Hypersensitivity of the nicotinic acetylcholine receptor subunit (CHRNA2L9'S/L9'S) in female adolescent mice produces deficits in nicotine-induced facilitation of hippocampal-dependent learning and memory.

Adolescence is characterized by a critical period of maturation and growth, during which regions of the brain are vulnerable to long-lasting cognitive disturbances. Adolescent exposure to nicotine can lead to deleterious neurological and psychological outcomes. Moreover, the nicotinic acetylcholine receptor (nAChR) has been shown to play a functionally distinct role in the development of the adolescent brain. CHRNA2 encodes for the α2 subunit of nicotinic acetylcholine receptors associated with CA1 oriens lacunosum moleculare GABAergic interneurons and is associated with learning and memory. Previously, we found that adolescent male hypersensitive CHRNA2L9'S/L9' mice had impairments in learning and memory during a pre-exposure-dependent contextual fear conditioning task that could be rescued by low-dose nicotine exposure. In this study, we assessed learning and memory in female adolescent hypersensitive CHRNA2L9'S/L9' mice exposed to saline or a subthreshold dose of nicotine using a hippocampus-dependent task of pre-exposure-dependent contextual fear conditioning. We found that nicotine-treated wild-type female mice had significantly greater improvements in learning and memory than both saline-treated wild-type mice and nicotine-treated CHRNA2L9'S/L9' female mice. Thus, hyperexcitability of CHRNA2 in female adolescent mice ablated the nicotine-mediated potentiation of learning and memory seen in wild-types. Our results indicate that nicotine exposure during adolescence mediates sexually dimorphic patterns of learning and memory, with wild-type female adolescents being more susceptible to the effects of sub-threshold nicotine exposure. To understand the mechanism underlying sexually dimorphic behavior between hyperexcitable CHRNA2 mice, it is critical that further research be conducted.

The effects of estrogens on spatial learning and memory in female rodents - A systematic review and meta-analysis.

Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17ß-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.

All IEGs Are Not Created Equal-Molecular Sorting Within the Memory Engram.

When neurons are recruited to form the memory engram, they are driven to activate the expression of a series of immediate-early genes (IEGs). While these IEGs have been used relatively indiscriminately to identify the so-called engram neurons, recent research has demonstrated that different IEG ensembles can be physically and functionally distinct within the memory engram. This inherent heterogeneity of the memory engram is driven by the diversity in the functions and distributions of different IEGs. This process, which we call molecular sorting, is analogous to sorting the entire population of engram neurons into different sub-engrams molecularly defined by different IEGs. In this chapter, we will describe the molecular sorting process by systematically reviewing published work on engram ensemble cells defined by the following four major IEGs: Fos, Npas4, Arc, and Egr1. By comparing and contrasting these likely different components of the memory engram, we hope to gain a better understanding of the logic and significance behind the molecular sorting process for memory functions.

Hippocampal activations obtained during language fMRI tasks: A complementary tool for predicting postoperative memory prognosis.

In medial temporal lobe epilepsy (MTLE), the benefits of surgery must be balanced against the risk of post-operative memory decline. Prediction of postoperative outcomes based on functional magnetic resonance imaging (fMRI) tasks is increasingly common but remains uncertain. The aim of this retrospective study was to determine whether hippocampal activations elicited by fMRI language tasks could enhance or refine memory fMRI in MTLE patients candidates to surgery. Forty-six patients were included: 30 right and 16 left MTLE, mostly with hippocampal sclerosis. Preoperative assessment included neuropsychological tests and fMRI with language (syntactic verbal fluency) and memory tasks (encoding, delayed, and immediate recognition of images of objects). Thirty patients underwent surgery and had neuropsychological evaluations one year after surgery. Worsening was defined as a degradation of more than 10 % in postoperative forgetting scores compared to preoperative scores in verbal, non-verbal and global memory. Memory fMRI had the best sensitivity with hippocampal activations obtained in 95 % of patients, versus 65 % with language fMRI. Considering the patients who elicited an hippocampal activation, language fMRI led to 80 %, 65 % and 85 % of correct predictions for respectively global, verbal and non verbal memory (versus 71 %, 64 % and 68 % with memory fMRI). Memory and language fMRI predictions outperformed those made by neuropsychological tests. In summary, language fMRI was less sensitive than memory fMRI to elicit hippocampal activations but when it did, the proportion of correct memory predictions was better. Moreover, it proved to be an independent predictive factor regardless of the side of the epileptic focus. Given the ease of setting up a language task in fMRI, we recommend the systematic combination of memory and language tasks to predict the post-operative memory outcome of MTLE patients undergoing epilepsy surgery.

