Pattern Separation Research Articles

Hippocampal neurogenesis facilitates cognitive flexibility in a fear discrimination task.

Hippocampal neurogenesis, the continuous creation of new neurons in the adult brain, influences memory, regulates the expression of defensive responses to threat (fear), and cognitive processes like pattern separation and behavioral flexibility. One hypothesis proposes that neurogenesis promotes cognitive flexibility by degrading established memories and promoting relearning. Yet, empirical evidence on its role in fear discrimination tasks is scarce. In this study, male rats were initially trained to differentiate between two similar environments, one associated with a threat. Subsequently, we enhanced neurogenesis through environmental enrichment and memantine treatments. We then reversed the emotional valence of these contexts. In both cases, neurogenesis improved the rats' ability to relearn the aversive context. Interestingly, we observed increased hippocampal activity, and decreased activity in the prelimbic cortex and lateral habenula, while the infralimbic cortex remained unchanged, suggesting neurogenesis-induced plasticity changes in this brain network. Moreover, when we pharmacologically inhibited the increased neurogenesis with Methotrexate, rats struggled to relearn context discrimination, confirming the crucial role of neurogenesis in this cognitive process. Overall, our findings highlight neurogenesis's capacity to facilitate changes in fear discrimination and emphasize the involvement of a prefrontal-hippocampal-habenula mechanism in this process. This study emphasizes the intricate relationship between hippocampal neurogenesis, cognitive flexibility, and the modulation of fear-related memories.

Seizure-induced LIN28A disrupts pattern separation via aberrant hippocampal neurogenesis.

Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of pilocarpine-induced status epilepticus (SE), we characterized spatiotemporal expression of Lin28a mRNA and proteins after SE. Unlike Lin28a transcripts, induction of LIN28A protein after SE was detected mainly in the subgranular zone, where immunoreactivity was found in progenitors, neuroblasts, and immature and mature granule neurons. To investigate roles of LIN28A in epilepsy, we generated Nestin-Cre:Lin28aloxP/loxP (conditional KO [cKO]) and Nestin-Cre:Lin28a+/+ (WT) mice to block LIN28A upregulation in all neuronal lineages after acute seizure. Adult-generated neuron- and hippocampus-associated cognitive impairments were absent in epileptic LIN28A-cKO mice, as evaluated by pattern separation and contextual fear conditioning tests, respectively, while sham-manipulated WT and cKO animals showed comparable memory function. Moreover, numbers of hilar PROX1-expressing ectopic granule cells (EGCs), together with PROX1+/NEUN+ mature EGCs, were significantly reduced in epileptic cKO mice. Transcriptomics analysis and IHC validation at 3 days after pilocarpine administration provided potential LIN28A downstream targets such as serotonin receptor 4. Collectively, our findings indicate that LIN28A is a potentially novel target for regulation of newborn neuron-associated memory dysfunction in epilepsy by modulating seizure-induced aberrant neurogenesis.

Azithromycin preserves adult hippocampal neurogenesis and behavior in a mouse model of sepsis

The mammalian hippocampus can generate new neurons throughout life. Known as adult hippocampal neurogenesis (AHN), this process participates in learning, memory, mood regulation, and forgetting. The continuous incorporation of new neurons enhances the plasticity of the hippocampus and contributes to the cognitive reserve in aged individuals. However, the integrity of AHN is targeted by numerous pathological conditions, including neurodegenerative diseases and sustained inflammation. In this regard, the latter causes cognitive decline, mood alterations, and multiple AHN impairments. In fact, the systemic administration of Lipopolysaccharide (LPS) from E. coli to mice (a model of sepsis) triggers depression-like behavior, impairs pattern separation, and decreases the survival, maturation, and synaptic integration of adult-born hippocampal dentate granule cells. Here we tested the capacity of the macrolide antibiotic azithromycin to neutralize the deleterious consequences of LPS administration in female C57BL6J mice. This antibiotic exerted potent neuroprotective effects. It reversed the increased immobility time during the Porsolt test, hippocampal secretion of pro-inflammatory cytokines, and AHN impairments. Moreover, azithromycin promoted the synaptic integration of adult-born neurons and functionally remodeled the gut microbiome. Therefore, our data point to azithromycin as a clinically relevant drug with the putative capacity to ameliorate the negative consequences of chronic inflammation by modulating AHN and hippocampal-related behaviors.

