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There is still limited mechanistic insight into how the interaction of individuals with their environment results in the emergence of individuality in behavior and brain structure. Nevertheless, the idea that personal activity shapes the brain is implicit in strategies for healthy cognitive aging as well as in the idea that individuality is reflected in the brain's connectome. We have shown that even isogenic mice kept in a shared enriched environment (ENR) developed divergent and stable social and exploratory trajectories. As these trajectories-measured as roaming entropy (RE)-positively correlated with adult hippocampal neurogenesis, we hypothesized that a feedback between behavioral activity and adult hippocampal neurogenesis might be a causal factor in brain individualization. We used cyclin D2 knockout mice with constitutively extremely low levels of adult hippocampal neurogenesis and their wild-type littermates. We housed them for 3 months in a novel ENR paradigm, consisting of 70 connected cages equipped with radio frequency identification antennae for longitudinal tracking. Cognitive performance was evaluated in the Morris Water Maze task (MWM). With immunohistochemistry we confirmed that adult neurogenesis correlated with RE in both genotypes and that D2 knockout mice had the expected impaired performance in the reversal phase of the MWM. But whereas the wild-type animals developed stable exploratory trajectories with increasing variance, correlating with adult neurogenesis, this individualizing phenotype was absent in D2 knockout mice. Here the behaviors started out more random and revealed less habituation and low variance. Together, these findings suggest that adult neurogenesis contributes to experience-dependent brain individualization.

Makale (Early Access), WOS:000926317400001, PubMed ID: 36745246, Alzheimer's disease (AD) is accepted as a form of progressive dementia. Cholinergic systems are commonly affected in AD. Neurokinin 3 receptor (NK3R) is involved in learning memory-related processes. It is known that the activation of NK3R affects the release of many neurotransmitters. The aim of this project was to investigate the effects of NK3R agonist senktide administration on neurobehavioral mechanisms in the experimental AD-like rat model. 50 male Wistar albino rats were divided into Control (C), AD, Control + NK3R agonist (CS), AD + NK3R agonist (ADS), AD + NK3Ragonist + antagonist groups (ADSO). We designed AD-like model by intrahippocampal administration of A beta 1-42. After NK3R agonist + antagonist injections, open field (OF), Morris water maze (MWM) tests were applied. Cholinergic mechanism analysis from hippocampus-cortex tissues was performed by ELISA and catecholamine analysis from brain stem tissue were performed by HPLC method. The transitions from edge to center, rearing, grooming parameters were found to be reduced in final values of OF. While the group-time interaction was significant in the OF test findings, there was no significant difference between the groups. In MWM test, ADS group showed a learning level close to control group and animals in AD and ADSO groups could not learn target quadrant in MWM test. The brain stem NA and DA concentrations were not statistically significant. Hippocampal AChE-ChAT levels were supported by positive effects of senktide on learning via the cholinergic mechanisms. As a result, NK3R agonists were found to be effective in improving cognitive functions in rats with AD pathology. In the experimental AD model, positive effects of NK3R on learning memory may be mediated by cholinergic mechanisms., Scientific Research Projects (BAP) Coordination Unit of Necmettin Erbakan University

Novel monoterpene-based hydroxamic acids of two structural types were synthesized for the first time. The first type consisted of compounds with a hydroxamate group directly bound to acyclic, monocyclic and bicyclic monoterpene scaffolds. The second type included hydroxamic acids connected with the monoterpene moiety through aliphatic (hexa/heptamethylene) or aromatic linkers. An in vitro analysis of biological activity demonstrated that some of these molecules had powerful HDAC6 inhibitory activity, with the presence of a linker area in the structure of compounds playing a key role. In particular, it was found that hydroxamic acids containing a hexa- and heptamethylene linker and (-)-perill fragment in the Cap group exhibit excellent inhibitory activity against HDAC6 with IC50 in the submicromolar range from 0.56 ± 0.01 µM to 0.74 ± 0.02 µM. The results of the study of antiradical activity demonstrated the presence of moderate ability for some hydroxamic acids to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2ROO• radicals. The correlation coefficient between the DPPH radical scavenging activity and oxygen radical absorbance capacity (ORAC) value was R2 = 0.8400. In addition, compounds with an aromatic linker based on para-substituted cinnamic acids, having a monocyclic para-menthene skeleton as a Cap group, 35a, 38a, 35b and 38b, demonstrated a significant ability to suppress the aggregation of the pathological β-amyloid peptide 1-42. The 35a lead compound with a promising profile of biological activity, discovered in the in vitro experiments, demonstrated neuroprotective effects on in vivo models of Alzheimer’s disease using 5xFAD transgenic mice. Together, the results obtained demonstrate a potential strategy for the use of monoterpene-derived hydroxamic acids for treatment of various aspects of Alzheimer’s disease.

