Hippocampal lesions impair non-navigational spatial memory in macaques.

Decades of studies robustly support a critical role for the hippocampus in spatial memory across a wide range of species. Hippocampal damage produces clear and consistent deficits in allocentric spatial memory that requires navigating through space in rodents, non-human primates, and humans. By contrast, damage to the hippocampus spares performance in most non-navigational spatial memory tasks-which can typically be resolved using egocentric cues. We previously found that transient inactivation of the hippocampus impairs performance in the Hamilton Search Task (HST), a self-ordered non-navigational spatial search task. A key question, however, still needs to be addressed. Acute, reversible inactivation of the hippocampus may have resulted in an impairment in the HST because this approach does not allow for neuroplastic compensation, may prevent the development of an alternative learning strategy, and/or may produce network-based effects that disrupt performance. We compared learning and performance on the HST in male rhesus macaques (six unoperated control animals and six animals that underwent excitotoxic lesions of the hippocampus). We found a significant impairment in animals with hippocampal lesions. While control animals improved in performance over the course of 45 days of training, performance in animals with hippocampal lesions remained at chance levels. The HST thus represents a sensitive assay for probing the integrity of the hippocampus in non-human primates. These data provide evidence demonstrating that the hippocampus is critical for this type of non-navigational spatial memory, and help to reconcile the many null findings previously reported.

Can a failure in the error-monitoring system explain unawareness of memory deficits in Alzheimer's disease?

Unawareness of memory deficits is an early manifestation in patients with Alzheimer's disease (AD), which often delays diagnosis. This intriguing behavior constitutes a form of anosognosia, whose neural mechanisms remain largely unknown. We hypothesized that anosognosia may depend on a critical synaptic failure in the error-monitoring system, which would prevent AD patients from being aware of their own memory impairment. To investigate, we measured event-related potentials (ERPs) evoked by erroneous responses during a word memory recognition task in two groups of amyloid positive individuals with only subjective memory complaints at study entry: those who progressed to AD within the five-year study period (PROG group), and those who remained cognitively normal (CTRL group). A significant reduction in the amplitude of the positivity error (Pe), an ERP related to error awareness, was observed in the PROG group at the time of AD diagnosis (vs study entry) in intra-group analysis, as well as when compared with the CTRL group in inter-group analysis, based on the last EEG acquisition for all subjects. Importantly, at the time of AD diagnosis, the PROG group exhibited clinical signs of anosognosia, overestimating their cognitive abilities, as evidenced by the discrepancy scores obtained from caregiver/informant vs participant reports on the cognitive subscale of the Healthy Aging Brain Care Monitor. To our knowledge, this is the first study to reveal the emergence of a failure in the error-monitoring system during a word memory recognition task at the early stages of AD. This finding, along with the decline of awareness for cognitive impairment observed in the PROG group, strongly suggests that a synaptic dysfunction in the error-monitoring system may be the critical neural mechanism at the origin of unawareness of deficits in AD.

Limbic progesterone receptors regulate spatial memory.

Progesterone and its receptors (PRs) participate in mating and reproduction, but their role in spatial declarative memory is not understood. Male mice expressed PRs, predominately in excitatory neurons, in brain regions that support spatial memory, such as the hippocampus and entorhinal cortex (EC). Furthermore, segesterone, a specific PR agonist, activates neurons in both the EC and hippocampus. We assessed the contribution of PRs in promoting spatial and non-spatial cognitive learning in male mice by examining the performance of mice lacking this receptor (PRKO), in novel object recognition, object placement, Y-maze alternation, and Morris-Water Maze (MWM) tasks. In the recognition test, the PRKO mice preferred the familiar object over the novel object. A similar preference for the familiar object was also seen following the EC-specific deletion of PRs. PRKO mice were also unable to recognize the change in object position. We confirmed deficits in spatial memory of PRKO mice by testing them on the Y-maze forced alternation and MWM tasks; PR deletion affected animal's performance in both these tasks. In contrast to spatial tasks, PR removal did not alter the response to fear conditioning. These studies provide novel insights into the role of PRs in facilitating spatial, declarative memory in males, which may help with finding reproductive partners.