Neural correlates of learning and memory are altered by early-life stress.

The ability to learn and remember, which is fundamental for behavioral adaptation, is susceptible to stressful experiences during the early postnatal period, such as abnormal levels of maternal care. The exact mechanisms underlying these effects still remain elusive. This study examined whether early life stress (ELS) alters memory and brain activation patterns in male mice. Therefore, we examined the expression of the immediate early genes (IEGs) c-Fos and Arc in the dentate gyrus (DG) and basolateral amygdala (BLA) after training and memory retrieval in a fear conditioning task. Furthermore, we examined the potential of RU38486 (RU486), a glucocorticoid receptor antagonist, to mitigate ELS-induced memory deficits by blocking stress signalling during adolescence. Arc::dVenus reporter mice, which allow investigating experience-dependent expression of the immediate early gene Arc also at more remote time points, were exposed to ELS by housing dams and offspring with limited bedding and nesting material (LBN) between postnatal days (PND) 2-9 and trained in a fear conditioning task at adult age. We found that ELS reduced both fear acquisition and contextual memory retrieval. RU486 did not prevent these effects. ELS reduced the number of Arc::dVenus+ cells in DG and BLA after training, while the number of c-Fos+ cells were left unaffected. After memory retrieval, ELS decreased c-Fos+ cells in the ventral DG and BLA. ELS also altered the colocalization of c-Fos+ cells with Arc::dVenus+ cells in the ventral DG, possibly indicating impaired engram allocation in the ventral DG after memory retrieval. In conclusion, this study shows that ELS alters neuronal activation patterns after fear acquisition and retrieval, which may provide mechanistic insights into enduring impact of ELS on the processing of fear memories, possibly via changes in cell (co-) activation and engram cell allocation.

Electroacupuncture improves the learning and memory abilities of rats with PSCI by attenuating the TLR4/NF-κB/NLRP3 signaling pathway on the hippocampal microglia.

This study aims to investigate how electroacupuncture regulates the learning and memory abilities of poststroke cognitive impairment (PSCI) rats through the TLR4/NF-κB/NLRP3 signaling pathway on the hippocampal microglia. Thirty male rats were randomly divided into three groups: sham surgery group, PSCI model group, and electroacupuncture group, with 10 rats in each group. Middle cerebral artery occlusion was used to establish the PSCI model. The Zea Longa method was used to score the rats' neurological function. Electroacupuncture was utilized for 21 days to improve PSCI. The learning and memory abilities of rats were tested using the Morris water maze. Hematoxylin-eosin staining and immunofluorescence were used to find the hippocampus' pathological changes. The concentration of interleukin-1ß, interleukin-6, tumor necrosis factor-α, and interleukin-18 were detected by ELISA. The mRNA expression levels of associated inflammatory corpuscles were measured by quantitative real-time PCR. The protein expression levels of TLR4, MyD88, NF-κB, and NLRP3 were measured using western blotting. Electroacupuncture improved not only the learning and memory abilities of PSCI rats but also hippocampal morphology. Electroacupuncture inhibited the activation of microglia and the TLR4/NF-κB/NLRP3 signaling pathway. Electroacupuncture also reduced proinflammatory factors and restrained the mRNA levels of NLRP3-associated inflammatory cytokines. Its mechanism was related to inhibiting the expression of the TLR4/NF-κB/NLRP3 signaling pathway, attenuating the release of inflammatory factors, and regulating the activation of hippocampal microglia in the brain.

Moxibustion Promoted Axonal Regeneration and Improved Learning and Memory of Post-stroke Cognitive Impairment by Regulating PI3K/AKt and TACC3.