Research on face impressions has often focused on a fixed, universal architecture, treating regional variability as noise. Here, we demonstrated a crucial yet neglected role of cultural learning processes in forming face impressions. In Study 1, we found that variability in the structure of adult perceivers’ face impressions across 42 world regions ( N = 287,178) could be explained by variability in the actual personality structure of people living in those regions. In Study 2, data from 232 world regions ( N = 307,136) revealed that adult perceivers use the actual personality structure learned from their local environment to form lay beliefs about personality, and these beliefs in turn support the structure of perceivers’ face impressions. Together, these results suggest that people form face impressions on the basis of a conceptual understanding of personality structure that they have come to learn from their regional environment. The findings suggest a need for greater attention to the regional and cultural specificity of face impressions.

Major depressive disorder is a debilitating and common mental health condition that results in reduced quality of life, diminished cognitive ability, and suicidal ideation. In recent years, dimethyl fumarate (DMF), an activator of the Nrf2 antioxidant pathway, has presented potent ameliorative capabilities to reduce inflammation, improve learning and memory, and reduce depressive-like behaviour in male rodent models of depression and neurodegeneration. Here we demonstrate the efficacy of DMF treatment in male and female Wistar rats exposed to the chronic unpredictable mild stress (CUS) model of depression. CUS induced behavioural despair, anhedonia, anxiety, and weight reductions in both sexes with sex-specific impairments in memory. DMF treatment produced antidepressant effects in male rats and improved CUS induced recognition memory and spatial memory. In female rats, DMF selectively improved spatial memory with no antidepressant effects. Additionally, DMF selectively normalized CUS induced alterations in microglial activity in subregions of the dorsal hippocampus of both sexes. These results demonstrate a sex-specific response to DMF treatment following stress, highlighting its potential as a depression therapeutic with enhanced effect in males Ontario Veterinary College

Docosahexaenoic acid (DHA) is highly enriched in the brain, and is essential for normal brain development and function. However, evidence suggests that currently used supplements, such as fish oil, do not significantly increase brain DHA levels. Therefore, this study aimed to investigate whether combined fish oil and choline supplementation could affect the type and enrich the content of DHA in the brain. The results revealed that the combined intake of fish oil and choline upregulated the expression of key transporters and receptors, including MFSD2A, FATP1, and FABP5, which increased the uptake of DHA in the brain. Additionally, this supplementation improved the synthesis and release of acetylcholine in the brain, which, in turn, enhanced the learning and memory abilities of mice. These findings suggest that the combined intake of fish oil and choline improves the bioavailability of DHA in the brain.

Chemotherapy-induced cognitive impairment (chemobrain) and muscle wasting (cachexia) are persisting side effects which adversely affect the quality of life of cancer survivors. We therefore investigated the efficacy of physical exercise as a non-pharmacological intervention to reverse the adverse effects of chemotherapy. We examined whether physical exercise in terms of voluntary wheel running could prevent chemotherapy-induced cognitive and motor impairments in mice treated with the multi-kinase inhibitor sorafenib. Adult male BALB/c mice were subdivided into runner and non-runner groups and orally administered with sorafenib (60 mg/kg) or vehicle continuously for four weeks. Mice could freely access the running wheel anytime during sorafenib or vehicle treatment. We found that sorafenib treatment reduced body weight gain (% of change, vehicle: 3.28 ± 3.29, sorafenib: −9.24 ± 1.52, p = 0.0004), impaired hippocampal-dependent spatial memory in the Y maze (exploration index, vehicle: 35.57 ± 11.38%, sorafenib: −29.62 ± 7.90%, p < 0.0001), increased anhedonia-like behaviour in the sucrose preference test (sucrose preference, vehicle: 66.57 ± 3.52%, sorafenib: 44.54 ± 4.25%, p = 0.0005) and impaired motor skill acquisition in rotarod test (latency to fall on day 1: 37.87 ± 8.05 and day 2: 37.22 ± 12.26 s, p > 0.05) but did not induce muscle wasting or reduce grip strength. Concomitant voluntary running reduced anhedonia-like behaviour (sucrose preference, sedentary: 44.54 ± 4.25%, runners: 59.33 ± 4.02%, p = 0.0357), restored impairment in motor skill acquisition (latency to fall on day 1: 50.85 ± 15.45 and day 2: 168.50 ± 37.08 s, p = 0.0004), but failed to rescue spatial memory deficit. Immunostaining results revealed that sorafenib treatment did not affect the number of proliferating cells and immature neurons in the hippocampal dentate gyrus (DG), whereas running significantly increased cell proliferation in both vehicle- (total Ki-67+ cells, sedentary: 16,687.34 ± 72.63, exercise: 3320.03 ± 182.57, p < 0.0001) and sorafenib-treated mice (Ki-67+ cells in the ventral DG, sedentary: 688.82.34 ± 38.16, exercise: 979.53 ± 73.88, p < 0.0400). Our results suggest that spatial memory impairment and anhedonia-like behaviour precede the presence of muscle wasting, and these behavioural deficits are independent of the changes in adult hippocampal neurogenesis. Running effectively prevents body weight loss, improves motor skill acquisition and reduces anhedonia-like behaviour associated with increased proliferating cells and immature neurons in DG. Taken together, they support physical exercise rehabilitation as an effective strategy to prevent chemotherapy side effects in terms of mood dysregulation and motor deficit.

