task. Taken together, our results provide evidence that an increased NR2A:NR2B ratio in the forebrain leads to reduced long‐term memory function, including the ethologically important memories such as social recognition and olfactory memory .     

Isoform‐specific effects of apolipoprotein E on cognitive performance in targeted‐replacement mice overexpressing human APP

The ε4 allele of apolipoprotein E (apoE4) is the predominant genetic risk factor for late‐onset Alzheimer's disease (AD) and is also implicated in cognitive deficits associated with normal aging. The biological mechanisms by which APOE genotype affects cognitive processes or AD pathogenesis remain unclear, but interactions of apoE with amyloid β peptide (Aβ) are thought to play an important role in mediating apoE's isoform‐specific effects on brain function. Here, we investigated the potential isoform‐dependent effects of apoE on behavioral and cognitive performance in human apoE3 and apoE4 targeted‐replacement (TR) mice that also overexpress the human amyloid precursor protein (APP). Beginning at 6–7 months of age, female APP‐Yac/apoE3‐TR (‘poE3’) and APP‐Yac/apoE4‐TR (‘poE4’) mice were tested on a battery of tests to evaluate basic sensorimotor functioning, spatial working memory, spatial recognition, episodic‐like memory and attentional processing. Compared with apoE3 mice, a generalized reduction in locomotor activity was observed in apoE4 mice. Moderate, but significant, cognitive impairments were also detected in apoE4 mice in the novel object‐location preference task, the contextual fear conditioning test, and a two‐choice visual discrimination/detection test, however spontaneous alternation performance in the Y‐maze was spared. These results offer additional support for the negative impact of apoE4 on both memory and attention and further suggest that APP‐Yac/apoE‐TR mice provide a novel and useful model for investigating the role of apoE in mediating susceptibility to cognitive decline.     

TIP39 modulates effects of novelty‐induced arousal on memory

Tuberoinfundibular peptide of 39 residues (TIP39) is a neuropeptide localized to neural circuits subserving emotional processing. Recent work showed that mice with null mutation for the gene coding TIP39 (TIP39‐KO mice) display increased susceptibility to environmental provocation. Based on this stressor‐dependent phenotype, the neuroanatomical distribution of TIP39, and knowledge that novelty‐induced arousal modulates memory functions via noradrenergic activation, we hypothesized that exposure to a novel environment differently affects memory performance of mice with or without TIP39 signaling, potentially by differences in sensitivity of the noradrenergic system. We tested TIP39‐KO mice and mice with null mutation of its receptor, the parathyroid hormone 2 receptor (PTH2‐R), in tasks of short‐term declarative and social memory (object recognition and social recognition tests, respectively), and of working memory (Y‐maze test) under conditions of novelty‐induced arousal or acclimation to the test conditions. Mice lacking TIP39 signaling showed memory impairment selectively under conditions of novelty‐induced arousal. Acute administration of a PTH2‐R antagonist in wild‐type mice had a similar effect. The restoration of memory functions in TIP39‐KO mice after injection of a β‐adrenoreceptor‐blocker, propranolol, suggested involvement of the noradrenergic system. Collectively, these results suggest that the TIP39/PTH2‐R system modulates the effects of novelty exposure on memory performance, potentially by acting on noradrenergic signaling.     

Fur seal mothers memorize subsequent versions of developing pups’ calls: adaptation to long‐term recognition or evolutionary by‐product?

In pinnipeds and especially in otariids, mothers and pups develop the capacity to recognize each other's voices. Pups become able to discriminate their mother's voice a few days after birth. For females, this discrimination seems to occur earlier, probably during the few hours after parturition. However, during lactation, mothers are confronted with a major problem: the change of the characteristics of their pup's calls. To investigate this problem, we first performed an acoustic analysis of pups' calls from birth to weaning to identity the successive different versions of these calls. Secondly, we performed playback experiments just before weaning to test if females retain these different versions over a long time period. The acoustic analysis of pups' calls reveals that several characteristics of their vocalizations change with age. Playback experiments demonstrate that females still recognize all the successive immature and mature versions of their pup's calls. In our opinion, this long-term memorization seems to be a by-product of the permanent pups' voice learning from birth to weaning since no apparent adaptive benefit seems to arise from this capacity.  © 2003 The Linnean Society of London, Biological Journal of the Linnean Society , 2003, 80 , 305–312.     

Study of trivalent samarium ion embedded lithium‐based borate glass for high‐density optical memory devices

Sm³⁺ ions doped strontium lithium lead borate glasses (SLLB:Sm) were prepared using a conventional melt‐quenching technique. The glasses were analyzed using X‐ray diffractometry and Fourier transform infrared spectroscopy, optical absorption, fluorescence spectral analysis, and fluorescence lifetime decay. The Judd–Ofelt (J–O) parameters and radiative parameters of the SLLB:Sm10 glass (1.0 mol% Sm³⁺ ion‐doped glass) were calculated using J–O theory. From the emission spectra, among all the synthesized glass, SLLB:Sm10 glass had the highest emission intensity for ⁴G_5/2→⁶H_11/2 transition (610 nm). Emission parameters, such as stimulated emission cross‐section and optical gain bandwidth, were calculated. For all concentrations of Sm³⁺ ions, the decay profile showed an exponential nature and decreased when the Sm³⁺ ion concentration was increased due to a concentration quenching effect. This result suggests that the synthesized SLLB:Sm10 glass could be used for application in high‐density optical memory devices.     