BACKGROUND: This study aimed to investigate whether moxibustion could affect PI3K/Akt pathway to regulate Transforming acidic coiled-coil containing protein 3 (TACC3) and promote axonal regeneration to improve learning and memory function in middle cerebral artery occlusion (MCAO) rats. METHODS: Sixty SD rats were randomly divided into 4 groups: sham-operated control group (SC), model control group (MC), model + moxibustion group (MM), and model + inhibitor + moxibustion group (MIM). The rats in MC, MM, and MIM groups were made into MCAO models, and PI3K inhibitor LY294002 was injected into the rats in MIM group before modeling; while the rats in SC group were only treated with artery separation without monofilament inserting. After that, the rats in MM and MIM groups were intervented with moxibustion. We used the Zea-Longa scale, micro-Magnetic Resonance Imaging (micro-MRI), Morris water maze (MWM), TUNEL, western blot (WB), immunofluorescence and immunohistochemistry to evaluate the neurological deficits, cerebral infarct volume, learning and memory, apoptotic cell percentage in the hippocampal, the expression level of axonal regeneration and PI3K/AKt related proteins, the expression level of TACC3. The detection of 2 h after surgery showed the result before moxibustion and 7 days after the intervention showed the results after moxibustion. RESULTS: After 7 d of intervention, the scores of Zea-Longa and the cerebral infarct volume, the escape latency, the percentage of apoptosis cells of MM group were lower than that of MC and MIM groups; the frequency of rats crossed the previous platform location, PI3K, p-Akt/t-Akt and TACC3, the level of GAP-43 in MM group was more than MC and MIM groups (P < 0.05). While no statistical difference existed between MIM group and MC group (P > 0.05). CONCLUSION: Moxibustion can promote axonal regeneration and improve learning and memory of Post-stroke cognitive impairment via activating the PI3K/AKT signaling pathway and TACC3.

Associations of Epigenetic Age Estimators With Cognitive Function Trajectories in the Women's Health Initiative Memory Study.

BACKGROUND AND OBJECTIVES: Epigenetic age estimators indicating faster/slower biological aging vs chronological age independently associate with several age-related outcomes; however, longitudinal associations with cognitive function are understudied. We examined associations of epigenetic age estimators with cognitive function measured annually. METHODS: This longitudinal study consisted of older women enrolled in the Women's Health Initiative Memory Study with DNA methylation (DNAm) collected at baseline (1995-1998) from 3 ancillary studies and were followed up to 13 years. Global cognitive function was measured annually by Modified Mini-Mental State Examination (3MS; baseline-2007) and by modified Telephone Interview for Cognitive Status (TICS-m, 2008-2021). We calculated 5 epigenetic age estimators: extrinsic AgeAccel, intrinsic AgeAccel, AgeAccelPheno, AgeAccelGrim2, Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), and AgeAccelGrim2 components (DNA-based plasma protein surrogates). We estimated longitudinal epigenetic age estimator-cognitive function associations using linear mixed-effects models containing age, education, race or ethnicity, and subsequently alcohol, smoking, body mass index, and comorbidities. We examined effect modification by APOE ε4 carriage. RESULTS: A total of 795 participants were enrolled. The mean baseline age was 70.8 ± 4 years (10.7% Black, 3.9% Hispanic or Latina, 85.4% White), A 1-SD (0.12) increment in DunedinPACE associated with faster annual declines in TICS-m scores in minimally adjusted (ß = -0.118, 95% CI -0.202 to -0.034; p = 0.0006) and fully adjusted (ß = -0.123, 95% CI -0.211 to -0.036; p = 0.006) models. AgeAccelPheno associated with faster annual declines in TICS-m with minimal adjustment (ß = -0.091, 95% CI -0.176 to -0.006; p = 0.035) but not with full adjustment. No other epigenetic age estimators associated with changes in 3MS or TICS-m. Higher values of DNAm-based surrogates of growth differentiation factor 15, beta-2 microglobulin, Cystatin C, tissue inhibitor metalloproteinase 1, and adrenomedullin associated with faster annual declines in 3MS and TICS-m. Higher DNAm log A1c associated with faster annual declines in TICS-m only. DunedinPACE associated with faster annual declines in 3MS among APOE ε4 carriers but not among noncarriers (p-interaction = 0.020). DISCUSSION: Higher DunedinPACE associated with faster declines in TICS-m and 3MS scores among APOE ε4 carriers. DunedinPACE may help identify older women at risk of future cognitive decline. Limitations include the ancillary studies that collected epigenetic data not designed to study epigenetics and cognitive function. We examined epigenetic age estimators with global cognitive function and not specific cognitive domains. Findings may not generalize to men and more diverse populations.