High-caloric diets induce several deleterious alterations in the human body, including the brain. However, information on the effects of these diets on the elderly brain is scarce. Therefore, we studied the effects of 2 months of treatment with high-fat (HF) and high-fat-high-sugar (HFHS) diets on aged male Wistar rats at 18 months. Anxiety levels were analyzed using the open-field and plus-maze tests, while learning and memory processes were analyzed using the Morris water maze test. We also analyzed neurogenesis using doublecortin (DCX) and neuroinflammation using glial fibrillary acidic protein (GFAP). In aged rats, the HFHS diet impaired spatial learning, memory, and working memory and increased anxiety levels, associated with a reduction in the number of DCX cells and an increase in GFAP cells in the hippocampus. In contrast, the effects of the HF diet were lighter, impairing spatial memory and working memory, and associated with a reduction in DCX cells in the hippocampus. Thus, our results suggest that aged rats are highly susceptible to high-caloric diets, even if they only started in the elderly, with an impact on cognition and emotions. Furthermore, diets rich in saturated fats and sugar are more detrimental to aged rats than high-fat diets are.

The seriousness of the diseases caused by aging have recently gained attention. Alzheimer’s disease (AD), a chronic neurodegenerative disease, accounts for 60–80% of senile dementia cases. Continuous research is being conducted on the cause of Alzheimer’s disease, and it is believed to include complex factors, such as genetic factors, the accumulation of amyloid beta plaques, a tangle of tau protein, oxidative stress, cholinergic dysfunction, neuroinflammation, and cell death. Sinapic acid is a hydroxycinnamic acid found in plant families, such as oranges, grapefruit, cranberry, mustard seeds, and rapeseeds. It exhibits various biological activities, including anti-inflammatory, anti-oxidant, anti-cancer, and anti-depressant effects. Sinapic acid is an acetylcholine esterase inhibitor that can be applied to the treatment of dementia caused by Alzheimer’s disease and Parkinson’s disease. However, electrophysiological studies on the effects of sinapic acid on memory and learning must still be conducted. Therefore, it was confirmed that sinapic acid was effective in long-term potentiation (LTP) using organotypic hippocampal segment tissue. In addition, the effect on scopolamine-induced learning and memory impairment was measured by oral administration of sinapic acid 10 mg/kg/day for 14 days, and behavioral experiments related to short-term and long-term spatial memory and avoidance memory were conducted. Sinapic acid increased the activity of the field excitatory postsynaptic potential (fEPSP) in a dose-dependent manner after TBS, and restored fEPSP activity in the CA1 region suppressed by scopolamine. The scopolamine-induced learning and memory impairment group showed lower results than the control group in the Y-maze, Passive avoidance (PA), and Morris water maze (MWM) experiments. Sinapic acid improved avoidance memory, short and long-term spatial recognition learning, and memory. In addition, sinapic acid weakened the inhibition of the brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and the activation of prostaglandin-endoperoxide synthase 2 (COX-2) and interleukin 1 beta (IL-1β) induced by scopolamine in the hippocampus. These results show that sinapic acid is effective in restoring LTP and cognitive impairment induced by the cholinergic receptor blockade. Moreover, it showed the effect of alleviating the reduction in scopolamine-induced BDNF and TrkB, and alleviated neuroinflammatory effects by inhibiting the increase in COX-2 and IL-1β. Therefore, we showed that sinapic acid has potential as a treatment for neurodegenerative cognitive impairment.