A neural network model for online one-shot storage of pattern sequences.

Based on the CRISP theory (Content Representation, Intrinsic Sequences, and Pattern completion), we present a computational model of the hippocampus that allows for online one-shot storage of pattern sequences without the need for a consolidation process. In our model, CA3 provides a pre-trained sequence that is hetero-associated with the input sequence, rather than storing a sequence in CA3. That is, plasticity on a short timescale only occurs in the incoming and outgoing connections of CA3, not in its recurrent connections. We use a single learning rule named Hebbian descent to train all plastic synapses in the network. A forgetting mechanism in the learning rule allows the network to continuously store new patterns while forgetting those stored earlier. We find that a single cue pattern can reliably trigger the retrieval of sequences, even when cues are noisy or missing information. Furthermore, pattern separation in subregion DG is necessary when sequences contain correlated patterns. Besides artificially generated input sequences, the model works with sequences of handwritten digits and natural images. Notably, our model is capable of improving itself without external input, in a process that can be referred to as 'replay' or 'offline-learning', which helps in improving the associations and consolidating the learned patterns.

Adult Neurogenesis, Context Encoding, and Pattern Separation: A Pathway for Treating Overgeneralization.

In mammals, the subgranular zone of the dentate gyrus is one of two brain regions (with the subventricular zone of the olfactory bulb) that continues to generate new neurons throughout adulthood, a phenomenon known as adult hippocampal neurogenesis (AHN) (Eriksson et al., Nat Med 4:1313-1317, 1998; García-Verdugo et al., J Neurobiol 36:234-248, 1998). The integration of these new neurons into the dentate gyrus (DG) has implications for memory encoding, with unique firing and wiring properties of immature neurons that affect how the hippocampal network encodes and stores attributes of memory. In this chapter, we will describe the process of AHN and properties of adult-born cells as they integrate into the hippocampal circuit and mature. Then, we will discuss some methodological considerations before we review evidence for the role of AHN in two major processes supporting memory that are performed by the DG. First, we will discuss encoding of contextual information for episodic memories and how this is facilitated by AHN. Second, will discuss pattern separation, a major role of the DG that reduces interference for the formation of new memories. Finally, we will review clinical and translational considerations, suggesting that stimulation of AHN may help decrease overgeneralization-a common endophenotype of mood, anxiety, trauma-related, and age-related disorders.

Exercise leads to sex-specific recovery of behavior and pathological AD markers following adolescent ethanol exposure in the TgF344-AD model.

Human epidemiological studies suggest that heavy alcohol consumption may lead to earlier onset of Alzheimer's Disease (AD), especially in individuals with a genetic predisposition for AD. Alcohol-related brain damage (ARBD) during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study investigates if voluntary exercise in mid-adulthood can recover memory deficits caused by the interactions between adolescence ethanol exposure and AD-transgenes. Male and female TgF344-AD and wildtype F344 rats were exposed to an intragastric gavage of water (control) or 5 g/kg of 20% ethanol (adolescent intermittent ethanol; AIE) for a 2 day on/off schedule throughout adolescence (PD27-57). At 6 months old, rats either remained in their home cage (stationary) or were placed in a voluntary wheel running apparatus for 4 weeks and then underwent several behavioral tests. The number of cholinergic neurons in the basal forebrain and measure of neurogenesis in the hippocampus were assessed. Voluntary wheel running recovers spatial working memory deficits selectively in female TgF344-AD rats exposed to AIE and improves pattern separation impairment seen in control TgF344-AD female rats. There were sex-dependent effects on brain pathology: Exercise improves the integration of recently born neurons in AIE-exposed TgF344-AD female rats. Exercise led to a decrease in amyloid burden in the hippocampus and entorhinal cortex, but only in male AIE-exposed TgF344-AD rats. Although the number of basal forebrain cholinergic neurons was not affected by AD-transgenes in either sex, AIE did reduce the number of basal forebrain cholinergic neurons in female rats. These data provide support that even after symptom onset, AIE and AD related cognitive decline and associated neuropathologies can be rescued with exercise in unique sex-specific ways.