Animal Model of Neonatal Immune Challenge by Lipopolysaccharide: A Study of Sex Influence in Behavioral and Immune/Neurotrophic Alterations in Juvenile Mice.

INTRODUCTION: The prenatal/perinatal exposure to infections may trigger neurodevelopmental alterations that lead to neuropsychiatric disorders such as autism spectrum disorder (ASD). Previous evidence points to long-term behavioral consequences, such as autistic-like behaviors in rodents induced by lipopolysaccharide (LPS) pre- and postnatal (PN) exposure during critical neurodevelopmental periods. Additionally, sex influences the prevalence and symptoms of ASD. Despite this, the mechanisms underlying this influence are poorly understood. We aim to study sex influences in behavioral and neurotrophic/inflammatory alterations triggered by LPS neonatal exposure in juvenile mice at an approximate age of ASD diagnosis in humans. METHODS: Swiss male and female mice on PN days 5 and 7 received a single daily injection of 500 µg/kg LPS from Escherichia coli or sterile saline (control group). We conducted behavioral determinations of locomotor activity, repetitive behavior, anxiety-like behavior, social interaction, and working memory in animals on PN25 (equivalent to 3-5 years old of the human). To determine BDNF levels in the prefrontal cortex and hippocampus, we used animals on PN8 (equivalent to a human term infant) and PN25. In addition, we evaluated iba-1 (microglia marker), TNFα, and parvalbumin expression on PN25. RESULTS: Male juvenile mice presented repetitive behavior, anxiety, and working memory deficits. Females showed social impairment and working memory deficits. In the neurochemical analysis, we detected lower BDNF levels in brain areas of female mice that were more evident in juvenile mice. Only LPS-challenged females presented a marked hippocampal expression of the microglial activation marker, iba-1, and increased TNFα levels, accompanied by a lower parvalbumin expression. DISCUSSION/CONCLUSION: Male and female mice presented distinct behavioral alterations. However, LPS-challenged juvenile females showed the most prominent neurobiological alterations related to autism, such as increased microglial activation and parvalbumin impairment. Since these sex-sensitive alterations seem to be age-dependent, a better understanding of changes induced by the exposure to specific risk factors throughout life represents essential targets for developing strategies for autism prevention and precision therapy.

Mechanistic insight into the role of metformin in Alzheimer's disease.

Alzheimer's disease (AD), a type of dementia, is characterized by progressive memory decline and cognition impairment. Despite the considerable body of evidence regarding AD pathophysiology, current therapies merely slow down the disease progression, and a comprehensive therapeutic approach is unavailable. Accordingly, finding an efficient multifunctional remedy is necessary to blunt the increasing rate of AD incidence in the upcoming years. AD shares pathophysiological similarities (e.g., impairment of cognitive functions, insulin sensitivity, and brain glucose metabolism) with noninsulin-dependent diabetes mellitus (NIDDM), which offers the utilization of metformin, a biguanide hypoglycemic agent, as an alternative therapeutic approach in AD therapy. Emerging evidence has revealed the impact of metformin in patients suffering from AD. It has been described that metformin employs multiple mechanisms to improve cognition and memory impairment in pre-clinical AD models, including reduction of hippocampal amyloid-beta (Aß) plaque and neurofibrillary tangles (NFTs) load, suppression of inflammation, amelioration of mitochondrial dysfunction and oxidative stress, restriction of apoptotic neuronal death, and induction of neurogenesis. This review discusses the pre-clinical evidence, which may shed light on the role of metformin in AD and provide a more comprehensive mechanistic insight for future studies in this area of research.

Treadmill Exercise Prevents Decline in Spatial Learning and Memory in 3×Tg-AD Mice through Enhancement of Structural Synaptic Plasticity of the Hippocampus and Prefrontal Cortex.