This mixed-method quasi-experimental study examined whether metaconceptual grammar teaching impacts on (a) students’ L1 grammatical understanding, (b) their ‘blind’ use of grammatical concepts and (c) their preference of using explicit grammatical concepts over everyday concepts in explaining grammatical problems. Previous research, involving single group pre-postintervention designs, found positive effects for metaconceptual interventions on secondary school students’ grammatical reasoning ability, although a negative side effect seemed to be that some students started using grammatical concepts ‘blindly’ (i.e., in an inaccurate way). While there are thus important clues that metaconceptual grammar teaching may lead to increased grammatical understanding, there is a great need for more robust empirical research. The current study, involving 196 Dutch 14-year old pre-university students, is a methodological improvement of previous work, adopting a switching replications design. Bayesian multivariate analyses indicate medium to large effects from the metaconceptual intervention on students’ grammatical understanding. The study found a similar effect of the intervention on students’ ability to use explicit grammatical concepts over everyday concepts in tackling grammatical problems. No evidence for increased ‘blind’ concept use as a negative byproduct of the intervention was found. Additional qualitative analyses of in-intervention tasks provided further evidence for the effectiveness of metaconceptual interventions, and seemed to indicate that cases of blind concept use, rather than being a negative side effect, might actually be part of a gradual process of students’ growing understanding of grammatical (meta)concepts. We discuss these findings in relation to previous work and conclude that linguistic metaconcepts can improve L1 grammatical understanding.

Shan Jiang,1,&ast; Yong-Qiang Wang,2,&ast; Yifei Tang,1 Xi Lu,1 Dan Guo1 1Department of Rehabilitation Medicine, the China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China; 2Department of Ophthalmology, the Sunshine Union Hospital, Weifang, Shandong, 261071, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shan JiangDepartment of Rehabilitation Medicine, the China-Japan Friendship Hospital, No. 2 Ying Hua Yuan East Street, Beijing, 100029, People’s Republic of China, Tel +86 10 84205288, Fax +86 10 64217749, Email landjiang@126.comBackground: As a severe complication of sepsis, sepsis-associated encephalopathy (SAE) usually manifests as impaired learning and memory ability in survivors. Previous studies have reported that environmental enrichment (EE) can increase the learning and memory ability in different brain injury models. However, there has been no research on the possible positive effect of EE on SAE.Aim: The present study aimed to test the effect of EE on SAE-induced impairment of learning and memory and its related mechanisms.Methods: A Morris water maze test (MWM) was used to evaluate the learning and memory ability of SAE rats that received EE housing or not. The expression of vasopressin (VP) was assessed using immunofluorescence microscopy and enzyme-linked immunosorbent assays (ELISAs). The synthesis of VP in the supraoptic nucleus (SON) was determined using quantitative real-time reverse transcription-PCR analysis. Moreover, inflammatory markers and brain-derived neurotrophic factor (BDNF) were detected using ELISA.Results: The results showed that SAE induced a decreased learning and memory ability, while EE reversed this impairment. EE also enhanced the synthesis and secretion of VP in the SON. Blocking the action of VP in the hippocampus interrupted the EE-induced amelioration of learning and memory impairment. Moreover, EE induced changes to the levels of BDNF and cytokines in the hippocampus and these effects were mediated by VP binding to the VP receptor 1a.Conclusion: Our findings demonstrated that the enhanced synthesis and secretion of VP in the SON are a key determinant responsible for EE-induced alleviation of learning and memory deficits caused by SAE.Keywords: sepsis associated encephalopathy, environmental enrichment, vasopressin, learning and memory, vasopressin receptor 1a

Chromatin dysregulation has emerged as a major hallmark of neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). The prevalence of ID and ASD is higher in males compared to females, with unknown mechanisms. Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (MRXSCJ), is caused by loss-of-function mutations of lysine demethylase 5C (KDM5C), a histone H3K4 demethylase gene. KDM5C escapes X-inactivation, thereby presenting at a higher level in females. Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous KDM5C mutations can show cognitive deficits. The mouse model of MRXSCJ, male Kdm5c-hemizygous knockout animals, recapitulates key features of human male patients. However, the behavioral and molecular traits of Kdm5c-heterozygous female mice remain incompletely characterized. Here, we report that gene expression and behavioral abnormalities are readily detectable in Kdm5c-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females. Furthermore, we found both shared and sex-specific consequences of a reduced KDM5C dose in social behavior, gene expression, and genetic interaction with the counteracting enzyme KMT2A. These observations provide an essential insight into the sex-biased manifestation of neurodevelopmental disorders and sex chromosome evolution.