Environmental enrichment in middle age rats improves spatial and object memory discrimination deficits.

Changes in memory performance are one of the main symptoms of normal aging. The storage of similar experiences as different memories (ie. behavioral pattern separation), becomes less efficient as aging progresses. Studies have focused on hippocampus dependent spatial memories and their role in the aging related deficits in behavioral pattern separation (BPS) by targeting high similarity interference conditions. However, parahippocampal cortices such as the perirhinal cortex are also particularly vulnerable to aging. Middle age is thought to be the stage where mild mnemonic deficits begin to emerge. Therefore, a better understanding of the timing of the spatial and object domain memory impairment could shed light over how plasticity changes in the parahipocampal-hippocampal system affects mnemonic function in early aging. In the present work, we compared the performance of young and middle-aged rats in both spatial (spontaneous location recognition) and non-spatial (spontaneous object recognition) behavioral pattern separation tasks to understand the comparative progression of these deficits from early stages of aging. Moreover, we explored the impact of environmental enrichment (EE) as an intervention with important translational value. Although a bulk of studies have examined the contribution of EE for preventing age related memory decline in diverse cognitive domains, there is limited knowledge of how this intervention could specifically impact on BPS function in middle-aged animals. Here we evaluate the effects of EE as modulator of BPS, and its ability to revert the deficits caused by normal aging at early stages. We reveal a domain-dependent impairment in behavioral pattern separation in middle-aged rats, with spatial memories affected independently of the similarity of the experiences and object memories only affected when the stimuli are similar, an effect that could be linked to the higher interference seen in this group. Moreover, we found that EE significantly enhanced behavioral performance in middle-aged rats in the spatial and object domain, and this improvement is specific of the high similarity load condition. In conclusion, these results suggest that memory is differentially affected by aging in the object and spatial domains, but that BPS function is responsive to an EE intervention in a multidomain manner.

Radar Waveform Design Based on Target Pattern Separability via Fractional Programming

Radar Waveform Design Based on Target Pattern Separability via Fractional Programming

A String-Select-Line Separation Patterning Scheme for Low Voltage and High-Speed Program Operation in 3D NAND Flash Memory with Separated Source-Line

A String-Select-Line Separation Patterning Scheme for Low Voltage and High-Speed Program Operation in 3D NAND Flash Memory with Separated Source-Line

Defect Isolation from Whole to Local Field Separation in Complex Interferometry Fringe Patterns through Development of Weighted Least-Squares Algorithm

In this paper, based on Gaussian 1σ-criterion and histogram segmentation, a weighted least-squares algorithm is applied and validated on digital holographic speckle pattern interferometric data to perform phase separation on the complex interference fields. The direct structural diagnosis tool is used to investigate defects and their impact on a complex antique wall painting of Giotto. The interferometry data is acquired with a portable off-axis interferometer set-up with a phase-shifted reference beam coupled with the object beam in front of the digital photosensitive medium. A digital holographic speckle pattern interferometry (DHSPI) system is used to register digital recordings of interferogram sequences over time. The surface is monitored for as long as it deforms prior to returning to its initial reference equilibrium state prior to excitation. The attempt to separate the whole vs. local defect complex amplitudes from the interferometric data is presented. The main aim is to achieve isolation and visualization of each defect’s impact amplitude in order to obtain detailed documentation of each defect and its structural impact on the surface for structural diagnosis purposes.

Integration of lipidomics and metabolomics reveals plasma and urinary profiles associated with pediatric Mycoplasma pneumoniae infections and its severity.