Increased miR‐34c mediates synaptic deficits by targeting synaptotagmin 1 through ROS‐JNK‐p53 pathway in Alzheimer’s Disease

Alzheimer's disease (AD) and cancer have inverse relationship in many aspects. Some tumor suppressors, including miR‐34c, are decreased in cancer but increased in AD. The upstream regulatory pathways and the downstream mechanisms of miR‐34c in AD remain to be investigated. The expression of miR‐34c was detected by RT–qPCR in oxidative stressed neurons, hippocampus of SAMP8 mice, or serum of patients with amnestic mild cognitive impairment (aMCI). Dual luciferase assay was performed to confirm the binding sites of miR‐34c in its target mRNA. The Morris water maze (MWM) was used to evaluate learning and memory in SAMP8 mice administrated with miR‐34c antagomir (AM34c). Golgi staining was used to evaluate the synaptic function and structure. The dramatically increased miR‐34c was mediated by ROS‐JNK‐p53 pathway and negatively regulated synaptotagmin 1 (SYT1) expression by targeting the 3′‐untranslated region (3′‐UTR) of syt1 in AD. The expression of SYT1 protein was reduced by over expression of miR‐34c in the HT‐22 cells and vice versa. Administration of AM34c by the third ventricle injection or intranasal delivery markedly increased the brain levels of SYT1 and ameliorated the cognitive function in SAMP8 mice. The serum miR‐34c was significantly increased in patients with aMCI and might be a predictive biomarker for diagnosis of aMCI. These results indicated that increased miR‐34c mediated synaptic and memory deficits by targeting SYT1 through ROS‐JNK‐p53 pathway and the miR‐34c/SYT1 pathway could be considered as a promising novel therapeutic target for patients with AD.     

Plasticity‐related genes in brain development and amygdala‐dependent learning

Learning about motivationally important stimuli involves plasticity in the amygdala, a temporal lobe structure. Amygdala‐dependent learning involves a growing number of plasticity‐related signaling pathways also implicated in brain development, suggesting that learning‐related signaling in juveniles may simultaneously influence development. Here, we review the pleiotropic functions in nervous system development and amygdala‐dependent learning of a signaling pathway that includes brain‐derived neurotrophic factor (BDNF), extracellular signaling‐related kinases (ERKs) and cyclic AMP‐response element binding protein (CREB). Using these canonical, plasticity‐related genes as an example, we discuss the intersection of learning‐related and developmental plasticity in the immature amygdala, when aversive and appetitive learning may influence the developmental trajectory of amygdala function. We propose that learning‐dependent activation of BDNF, ERK and CREB signaling in the immature amygdala exaggerates and accelerates neural development, promoting amygdala excitability and environmental sensitivity later in life.     

Different effects of bisphenol‐A on memory behavior and synaptic modification in intact and estrogen‐deprived female mice

Bisphenol‐A (BPA) has the capability of interfering with the effects of estrogens on modulating brain function. The purpose of this study was to investigate the effects of BPA on memory and synaptic modification in the hippocampus of female mice under different levels of cycling estrogen. BPA exposure (40, 400 μg/kg/day) for 8 weeks did not affect spatial memory and passive avoidance task of gonadally intact mice but improved ovariectomy (Ovx)‐induced memory impairment, whereas co‐exposure of BPA with estradiol benzoate (EB) diminished the rescue effect of EB on memory behavior of Ovx mice. The results of morphometric measurement showed that BPA positively modified the synaptic interface structure and increased the synaptic density of CA1 pyramidal cell in the hippocampus of Ovx females, but inhibited the enhancement of EB on synaptic modification and synaptogenesis of Ovx mice. Furthermore, BPA up‐regulated synaptic proteins synapsin I and PSD‐95 and NMDA receptor NR2B but inhibited EB‐induced increase in PSD‐95 and NR2B in the hippocampus of Ovx mice. These results suggest that BPA interfered with normal hormonal regulation in synaptic plasticity and memory of female mice as a potent estrogen mimetic and as a disruptor of estrogen under various concentrations of cycling estrogen.

     

Gender differences in brain networks during verbal Sternberg tasks: A simultaneous near‐infrared spectroscopy and electro‐encephalography study

Gender differences in psychological processes have been of great interest in a variety of fields including verbal fluency, emotion processing and working memory. Previous studies suggested that women outperform men in verbal working memory (VWM). However, the inherent mechanisms are still unclear. To obtain a deeper insight into the gender differences in brain networks in VWM, this study used near‐infrared spectroscopy (NIRS) and electro‐encephalography (EEG) simultaneously to investigate gender‐related brain networks during verbal Sternberg tasks. NIRS results confirmed that women surpass men in VWM from the perspective of both brain activation and connectivity. Results of EEG (effective connectivity and event‐related spectral power) showed that men tend to use a more visuospatial strategy to encode memory. In addition, novel analysis methods of brain networks can provide useful information about the gender specifics of brain functions. Gender‐related pseudo‐color maps constructed from all channels of average HbO₂ activity during low‐ and high‐load tasks (from 0 to 6 seconds after beginning).