Alzheimer's disease (AD) is characterized by deficits in learning and memory. A pathological feature of AD is the alterations in the number and size of synapses, axon length, dendritic complexity, and dendritic spine numbers in the hippocampus and prefrontal cortex. Treadmill exercise can enhance synaptic plasticity in mouse or rat models of stroke, ischemia, and dementia. The aim of this study was to examine the effects of treadmill exercise on learning and memory, and structural synaptic plasticity in 3×Tg-AD mice, a mouse model of AD. Here, we show that 12 weeks treadmill exercise beginning in three-month-old mice improves spatial working memory in six-month-old 3×Tg-AD mice, while non-exercise six-month-old 3×Tg-AD mice exhibited impaired spatial working memory. To investigate potential mechanisms for the treadmill exercise-induced improvement of spatial learning and memory, we examined structural synaptic plasticity in the hippocampus and prefrontal cortex of six-month-old 3×Tg-AD mice that had undergone 12 weeks of treadmill exercise. We found that treadmill exercise led to increases in synapse numbers, synaptic structural parameters, the expression of synaptophysin (Syn, a presynaptic marker), the axon length, dendritic complexity, and the number of dendritic spines in 3×Tg-AD mice and restored these parameters to similar levels of non-Tg control mice without treadmill exercise. In addition, treadmill exercise also improved these parameters in non-Tg control mice. Strengthening structural synaptic plasticity may represent a potential mechanism by which treadmill exercise prevents decline in spatial learning and memory and synapse loss in 3×Tg-AD mice.

BDNF Val66Met gene polymorphism modulates brain activity following rTMS-induced memory impairment.

The BDNF Val66Met gene polymorphism is a relevant factor explaining inter-individual differences to TMS responses in studies of the motor system. However, whether this variant also contributes to TMS-induced memory effects, as well as their underlying brain mechanisms, remains unexplored. In this investigation, we applied rTMS during encoding of a visual memory task either over the left frontal cortex (LFC; experimental condition) or the cranial vertex (control condition). Subsequently, individuals underwent a recognition memory phase during a functional MRI acquisition. We included 43 young volunteers and classified them as 19 Met allele carriers and 24 as Val/Val individuals. The results revealed that rTMS delivered over LFC compared to vertex stimulation resulted in reduced memory performance only amongst Val/Val allele carriers. This genetic group also exhibited greater fMRI brain activity during memory recognition, mainly over frontal regions, which was positively associated with cognitive performance. We concluded that BDNF Val66Met gene polymorphism, known to exert a significant effect on neuroplasticity, modulates the impact of rTMS both at the cognitive as well as at the associated brain networks expression levels. This data provides new insights on the brain mechanisms explaining cognitive inter-individual differences to TMS, and may inform future, more individually-tailored rTMS interventions.

Aging-related episodic-like memory decline in dogs.

Episodic memory, in humans, is the memory most affected by age-related deterioration or the constitution of neurodegenerative pathologies, such as Alzheimer's disease. However, it is unknown whether this relationship is also present in nonhuman animals. Since studies in birds, rats, primates, and dogs have been shown to have episodic-like memory, more studies aiming to improve the present understanding of this relationship in nonhuman animals are important to aid the development of new translational models for neurodegenerative disorders. Knowing that dogs (Canis familiaris) represent a promising experimental model for neurodegenerative disorders, a memory retrieval test was conducted with 90 clinically healthy domestic dogs of different ages, both sexes, and distinct breeds, for the purpose of evaluating episodic-like memory. The present study adapted a test that corroborates episodic memory requirements through incidental codification of experienced events. We performed a test with two exposure phases, with different characteristics between them, so that in the third phase it was necessary to integrate previous experiences in order to achieve success in the test. In our study, it was possible to verify the decline of episodic memory in elderly dogs, even clinically healthy, regardless of the dogs' sex and size. This episodic-like memory decline observed in elderly dogs may be related to the physiological process of aging or preclinical pathological manifestation of cognitive impairment, similar as reported in humans. More studies should be carried out evaluating episodic-like memory in dogs with suspected of canine cognitive dysfunction syndrome in order to better understand the physiological and pathological behavior of this type of memory in canine species.

A role of Na+, K+ -ATPase in spatial memory deficits and inflammatory/oxidative stress after recurrent concussion in adolescent rats.