Anesthetics have been shown to cause cytotoxicity, cell death, affect neuronal growth and connectivity in animal models; however, their effects on learning and memory remain to be fully defined. Here, we examined the effects of the inhalation anesthetic sevoflurane (SEV)—both in vivo by examining learning and memory in freely behaving animals, and in vitro using cultured neurons to assess its impact on viability, mitochondrial structure, and function. We demonstrate here that neonatal exposure to sub-clinically used concentrations of SEV results in significant, albeit subtle and previously unreported, learning and memory deficits in adult animals. These deficits involve neuronal cell death, as observed in cell culture, and are likely mediated through perturbed mitochondrial structure and function. Parenthetically, both behavioural deficits and cell death were prevented when the animals and cultured neurons were pre-treated with the anesthetic adjuvant Dexmedetomidine (DEX). Taken together, our data provide direct evidence for sevoflurane-induced cytotoxic effects at the neuronal level while perturbing learning and memory at the behavioural level. In addition, our data underscore the importance of adjuvant agents such as DEX that could potentially counter the harmful effects of commonly used anesthetic agents for better clinical outcomes.

The current study investigates the emergence of value-based remembering (i.e., the ability to prioritize remembering information based on value) in children ages 3.5-5. We will examine whether value-based remembering emerges and develops within this age range, and underlying factors that contribute to this skill (e.g., encoding strategies, executive function).

Associative learning is driven by survival incentives that naturally dispose animals towards risk avoidance and reward seeking in the natural world. In the case of conditioned taste aversion (CTA), animals learn to avoid a palatable taste stimulus after associating it with gastric malaise. In a previous study, an activity-dependent immediate early gene, Fos, and a gene encoding the master kinase for metabolic control, serine/threonine kinase 11 (Stk11), were identified as key regulators for long-term memory formation. Deletion of either Fos or Stk11 in basolateral amygdala projection neurons (BLApn) prevent CTA acquisition yet increase neuronal intrinsic excitability, and the mechanistic connection between enhanced intrinsic excitability and learning impairment is unclear. Recent studies show that the anterior BLA consists of functionally divergent subpopulations of projection neurons that drive motivationally opposing behaviors. In order to further understand the subtype-specific molecular mechanisms of learning and motivation, we used a multiplex labeling system to investigate whether CTA would induce differential transcriptional changes of Fos and Stk11 in different BLApn subpopulations. Results show that Fos mRNA fold change significantly increases in negative valence subpopulations and significantly decreases in positive valence subpopulations after CTA training. On the other hand, expression of Stk11 and Mark2 underwent a global reduction across subpopulations after CTA training. Overall, these findings suggest that cell type-specific expression of Fos and experience-dependent expression of Stk11 takes place during CTA acquisition. These results suggest that Fos and Stk11 pathways are likely activated by different components of gustatory learning, and the means by which both pathways independently regulate learning and memory is yet to be determined.

Neurotrypsin (NT) is a neuronal trypsin-like serine protease whose mutations cause severe mental retardation in humans. NT is activated in vitro by Hebbian-like conjunction of pre- and postsynaptic activities, which promotes the formation of dendritic filopodia via proteolytic cleavage of the proteoglycan agrin. Here, we investigated the functional importance of this mechanism for synaptic plasticity, learning, and extinction of memory. We report that juvenile neurotrypsin-deficient (NT−/−) mice exhibit impaired long-term potentiation induced by a spaced stimulation protocol designed to probe the generation of new filopodia and their conversion into functional synapses. Behaviorally, juvenile NT−/− mice show impaired contextual fear memory and have a sociability deficit. The latter persists in aged NT−/− mice, which, unlike juvenile mice, show normal recall but impaired extinction of contextual fear memories. Structurally, juvenile mutants exhibit reduced spine density in the CA1 region, fewer thin spines, and no modulation in the density of dendritic spines following fear conditioning and extinction in contrast to wild-type littermates. The head width of thin spines is reduced in both juvenile and aged NT−/− mice. In vivo delivery of adeno-associated virus expressing an NT-generated fragment of agrin, agrin-22, but not a shorter agrin-15, elevates the spine density in NT−/− mice. Moreover, agrin-22 co-aggregates with pre- and postsynaptic markers and increases the density and size of presynaptic boutons and presynaptic puncta, corroborating the view that agrin-22 supports the synaptic growth.

Survival in complex environments necessitates a flexible navigation system that incorporates memory of recent behavior and associations. Yet, how the hippocampal spatial circuit represents latent information independent of sensory inputs and future goals has not been determined. To address this, we image the activity of large ensembles in subregion CA1 via wide-field fluorescent microscopy during a novel behavioral paradigm. Our results demonstrate that latent information is represented through reliable firing rate changes during unconstrained navigation. We then hypothesize that the representation of latent information in CA1 is mediated by pattern separation/completion processes instantiated upstream within the dentate gyrus (DG) and CA3 subregions. Indeed, CA3 ensemble recordings reveal an analogous code for latent information. Moreover, selective chemogenetic inactivation of DG–CA3 circuitry completely and reversibly abolishes the CA1 representation of latent information. These results reveal a causal and specific role of DG–CA3 circuitry in the maintenance of latent information within the hippocampus., Keinath et al. show that information about the recent past is represented in the hippocampus through changes in firing rates in the absence of task demands. This representation is eliminated when DG–CA3 circuitry is inhibited.