Healthy lifestyle and cognitive decline in middle-aged and older adults residing in 14 European countries.

Studies examining lifestyle and cognitive decline often use healthy lifestyle indices, making it difficult to understand implications for interventions. We examined associations of 16 lifestyles with cognitive decline. Data from 32,033 cognitively-healthy adults aged 50-104 years participating in prospective cohort studies of aging from 14 European countries were used to examine associations of lifestyle with memory and fluency decline over 10 years. The reference lifestyle comprised not smoking, no-to-moderate alcohol consumption, weekly moderate-plus-vigorous physical activity, and weekly social contact. We found that memory and fluency decline was generally similar for non-smoking lifestyles. By contrast, memory scores declined up to 0.17 standard deviations (95% confidence interval= 0.08 - 0.27) and fluency scores up to 0.16 standard deviations (0.07 - 0.25) more over 10 years for those reporting smoking lifestyles compared with the reference lifestyle. We thus show that differences in cognitive decline between lifestyles were primarily dependent on smoking status.

Conditional knockout of Shank3 in the ventral CA1 by quantitative in vivo genome-editing impairs social memory in mice.

Individuals with autism spectrum disorder (ASD) have a higher prevalence of social memory impairment. A series of our previous studies revealed that hippocampal ventral CA1 (vCA1) neurons possess social memory engram and that the neurophysiological representation of social memory in the vCA1 neurons is disrupted in ASD-associated Shank3 knockout mice. However, whether the dysfunction of Shank3 in vCA1 causes the social memory impairment observed in ASD remains unclear. In this study, we found that vCA1-specific Shank3 conditional knockout (cKO) by the adeno-associated virus (AAV)- or specialized extracellular vesicle (EV)- mediated in vivo gene editing was sufficient to recapitulate the social memory impairment in male mice. Furthermore, the utilization of EV-mediated Shank3-cKO allowed us to quantitatively examine the role of Shank3 in social memory. Our results suggested that there is a certain threshold for the proportion of Shank3-cKO neurons required for social memory disruption. Thus, our study provides insight into the population coding of social memory in vCA1, as well as the pathological mechanisms underlying social memory impairment in ASD.

Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice.

Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age.

Associations of modifiable and non-modifiable risk factors with cognitive functions - a prospective, population-based, 17 years follow-up study of 3,229 individuals.

BACKGROUND: Although several cardiovascular, demographic, genetic and lifestyle factors have been associated with cognitive function, little is known about what type of cognitive impairment they are associated with. The aim was to examine the associations between different risk factors and future memory and attention/executive functions, and their interaction with APOE genotype. METHODS: Participants from a large, prospective, population-based, Swedish study were included (n = 3,229). Linear regression models were used to examine baseline hypertension, body mass index (BMI), long-term glucose levels (HbA1c), different lipid levels, physical activity, alcohol consumption, smoking, education, APOE genotype, age and sex. All models were adjusted for follow-up time and basic demographics, and, in a second step, all significant predictors were included to examine independent effects. Follow-up outcomes were memory and attention/executive functions. RESULTS: The mean age at baseline was 56.1 (SD 5.7) years and 59.7% were women. The mean follow-up time was 17.4 (range 14.3-20.8) years. When examining independent effects, APOE ε4 genotype(p < 0.01), and higher HbA1c(p < 0.001), were associated with future low memory function. Higher BMI (p < 0.05), and HbA1c(p < 0.05), lower high-density lipoprotein cholesterol (HDL-C)(p < 0.05)and stroke(p < 0.001) were associated with future low attention/executive function. The strongest factors associated with both better memory and attention/executive functions were higher education and alcohol consumption. Further, significant interaction effects between predictors and APOE genotype were found. For memory function, the protective effects of education were greater among ɛ4-carriers(p < 0.05). For attention/executive function, the protective effects of alcohol were greater among ɛ2 or ɛ4-carriers(p < 0.05). Also, attention/executive function was lower among ɛ4-carriers with higher BMI(p < 0.05) and ɛ2-carriers with higher HbA1c-levels(p < 0.05). CONCLUSIONS: Targeting cardiovascular risk factors in mid-life could have greater effect on future attention/executive functions rather than memory, whereas targeting diabetes could be beneficial for multiple cognitive domains. In addition, effects of different risk factors may vary depending on the APOE genotype. The varied cognitive profiles suggest that different mechanisms and brain regions are affected by the individual risk factors. Having detailed knowledge about the specific cognitive effects of different risk factors might be beneficial in preventive health counseling.