Sports-related concussions are particularly common during adolescence, and there is insufficient knowledge about how recurrent concussions in this phase of life alter the metabolism of essential structures for memory in adulthood. In this sense, our experimental data revealed that seven recurrent concussions (RC) in 35-day-old rats decreased short-term and long-term memory in the object recognition test (ORT) 30 days after injury. The RC protocol did not alter motor and anxious behavior and the immunoreactivity of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Recurrent concussions induced the inflammatory/oxidative stress characterized here by increased glial fibrillary acidic protein (GFAP), interleukin 1ß (IL 1ß), 4-hydroxynonenal (4 HNE), protein carbonyl immunoreactivity, and 2',7'-dichlorofluorescein diacetate oxidation (DCFH) levels and lower total antioxidant capacity (TAC). Inhibited Na+,K+-ATPase activity (specifically isoform α2/3) followed by Km (Michaelis-Menten constant) for increased ATP levels and decreased immunodetection of alpha subunit of this enzyme, suggesting that cognitive impairment after RC is caused by the inability of surviving neurons to maintain ionic gradients in selected targets to inflammatory/oxidative damage, such as Na,K-ATPase activity.

Inescapable footshocks induce molecular changes in the prefrontal cortex of rats in an amyloid-beta-42 model of Alzheimer's disease.

Alzheimer's disease (AD) affects several brain areas, including the prefrontal cortex (PFC) involved in execution, working memory, and fear extinction. Despite these critical roles, the PFC is understudied in AD pathology. People with post-traumatic stress disorder (PTSD) have twice the risk of developing AD, and the underlying mechanisms linking these two diseases are less understood. Here, we investigated the effect of footshock stress on behavioural vis-a-vis molecular changes in the PFC of an amyloid-beta (Aß)-42 lesion rat model of AD. Trauma-like conditions were induced by exposing the animals to several footshocks. AD-like condition was induced via intra-hippocampal injection of Aß-42 peptide. Following Aß-42 injections, animals were tested for behavioural changes using the Open Field Test (OFT) and Y-maze test. The PFC was later harvested for neurochemical analyses. Our results showed an interactive effect of footshocks and Aß-42 lesion on: reduced percentage alternation in the Y-maze test, suggesting memory impairment; reduced number of line crosses and time spent in the centre square of the OFT, indicating anxiogenic responses. Similarly, there was an interactive effect of footshocks and Aß-42 lesion on: increased FK506 binding protein 51 (FKBP5) expression, which can be associated with stress-induced anxiogenic behaviours; and increased neuronal apoptosis in the PFC of the animals. In addition, footshocks, as well as Aß-42 lesion, reduced superoxide dismutase levels and Bridging Integrator-1 (BIN1) expression in the PFC of the animals, which can be linked to the observed memory impairment. In conclusion, our findings indicate that footshocks exaggerate PFC-associated behavioural and molecular changes induced by an AD-like pathology.

Comparing behavior following binge ethanol in adolescent and adult DBA/2 J mice.

The adolescent brain undergoes maturation in areas critically involved in reward, addiction, and memory. Adolescents consume alcohol more than any other drug, typically in a binge-like manner. While adults also binge on alcohol, the adolescent brain is more susceptible to ethanol-related damages due to its ongoing development, which may result in persistent behavioral and physical changes, including differences in myelination in the frontal cortex. Sex also impacts ethanol metabolism and addiction progression, suggesting females are more sensitive than males. This study addressed memory, sociability, ethanol sensitivity, and myelin gene expression changes due to binge ethanol, sex, and age. DBA/2 J males and females were exposed to intermittent binge ethanol (4 g/kg, i.g.) from postnatal day (PND) 29-42 or as adults from PND 64-77. Age groups were tested for behaviors at the early phase (24 h - 7 days) and late phase (starting 3 weeks) after the last dose. Adult prefrontal cortex was collected at both phases. Adolescent ethanol impaired late phase memory while adult ethanol showed no impairment. Meanwhile, adolescent males showed early phase tolerance to ethanol-induced locomotor activation, while adult females showed tolerance at both phases. Adult-treated mice displayed reductions in social interaction. Adult ethanol decreased Mal expression, a gene involved in myelin integrity, at the early phase. No differences in myelin gene expression were observed at the late phase. Thus, adolescent binge ethanol more severely impacts memory and myelin gene expression compared to adult exposure, while adult mice display ethanol-induced reductions in social interaction and tolerance to ethanol's locomotor activation.