The Basolateral Amygdala (BLA) has been shown to have an important role in food-related learning behaviors. Using a novel approach, we have evaluated the role of BLA in food preference and Food memory related to visual cues in rats. Thirty-two adult male Wistar rats, weighing 200–250 g, were used for the experiments. Electric lesion of BLA was produced by passing 1.5 mA of current for 7 s. Food-related behaviors and preferences were evaluated by using an automated apparatus. Geometric visual cues were also constructed. Food-deprived rats were presented with different diets in 6 consecutive trial performances. The number of visits, time consumed on each food zone and port, distance traveled in each visit, and the total amount of food eaten was evaluated. The changes in hippocampal c-Fos expression were determined by immunoblotting. The control sham group showed a high and low preference for biscuit and white flour, respectively. BLA lesion rats exhibited a shifted preference curve. In the sham group, a more significant amount of food consumption was associated with an increased number of references to each zone and port, along with more time spent there. Furthermore, a decrease in hippocampal c-Fos expression was observed in the BLA-lesion animals. Taken together, the basolateral amygdala has a significant role in rats’ food-matched visual-cue memory and high-calorie/sweetness preferences.

Motor skills are acquired and refined across alternating phases of practice (online) and subsequent consolidation in the absence of further skill execution (offline). Both stages of learning are sustained by dynamic interactions within a widespread motor learning network including the premotor and primary motor cortices. Here, we aimed to investigate the role of the dorsal premotor cortex (dPMC) and its interaction with the primary motor cortex (M1) during motor memory consolidation. Forty-eight healthy human participants (age 22.1 ± 3.1 years) were assigned to three different groups corresponding to either low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of left dPMC, rTMS of left M1, or sham rTMS. rTMS was applied immediately after explicit motor sequence training with the right hand. Motor evoked potentials were recorded before training and after rTMS to assess potential stimulation-induced changes in corticospinal excitability (CSE). Participants were retested on motor sequence performance after eight hours to assess consolidation. While rTMS of dPMC significantly increased CSE and rTMS of M1 significantly decreased CSE, no CSE modulation was induced by sham rTMS. However, all groups demonstrated similar significant offline learning indicating that consolidation was not modulated by the post-training low-frequency rTMS intervention despite evidence of an interaction of dPMC and M1 at the level of CSE. Motor memory consolidation ensuing explicit motor sequence training seems to be a rather robust process that is not affected by low-frequency rTMS-induced perturbations of dPMC or M1. Findings further indicate that consolidation of explicitly acquired motor skills is neither mediated nor reflected by post-training CSE.

Learned associations between stimuli in different sensory modalities can shape the way we perceive these stimuli. However, it is not well understood how these interactions are mediated or at what level of the processing hierarchy they occur. Here we describe a neural mechanism by which an auditory input can shape visual representations of behaviorally relevant stimuli through direct interactions between auditory and visual cortices in mice. We show that the association of an auditory stimulus with a visual stimulus in a behaviorally relevant context leads to experience-dependent suppression of visual responses in primary visual cortex (V1). Auditory cortex axons carry a mixture of auditory and retinotopically matched visual input to V1, and optogenetic stimulation of these axons selectively suppresses V1 neurons that are responsive to the associated visual stimulus after, but not before, learning. Our results suggest that cross-modal associations can be communicated by long-range cortical connections and that, with learning, these cross-modal connections function to suppress responses to predictable input., What you hear influences what you see. The authors show that experience with an audio-visual stimulus reshapes the input from auditory cortex to visual cortex, suppressing predictable visual input to amplify the unpredictable.

Schizotypy can be defined as a combination of traits qualitatively similar to those found in schizophrenia, but milder in their expression, that can be found in clinical and non-clinical populations. In this research, we explore, to our knowledge, for the first time, whether schizotypal personality traits may affect the acquisition of conditioned fear by social means only. Apart from being an essential capacity to ensure learning in safe environments, social fear learning shares important characteristics with direct fear acquisition, which also makes it a great candidate for developing successful extinction procedures. Undergraduate students (n = 72) performed a task of social fear learning. In this task, participants watched a video of a person that simulated to receive electric shocks (unconditioned stimulus; US) paired with a coloured square (conditioned stimulus plus; CS+), while another coloured square was never paired (conditioned stimulus minus; CS−) with the shock. After that, they were presented with a similar sequence of coloured screens. Their Skin Conductance Responses (SCRs) were registered during the whole process. Once they finished, they completed the Schizotypal Personality Questionnaire (SPQ). Our results revealed that participants with a low score in the Cognitive-Perceptual factor of the SPQ exhibited higher SCRs when they saw the US than when they saw the CS− (all ps ps > 0.05), a pattern that has been similarly found in schizophrenia. During the final trials of the test phase, participants with the highest scores in the Disorganized factor were the only ones that maintained a higher SCR towards the CS+ than towards the CS− (p = 0.006), which could be associated with an impairment in their extinction processes.