Synapses tagged, memories kept: synaptic tagging and capture hypothesis in brain health and disease.

The synaptic tagging and capture (STC) hypothesis lays the framework on the synapse-specific mechanism of protein synthesis-dependent long-term plasticity upon synaptic induction. Activated synapses will display a transient tag that will capture plasticity-related products (PRPs). These two events, tag setting and PRP synthesis, can be teased apart and have been studied extensively-from their electrophysiological and pharmacological properties to the molecular events involved. Consequently, the hypothesis also permits interactions of synaptic populations that encode different memories within the same neuronal population-hence, it gives rise to the associativity of plasticity. In this review, the recent advances and progress since the experimental debut of the STC hypothesis will be shared. This includes the role of neuromodulation in PRP synthesis and tag integrity, behavioural correlates of the hypothesis and modelling in silico. STC, as a more sensitive assay for synaptic health, can also assess neuronal aberrations. We will also expound how synaptic plasticity and associativity are altered in ageing-related decline and pathological conditions such as juvenile stress, cancer, sleep deprivation and Alzheimer's disease. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

AMPA and NMDA receptors in dentate gyrus mediate memory for sucrose in two port discrimination task.

Although the phenomenon of memory formation and recall associated with the use of psychotropic drugs has been extensively studied, mechanisms underlying memories for natural reward have not been clarified. Herein, we test the hypothesis that glutamatergic receptors in the dentate gyrus play a role in memories associated with sucrose. We used pellet self-administration protocol to generate memories in two-port nose-poke discrimination task using male Wistar rats. During non-rewarded probe trial, the conditioned animals readily discriminated the active port versus inactive port and showed massive increase in mRNA expression of AMPA receptor subunit genes (gria2, gria3) as well as c-Fos protein in the DG. Access to sweet pellet further enhanced c-Fos expression in the DG. However, animals pre-treated with AMPA receptor antagonist CNQX (intra-DG), on exposure to operant chamber (no pellet), showed decreased discrimination as well as c-Fos expression. We suggest that AMPA receptors in DG mediate recall and consolidation of memories associated with sucrose consumption. CNQX pre-treated animals, if presented with sweet pellet on nose poke, exhibited high discrimination index coupled with increased c-Fos expression. In these CNQX treated rats, the DI was again decreased following administration of NMDA receptor antagonist AP5. We suggest that, although AMPA receptors are blocked, the access to sweet pellet may induce surge of glutamate in the DG, which in turn may reinstate memories via activation of erstwhile silent synapses in NMDA dependant manner.

Changes in overlap of subjective and objective cognition over time in epilepsy surgery candidates.

PURPOSE: Subjective and objective cognition often show weak overlap in persons with epilepsy (PWE). Over- as well as underestimation may occur. In particular after epilepsy surgery, objective memory decline is often not subjectively reported. Additionally, studies on how concordance of subjective and objective cognition changes over time are missing. Therefore, we study the extent of concordance in operated and non-operated PWE over time. METHODS: Candidates for resective epilepsy surgery were assessed between 03/18 and 12/20 (T1) with self-report questionnaires and underwent a neuropsychological examination. For 21 operated as well as 27 non-operated PWE follow-up data was obtained one to three years later (T2). Concordance of attention and memory were compared between groups and time points. Moreover, reliable change was calculated and compared between groups. RESULTS: Of the total sample, 42 % rated their attention performance realistically and 25 % showed memory concordance. Differences in patterns of over- and underestimation between groups and over time occurred for attention, but not for memory. Overestimation of memory was more frequent in operated than non-operated PWE, especially at T2 (67% vs. 11 %). In the operated group, we mainly observed reliable improvement in subjective cognition and decline in objective memory, whereas non-operated PWE showed more frequently decline of simple attention. Reliable subjective and objective change did not co-occur. CONCLUSION: Concordance of subjective and objective cognition is low. Over- as well as underestimation may persist over time. Domain-specific perspectives are necessary. Tendencies of operated PWE to develop overestimation of memory after surgery should be considered in neuropsychological interventions.