Mycoplasma pneumoniae is a significant contributor to lower respiratory infections in children. However, the lipidomics and metabolics bases of childhood M. pneumoniae infections remain unclear. In this study, lipidomics and metabolomics analyses were conducted using UHPLC-LTQ-Orbitrap XL mass spectrometry and gas chromatography-triple quadrupole mass spectrometry on plasma (n = 65) and urine (n = 65) samples. MS-DIAL software, in combination with LipidBlast and Fiehn BinBase DB, identified 163 lipids and 104 metabolites in plasma samples, as well as 208 metabolites in urine samples. Perturbed lipid species (adjusted p < 0.05) were observed, including lysophosphatidylethanolamines, phosphatidylinositols, phosphatidylcholines, phosphatidylethanol amines, and triglycerides. Additionally, differential metabolites (adjusted p < 0.05) exhibited associations with amino acid metabolism, nucleotide metabolism, and energy metabolism. Thirteen plasma metabolites, namely l-hydroxyproline, 3-phosphoglycerate, citric acid, creatine, inosine, ribitol, α tocopherol, cholesterol, cystine, serine, uric acid, tagatose, and glycine, showed significant associations with disease severity (p < 0.05) and exhibited distinct separation patterns in M. pneumoniae-infected bronchitis and pneumonia, with an area under the curve of 0.927. Nine of them exhibited either positive or negative correlations with neutrophil or lymphocyte percentages. These findings indicated significant systemic metabolic shifts in childhood M. pneumoniae infections, offering valuable insights into the associated metabolic alterations and their relationship with disease severity.

Formal and functional approaches to subordination in Kazakh

This paper investigates clausal subordination in Kazakh and its functional and formal properties. Kazakh subordinate clauses manifest typical Turkic nominalization, where the dependent predicate and the first argument (if overtly expressed) differ from those of main clauses. Such differences can be seen in three grammatical aspects: syntax, semantics and prosody. Regarding the semantic-syntactic features, subordinate clauses are morphologically reduced and display various degrees of syntactic downgrading; they can display first argument co-reference and semantic integration with their superordinate clauses. Prosodically, subordinate clauses have either a separate intonation pattern or one that follows the intonation of main clauses. The aim of the paper is to describe the syntactic, semantic and prosodic features of subordinate clauses in Kazakh and to compare these peculiarities in a hierarchical order.

Features of social protection by implementing the right to disconnect

The article examines the realisation of the right to disconnect in the framework of workers’ social protection. The study explores different approaches to the definition of a new right. The right to disconnect is analysed on the basis of targeting and universality of social protection, soft and hard measures, the components of the new right, which include workers’ opportunity, employers’ responsibility, communication between employers and workers, protection from adverse consequences. The legal acts that serve as a foundation of the right to disconnect create a separate work pattern of teleworkers, which affects the formation of the targeting approach to social protection. The regulation of the right to disconnect introduced in European Social Partner framework agreement on digitalisation and European Parliament resolution of 21 January 2021 with recommendations to the Commission on the right to disconnect gives a more universal approach. The Resolution acknowledges the right to disconnect as a fundamental right and proposes hard regulatory and technological measures to ensure observation of work and rest periods. The agreement is based on the change in corporate culture. It is revealed that nowadays the right to disconnect serves as the only project aimed at regulating digital working relations in the framework of social protection of remote workers, however R2D can be limited by a narrow category of teleworkers. Debates over the right to disconnect touch upon the issue of the effectiveness of social dialogue in the context of adaptation to digital work organisation, as well as the possibility of keeping binary understanding of work and rest periods.

EXPLORING VERY HIGH-RESOLUTION REMOTE SENSING FOR ASSESSING LAND SURFACE TEMPERATURE OF DIFFERENT URBAN LAND COVER PATTERNS