Exercise and Syzygium aromaticum reverse memory deficits, apoptosis and mitochondrial dysfunction of the hippocampus in Alzheimer's disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD), the most common disease in the brain, is associated with cognitive and mitochondrial dysfunction. Emerging evidence suggests that endurance training and Syzygium aromaticum (L.) Merrill and Perry (Myrtaceae) (commonly referred to as clove) are effective interventions to maintain oxidative balance and improve cognitive function. AIM OF THE STUDY: The present study aimed to investigate the effect of endurance training and clove oil affect spatial memory, apoptosis, mitochondrial homeostasis, and cognitive function in Alzheimer's rats. MATERIALS AND METHODS: 81 rats were randomly assigned to 9 groups: Healthy (H), sham (sh), Healthy-exercise (HE), Healthy-clove (HC), Healthy-exercise-clove (HEC), Alzheimer's (A), Alzheimer's-exercise (AE), Alzheimer's-clove (AC), and Alzheimer's-exercise-clove (AEC). Alzheimer's induction was induced by the injection of 1-42 amyloid into the CA1 region of the hippocampus. The exercise training protocol was performed for 3 weeks, every day for 30 min in swimming training, and clove oil supplementation (0.1 mg/kg) was gavaged daily for 3 weeks in the supplement rat. Shuttle box test was used to measure spatial memory after the last training session, and to determine the mRNAs and protein levels and apoptosis, Real-Time PCR, immunofluorescent, and tunnel methods were used, respectively. RESULTS: Alzheimer's caused a significant decrease in the PRDX6 and GCN5L1 mRNAs and protein levels and a significant increase in apoptosis in the hippocampus of the Alzheimer's group compared to the control group (P = 0.001). Alzheimer's also reduced the time delay in entering the dark environment and increased the time spent in the dark environment (P = 0.001). Following endurance training and consumption of clove oil, spatial memory (P = 0.001), apoptosis (P = 0.001) and mRNAs and protein levels of PRDX6 (P = 0.001) and GCN5L1 (P = 0.017), were recovered in AE, AC and AEC groups, as compared with A group. CONCLUSION: Swimming training and consumption of clove can possibly be considered as an effective intervention to maintain oxidative balance and improve mitochondrial homeostasis in Alzheimer's disease.

Imbalance Between Prefronto-Thalamic and Sensorimotor-Thalamic Circuitries Associated with Working Memory Deficit in Schizophrenia.

BACKGROUND: Thalamocortical circuit imbalance characterized by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity has been consistently documented at rest in schizophrenia (SCZ). However, this thalamocortical imbalance has not been studied during task engagement to date, limiting our understanding of its role in cognitive dysfunction in schizophrenia. METHODS: Both n-back working memory (WM) task-fMRI and resting-state fMRI data were collected from 172 patients with SCZ and 103 healthy control subjects (HC). A replication sample with 49 SCZ and 48 HC was independently obtained. Sixteen thalamic subdivisions were employed as seeds for the analysis. RESULTS: During both task-performance and rest, SCZ showed thalamic hyperconnectivity with sensorimotor cortices, but hypoconnectivity with prefrontal-cerebellar regions relative to controls. Higher sensorimotor-thalamic connectivity and lower prefronto-thalamic connectivity both relate to poorer WM performance (lower task accuracy and longer response time) and difficulties in discriminating target from nontarget (lower d' score) in n-back task. The prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity were anti-correlated both in SCZ and HCs; this anti-correlation was more pronounced with less cognitive demand (rest>0-back>2-back). These findings replicated well in the second sample. Finally, the hypo- and hyper-connectivity patterns during resting-state positively correlated with the hypo- and hyper-connectivity during 2-back task-state in SCZ respectively. CONCLUSIONS: The thalamocortical imbalance reflected by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity is present both at rest and during task engagement in SCZ and relates to working memory performance. The frontal reduction, sensorimotor enhancement pattern of thalamocortical imbalance is a state-invariant feature of SCZ that affects a core cognitive function.