Macrophage memories of early-life injury drive neonatal nociceptive priming.

The developing peripheral nervous and immune systems are functionally distinct from those of adults. These systems are vulnerable to early-life injury, which influences outcomes related to nociception following subsequent injury later in life (i.e., "neonatal nociceptive priming"). The underpinnings of this phenomenon are unclear, although previous work indicates that macrophages are trained by inflammation and injury. Our findings show that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming, possibly due to a long-lasting remodeling in chromatin structure. The p75 neurotrophic factor receptor is an important effector in regulating neonatal nociceptive priming through modulation of the inflammatory profile of rodent and human macrophages. This "pain memory" is long lasting in females and can be transferred to a naive host to alter sex-specific pain-related behaviors. This study reveals a mechanism by which acute, neonatal post-surgical pain drives a peripheral immune-related predisposition to persistent pain following a subsequent injury.

Montreal Cognitive Assessment (MoCA) XpressO: Validation of a digital self-administered cognitive prescreening tool.

BACKGROUND: The need for cognitive testing is increasing with the aging population and the advent of new Alzheimer disease therapies. To respond to the increased demand, the XpressO was developed as a self-administered digital cognitive prescreening tool that will help distinguish between populations of subjective and objective cognitive impairment according to the Montreal Cognitive Assessment (MoCA). METHODS: This is a prospective validation study. XpressO is composed of tasks that assess memory and executive functions. It is validated compared to the digital MoCA as a gold standard. Out of 118 participants screened from the MoCA Clinic and a family practice clinic, 88 met inclusion criteria, two participants had missing data due to incomplete tasks, 86 participants were included in the analysis; the mean age was 70.34 years. A logistic regression model was built, and its accuracy was evaluated by the sensitivity, specificity, and Area Under the Curve (AUC) of the Receiver Operating Characteristic. RESULTS: Analysis showed strong correlation between (1) XpressO memory tasks scores and the MoCA Memory Index Score (p-values < 0.001), and between (2) XpressO sub-test scores and MoCA total score (p-values < 0.005). The AUC for predicting MoCA performance is 0.845. To classify individuals with normal and abnormal MoCA scores, two threshold values were introduced for the total XpressO scores: sensitivity of 91% at a cutoff of 72, specificity of 90% at a cutoff of 42, and an undetermined range in between. CONCLUSION: XpressO demonstrated high AUC, high sensitivity and specificity to predict cognitive performance compared to the digital MoCA. It may provide efficient cognitive prescreening by identifying individuals who would benefit from further clinical assessments, potentially reducing waiting times and high burden on healthcare clinics.

Mouse hippocampal CA1 VIP interneurons detect novelty in the environment and support recognition memory.

In the CA1 hippocampus, vasoactive intestinal polypeptide-expressing interneurons (VIP-INs) play a prominent role in disinhibitory circuit motifs. However, the specific behavioral conditions that lead to circuit disinhibition remain uncertain. To investigate the behavioral relevance of VIP-IN activity, we employed wireless technologies allowing us to monitor and manipulate their function in freely behaving mice. Our findings reveal that, during spatial exploration in new environments, VIP-INs in the CA1 hippocampal region become highly active, facilitating the rapid encoding of novel spatial information. Remarkably, both VIP-INs and pyramidal neurons (PNs) exhibit increased activity when encountering novel changes in the environment, including context- and object-related alterations. Concurrently, somatostatin- and parvalbumin-expressing inhibitory populations show an inverse relationship with VIP-IN and PN activity, revealing circuit disinhibition that occurs on a timescale of seconds. Thus, VIP-IN-mediated disinhibition may constitute a crucial element in the rapid encoding of novelty and the acquisition of recognition memory.

LRP1 in GABAergic neurons is a key link between obesity and memory function.

OBJECTIVE: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. METHODS: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age. RESULTS: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition. CONCLUSIONS: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.