Abstract. Very-high-resolution thermal infrared data has a good potential to detect and monitor LST variations in urban areas. In this work, an attempt was made to estimate Land Surface Temperature (LST) from very high resolution (VHR) data using machine learning technics in an area of Botanical garden of Yerevan, Armenia; UAV-derived and in-situ measured high precision LST of various land cover (LC) patterns were then compared for September and October. The main purpose of this study was to explore the capabilities of UAV imagery (multispectral/TIR) in assessing LST of the different LC patterns. For this purpose, a UAV survey was performed, and VHR data were collected using multispectral and TIR thermal camera while in-situ measurements of temperature and surveying of the different LC patterns were performed. A significant correlation was detected between LSTs in situ measured and detected by UAV in 06 September (r=0.758; p-value &lt;0.01) and in 27 October (r=0.686; p-value &lt;0.01). When comparing the LSTs of separate land-cover patterns the best results were received for Bare soils (r=0.591; p-value &lt;0.05) and Concrete (r=0.927; p-value &lt;0.01) when the survey and measurements was done in September. Despite its limitations, it can be stated that UAV thermal survey has a good potential to detect and monitor LST variations in urban areas.

Cortical reactivations predict future sensory responses.

Many theories of offline memory consolidation posit that the pattern of neurons activated during a salient sensory experience will be faithfully reactivated, thereby stabilizing the pattern1,2. However, sensory-evoked patterns are not stable but, instead, drift across repeated experiences3-6. Here, to investigate the relationship between reactivations and the drift of sensory representations, we imaged the calcium activity of thousands of excitatory neurons in the mouse lateral visual cortex. During the minute after a visual stimulus, we observed transient, stimulus-specific reactivations, often coupled with hippocampal sharp-wave ripples. Stimulus-specific reactivations were abolished by local cortical silencing during the preceding stimulus. Reactivations early in a session systematically differed from the pattern evoked by the previous stimulus-they were more similar to future stimulus response patterns, thereby predicting both within-day and across-day representational drift. In particular, neurons that participated proportionally more or less in early stimulus reactivations than in stimulus response patterns gradually increased or decreased their future stimulus responses, respectively. Indeed, we could accurately predict future changes in stimulus responses and the separation of responses to distinct stimuli using only the rate and content of reactivations. Thus, reactivations may contribute to a gradual drift and separation in sensory cortical response patterns, thereby enhancing sensory discrimination7.

Bed Separation Formation Mechanism and Water Inrush Evaluation in Coal Seam Mining under a Karst Cave Landform

Understanding the formation mechanism of bed separation in coal seam mining under a karst landform is needed for the prevention and control of roof-separated water damage in such areas. This research used a mine in the northern Guizhou coalfield, China, as a case study, and applied theoretical analysis, numerical simulation, and on-site measurement to develop a circular cave structure model in a key stratum. The dynamic evolution of a separation bed was analyzed from several aspects, including the formation mechanism, development location, the mechanical condition of local karst caves, fracture evolution, and fractal rules. Verification using in situ measurements is presented for the case study mine, and a quantitative evaluation method for water inrush from bed separation and improved fusion weighting is proposed based on a cloud model. The research results indicate the following: (1) Tensile cracks are prone to occur above and below a karst cave, which produce an impact of connectivity on the separated space. (2) When the working face advances to 270 m in coal mining, longitudinal tensile cracks below the karst cave gradually increase and the width of the bed separation crack shrinks to 68.2 m, with a maximum separation layer height of 3.01 m. (3) Based on the cloud model and the improved weighted fusion method, the risk of water inrush in bed separation is judged as “high”. The En of the cloud digital features is 0.0622 and the He is 0.0307, achieving a quantitative evaluation of water inrush in the separation layer that is consistent with on-site practice, and is highly stable and reliable. This study improves the understanding of the development pattern of bed separation and water inrush risk assessment in coal seam mining under a karst cave landform.

Extracellular vesicles from hiPSC-NSCs can prevent peripheral inflammation-induced cognitive dysfunction with inflammasome inhibition and improved neurogenesis in the hippocampus