Hypothermic preconditioning attenuates hypobaric hypoxia induced spatial memory impairment in rats.

Hypobaric Hypoxia (HH) is known to cause oxidative stress in the brain that leads to spatial memory deficit and neurodegeneration. For decades therapeutic hypothermia is used to treat global and focal ischemia in preserving brain functions that proved to be beneficial in humans and rodents. Considering these previous reports, the present study was designed to establish the therapeutic potential of hypothermia preconditioning on HH induced spatial memory, biochemical and morphological changes in adult rats. Male Sprague Dawley rats were exposed to HH (7620 m, ~ 282 mmHg) for 1, 3 and 7 days with and without hypothermic preconditioning. Spatial learning memory was assessed by Morris water maze (MWM) test along with evaluation of hippocampal pyramidal neuron damage by histological study. Oxidative stress was measured by studying the levels of nitric oxide (NO), reactive oxygen species (ROS), lipid peroxidation (LPO), oxidized and reduced glutathione (GSSG and GSH). Results of MWM test indicated prolonged path length and latency to reach the platform in HH groups that regained to normal in cold pre-treated groups. A likely neurodegeneration was evident in HH groups that lessen in the cold pre-treated groups. Hypothermic preconditioning prevented spatial memory impairment and neurodegeneration in animals subjected to HH via decreasing the NO, ROS and LPO compared to control animals. The GSH level and GSH/GSSG ratio was found to be higher in preconditioned animals as compared to respective HH exposed animals, indicative of redox scavenging and restoration of hippocampal neuronal structure as well as spatial memory. Therefore, hypothermic preconditioning improves spatial memory deficit by reducing HH induced oxidative stress and hippocampal neurodegeneration, hence can be used as a multi-target prophylactic measure to combat HH induced neurodegeneration.

The association between socioeconomic disadvantage and children's working memory abilities: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Working memory is an essential cognitive skill for storing and processing limited amounts of information over short time periods. Researchers disagree about the extent to which socioeconomic position affects children's working memory, yet no study has systematically synthesised the literature regarding this topic. The current review therefore aimed to investigate the relationship between socioeconomic position and working memory in children, regarding both the magnitude and the variability of the association. METHODS: The review protocol was registered on PROSPERO and the PRISMA checklist was followed. Embase, Psycinfo and MEDLINE were comprehensively searched via Ovid from database inception until 3rd June 2021. Studies were screened by two reviewers at all stages. Studies were eligible if they included typically developing children aged 0-18 years old, with a quantitative association reported between any indicator of socioeconomic position and children's working memory task performance. Studies were synthesised using two data-synthesis methods: random effects meta-analyses and a Harvest plot. KEY FINDINGS: The systematic review included 64 eligible studies with 37,737 individual children (aged 2 months to 18 years). Meta-analyses of 36 of these studies indicated that socioeconomic disadvantage was associated with significantly lower scores working memory measures; a finding that held across different working memory tasks, including those that predominantly tap into storage (d = 0.45; 95% CI 0.27 to 0.62) as well as those that require processing of information (d = 0.52; 0.31 to 0.72). A Harvest plot of 28 studies ineligible for meta-analyses further confirmed these findings. Finally, meta-regression analyses revealed that the association between socioeconomic position and working memory was not moderated by task modality, risk of bias, socioeconomic indicator, mean age in years, or the type of effect size. CONCLUSION: This is the first systematic review to investigate the association between socioeconomic position and working memory in children. Socioeconomic disadvantage was associated with lower working memory ability in children, and that this association was similar across different working memory tasks. Given the strong association between working memory, learning, and academic attainment, there is a clear need to share these findings with practitioners working with children, and investigate ways to support children with difficulties in working memory.

Sex-specific accelerated decay in time/activity-dependent plasticity and associative memory in an animal model of Alzheimer's disease.