Extracellular vesicles (EVs) released by human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) are enriched with miRNAs and proteins capable of mediating robust antiinflammatory activity. The lack of tumorigenic and immunogenic properties and ability to permeate the entire brain to incorporate into microglia following intranasal (IN) administrations makes them an attractive biologic for curtailing chronic neuroinflammation in neurodegenerative disorders. We tested the hypothesis that IN administrations of hiPSC-NSC-EVs can alleviate chronic neuroinflammation and cognitive impairments induced by the peripheral lipopolysaccharide (LPS) challenge. Adult male, C57BL/6J mice received intraperitoneal injections of LPS (0.75 mg/kg) for seven consecutive days. Then, the mice received either vehicle (VEH) or hiPSC-NSC-EVs (~ 10 × 109 EVs/administration, thrice over 6 days). A month later, mice in all groups were investigated for cognitive function with behavioral tests and euthanized for histological and biochemical studies. Mice receiving VEH after LPS displayed deficits in associative recognition memory, temporal pattern processing, and pattern separation. Such impairments were associated with an increased incidence of activated microglia presenting NOD-, LRR-, and pyrin domain containing 3 (NLRP3) inflammasomes, elevated levels of NLRP3 inflammasome mediators and end products, and decreased neurogenesis in the hippocampus. In contrast, the various cognitive measures in mice receiving hiPSC-NSC-EVs after LPS were closer to naive mice. Significantly, these mice displayed diminished microglial activation, NLRP3 inflammasomes, proinflammatory cytokines, and a level of neurogenesis matching age-matched naïve controls. Thus, IN administrations of hiPSC-NSC-EVs are an efficacious approach to reducing chronic neuroinflammation-induced cognitive impairments.

Learning exceptions to category rules varies across the menstrual cycle

Ways in which ovarian hormones affect cognition have been long overlooked despite strong evidence of their effects on the brain. To address this gap, we study performance on a rule-plus-exception category learning task, a complex task that requires careful coordination of core cognitive mechanisms, across the menstrual cycle (N = 171). Results show that the menstrual cycle distinctly affects exception learning in a manner that parallels the typical rise and fall of estradiol across the cycle. Participants in their high estradiol phase outperform participants in their low estradiol phase and demonstrate more rapid learning of exceptions than a male comparison group. A likely mechanism underlying this effect is estradiol’s impact on pattern separation and completion pathways in the hippocampus. These results provide novel evidence for the effects of the menstrual cycle on category learning, and underscore the importance of considering female sex-related variables in cognitive neuroscience research.

A neural network model of hippocampal contributions to category learning

In addition to its critical role in encoding individual episodes, the hippocampus is capable of extracting regularities across experiences. This ability is central to category learning, and a growing literature indicates that the hippocampus indeed makes important contributions to this form of learning. Using a neural network model that mirrors the anatomy of the hippocampus, we investigated the mechanisms by which the hippocampus may support novel category learning. We simulated three category learning paradigms and evaluated the network’s ability to categorize and recognize specific exemplars in each. We found that the trisynaptic pathway within the hippocampus—connecting entorhinal cortex to dentate gyrus, CA3, and CA1—was critical for remembering exemplar-specific information, reflecting the rapid binding and pattern separation capabilities of this circuit. The monosynaptic pathway from entorhinal cortex to CA1, in contrast, specialized in detecting the regularities that define category structure across exemplars, supported by the use of distributed representations and a relatively slower learning rate. Together, the simulations provide an account of how the hippocampus and its constituent pathways support novel category learning.

Unmet Need for Family Planning and Spousal Separation in Nepal: A Spatial and Multilevel Analysis.

Objectives: In Nepal, where increasing numbers of married couples live apart due to migration, progress in reducing unmet need for family planning (UMN) is stagnant. This study aims to identify spatial patterns of UMN of married women and spousal separation in Nepal and explore associations between UMN and spousal separation at individual- and district-levels. Methods: We used 2016 Nepal Demographic and Health Surveys data to conduct spatial and multilevel logistic analyses. Results: This study shows evidence of similar geographical patterns in UMN of married women and spousal separation. At the individual level, women living with their spouses had 88% (aOR = 0.12, 95% CI 0.11-0.13) decreased odds of experiencing UMN compared to those living apart from their spouses. While not statistically significant, increasing odds of UMN were observed with higher prevalence of spousal separation at the district level. Conclusion: This study contributes to the existing literature by showing similar geographical patterns of UMN and spousal separation across Nepal and demonstrating both individual and contextual effects of spousal separation on UMN among married women. Theoretical and policy implications are discussed.