Clinical studies have shown that female brains are more predisposed to neurodegenerative diseases such as Alzheimer's disease (AD), but the cellular and molecular mechanisms behind this disparity remain unknown. In several mouse models of AD, synaptic plasticity dysfunction is an early event and appears before significant accumulation of amyloid plaques and neuronal degeneration. However, it is unclear whether sexual dimorphism at the synaptic level contributes to the higher risk and prevalence of AD in females. Our studies on APP/PS1 (APPSwe/PS1dE9) mouse model show that AD impacts hippocampal long-term plasticity in a sex-specific manner. Long-term potentiation (LTP) induced by strong tetanic stimulation (STET), theta burst stimulation (TBS) and population spike timing-dependent plasticity (pSTDP) show a faster decay in AD females compared with age-matched AD males. In addition, behavioural tagging (BT), a model of associative memory, is specifically impaired in AD females with a faster decay in memory compared with males. Together with the plasticity and behavioural data, we also observed an upregulation of neuroinflammatory markers, along with downregulation of transcripts that regulate cellular processes associated with synaptic plasticity and memory in females. Immunohistochemistry of AD brains confirms that female APP/PS1 mice carry a higher amyloid plaque burden and have enhanced microglial activation compared with male APP/PS1 mice. Their presence in the diseased mice also suggests a link between the impairment of LTP and the upregulation of the inflammatory response. Overall, our data show that synaptic plasticity and associative memory impairments are more prominent in females and this might account for the faster progression of AD in females.

Episodic memory enhancement versus impairment is determined by contextual similarity across events.

For over a century, stability of spatial context across related episodes has been considered a source of memory interference, impairing memory retrieval. However, contemporary memory integration theory generates a diametrically opposite prediction. Here, we aimed to resolve this discrepancy by manipulating local context similarity across temporally disparate but related episodes and testing the direction and underlying mechanisms of memory change. A series of experiments show that contextual stability produces memory integration and marked reciprocal strengthening. Variable context, conversely, seemed to result in competition such that new memories become enhanced at the expense of original memories. Interestingly, these patterns were virtually inverted in an additional experiment where context was reinstated during recall. These observations 1) identify contextual similarity across original and new memories as an important determinant in the volatility of memory, 2) present a challenge to classic and modern theories on episodic memory change, and 3) indicate that the sensitivity of context-induced memory changes to retrieval conditions may reconcile paradoxical predictions of interference and integration theory.

A simulation of older adults' associative memory deficit using structural process interference in young adults.

Associative memory deficit underlies a part of older adults' deficient episodic memory due to the reduced ability to bind units of information. In this article we further assess the mechanism underlying this deficit, by assessing the degree to which we can model it in young adults under conditions of divided attention. We shall describe two experiments in this paper; these experiments investigate item and associative recognition in young adults under full- or divided-attention conditions. The secondary tasks employed were N-back like (NBL), which serves as a working memory updating task, and parity judgement and visuospatial (VS) tasks, which serve as non-working memory tasks. The results of both experiments show that only the NBL specifically affected associative recognition, while the other tasks affected item and associative memory to the same degree, indicating a general resource competition. These results presented a convergence of evidence for the associative deficit in older adults by modelling it in young adults.

Long-term efavirenz exposure induced neuroinflammation and cognitive deficits in C57BL/6 mice.

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI), which is widely used for anti-HIV-1. Evidences revealed that several central nervous system side effects could be observed in mice and patients with administration of EFV. However, the detailed mechanisms are still unknown. In this study, we investigated the effects of long-term EFV treatment on cognitive functions and the potential underlying mechanisms in mice. We maintained C57BL/6 mice aged 2 months with treatment containing 40 or 80 mg/kg/day EFV for 5 months, while control group treated with saline. The cognitive functions were evaluated by novel object recognition test, Barnes maze test and Morris water maze. The results showed significant short-term memory impairment in 40 and 80 mg/kg groups, and notable spatial learning and memory impairments in 80 mg/kg group, without any spontaneous activity alteration. Moreover, EFV induced impairments in dendritic integrity and synaptic plasticity in hippocampus. Furthermore, Significant increases were observed in the expression levels of pro-IL-1ß, a similar tendency of TNF-α and phosphorylation of p65 of the 80 mg/kg group compared with control group. These results imply that long-term EFV treatment causes synaptic dysfunction resulting in cognitive deficits, which might be induced by the enhanced pro-inflammatory cytokines IL-1ß and TNF-α via activating NF-κB pathway.