Many types of social interaction require the ability to anticipate others' behavior, which is commonly referred to as strategic sophistication. In this context, observational learning can represent a decisive tool for behavioral adaptation. However, little is known on whether and when individuals learn from observation in interactive settings. In the current study, 321 participants played one-shot interactive games and, at a given time along the experiment, they could observe the choices of an overtly efficient player. This social feedback could be provided before or after the participant’s choice in each game. Results reveal that players with a sufficient level of strategic skills increased their level of sophistication only when the social feedback was provided after their choices, whereas they relied on blind imitation when they received feedback before their decision. Conversely, less sophisticated players did not increase their level of sophistication, regardless of the type of social feedback. Our findings disclose the interplay between endogenous and exogenous factors modulating observational learning in strategic interaction.

Methylphenidate (MPD), a psychostimulant, is the first line drug for improving cognitive performance in attention deficit hyperactivity disorder (ADHD). A non-prescription use of this drug for improving performance is also becoming increasingly known. A growing rise in its medical and nonmedical use suggests that the drug is addictive.The present study was designed to ascertain the reinforcing and withdrawal effects of clinically relevant doses of methylphenidate on cognitive behavior of normal adult rats. Potential addictive effects and withdrawal effects on cognition were also determined.Effects of MPD in improving cognition were monitored after drug administration as well as withdrawal using Morris Water Maze test. Taking behavioral sensitization as an important contributing factor of drug addiction; addictive effects of MPD were also determined. Data analysis was done on SPSS version 13 by one-way and two-way ANOVA (repeated measure design) where applicable; post hoc comparisons were done by Tukey’s test. Repeated oral administration of MPD (0.5 and 1mg/kg) for six days produced behavioral sensitization and reduced daily food intake. After six days of treatment rats were repeatedly administered/withdrawal from repeated administration of MPD to investigate effects of MPD on cognitive behaviors. Results showed an improvement in cognition in rats repeatedly administered with MPD (0.5 and 1 mg/kg). Whereas, withdrawal from repeated administration of MPD impaired short term memory, long term memory and memory retention. Doses of MPD which improve learning and memory are potentially addictive and elicit behavioral sensitization. Use of drug in healthy subjects can impair performance below basal levels particularly in drug withdrawal conditions.

The Basolateral Amygdala (BLA) has been shown to have an important role in food-related learning behaviors. Using a novel approach, we have evaluated the role of BLA in food preference and Food memory related to visual cues in rats. Thirty-two adult male Wistar rats, weighing 200–250 g, were used for the experiments. Electric lesion of BLA was produced by passing 1.5 mA of current for 7 s. Food-related behaviors and preferences were evaluated by using an automated apparatus. Geometric visual cues were also constructed. Food-deprived rats were presented with different diets in 6 consecutive trial performances. The number of visits, time consumed on each food zone and port, distance traveled in each visit, and the total amount of food eaten was evaluated. The changes in hippocampal c-Fos expression were determined by immunoblotting. The control sham group showed a high and low preference for biscuit and white flour, respectively. BLA lesion rats exhibited a shifted preference curve. In the sham group, a more significant amount of food consumption was associated with an increased number of references to each zone and port, along with more time spent there. Furthermore, a decrease in hippocampal c-Fos expression was observed in the BLA-lesion animals. Taken together, the basolateral amygdala has a significant role in rats’ food-matched visual-cue memory and high-calorie/sweetness preferences.

Spatial working memory can be assessed in mice through the spontaneous alternation T-maze test. The T-maze is a T-shaped apparatus featuring a stem (start arm) and two lateral goal arms (left and right arms). The procedure is based on the natural tendency of rodents to prefer exploring a novel arm over a familiar one, which induces them to alternate the choice of the goal arm across repeated trials. During the task, in order to successfully alternate choices across trials, an animal has to remember which arm had been visited in the previous trial, which makes spontaneous alternation T-maze an optimal test for spatial working memory. As this test relies on a spontaneous behaviour and does not require rewards, punishments or pre-training, it represents a particularly useful tool for cognitive evaluation, both time-saving and animal-friendly. We describe here in detail the apparatus and the protocol, providing representative results on wild-type healthy mice.

Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for the onset of symptoms in neurodevelopmental psychiatric disorders. Despite the wide use of rodent models to unravel neurobiological mechanisms underlying neurodevelopmental disorders, there is a surprising paucity of rigorous studies focusing on normal cognitive-developmental trajectories in such models. Here, we sought to behaviorally capture maturational changes in cognitive trajectories during adolescence and into adulthood in male and female mice using distinct behavioral paradigms. C57 BL/6J mice (4.5, 6, and 12 weeks of age) were assessed on three behavioral paradigms: drug-induced locomotor hyperactivity, prepulse inhibition, and a novel validated version of a visuospatial paired-associate learning touchscreen task. We show that the normal maturational trajectories of behavioral performance on these paradigms are dissociable. Responses in drug-induced locomotor hyperactivity and prepulse inhibition both displayed a ‘U-shaped’ developmental trajectory; lower during mid-adolescence relative to early adolescence and adulthood. In contrast, visuospatial learning and memory, memory retention, and response times indicative of motivational processing progressively improved with age. Our study offers a framework to investigate how insults at different developmental stages might perturb normal trajectories in cognitive development. We provide a brain maturational approach to understand resilience factors of brain plasticity in the face of adversity and to examine pharmacological and non-pharmacological interventions directed at ameliorating or rescuing perturbed trajectories in neurodevelopmental and neuropsychiatric disorders.

Associative memories are stored in distributed networks extending across multiple brain regions. However, it is unclear to what extent sensory cortical areas are part of these networks. Using a paradigm for visual category learning in mice, we investigated whether perceptual and semantic features of learned category associations are already represented at the first stages of visual information processing in the neocortex. Mice learned categorizing visual stimuli, discriminating between categories and generalizing within categories. Inactivation experiments showed that categorization performance was contingent on neuronal activity in the visual cortex. Long-term calcium imaging in nine areas of the visual cortex identified changes in feature tuning and category tuning that occurred during this learning process, most prominently in the postrhinal area (POR). These results provide evidence for the view that associative memories form a brain-wide distributed network, with learning in early stages shaping perceptual representations and supporting semantic content downstream., Goltstein et al. investigate the role of mouse visual cortical areas in information-integration category learning. They report widespread changes in neuronal response properties, most prominently in a higher visual area, the postrhinal cortex.

Type 1 spinocerebellar ataxia (SCA1) is a progressive neurodegenerative disorder with no effective treatment to date. Using mice modeling SCA1, it has been demonstrated that a drug that amplifies mGlu1 receptor activation (mGlu1 receptor PAM, Ro0711401) improves motor coordination without the development of tolerance when cerebellar dysfunction manifests (i.e., in 30-week-old heterozygous ataxin-1 [154Q/2Q] transgenic mice). SCA1 is also associated with cognitive dysfunction, which may precede cerebellar motor signs. Here, we report that otherwise healthy, 8-week-old SCA1 mice showed a defect in spatial learning and memory associated with reduced protein levels of mGlu1α receptors, the GluN2B subunit of NMDA receptors, and cannabinoid CB1 receptors in the hippocampus. Systemic treatment with Ro0711401 (10 mg/kg, s.c.) partially corrected the learning deficit in the Morris water maze and restored memory retention in the SCA1 mice model. This treatment also enhanced hippocampal levels of the endocannabinoid, anandamide, without changing the levels of 2-arachidonylglycerol. These findings suggest that mGlu1 receptor PAMs may be beneficial in the treatment of motor and nonmotor signs associated with SCA1 and encourage further studies in animal models of SCA1 and other types of SCAs.

International audience; Neural computational power is determined by neuroenergetics, but how and which energy substrates are allocated to various forms of memory engram is unclear. To solve this question, we asked whether neuronal fueling by glucose or lactate scales differently upon increasing neural computation and cognitive loads. Here, using electrophysiology, two-photon imaging, cognitive tasks, and mathematical modeling, we show that both glucose and lactate are involved in engram formation, with lactate supporting long-term synaptic plasticity evoked by high-stimulation load activity patterns and high attentional load in cognitive tasks and glucose being sufficient for less demanding neural computation and learning tasks. Indeed, we show that lactate is mandatory for demanding neural computation, such as theta-burst stimulation, while glucose is sufficient for lighter forms of activity-dependent long-term potentiation (LTP), such as spike timing–dependent plasticity (STDP). We find that subtle variations of spike number or frequency in STDP are sufficient to shift the on-demand fueling from glucose to lactate. Finally, we demonstrate that lactate is necessary for a cognitive task requiring high attentional load, such as the object-in-place task, and for the corresponding in vivo hippocampal LTP expression but is not needed for a less demanding task, such as a simple novel object recognition. Overall, these results demonstrate that glucose and lactate metabolism are differentially engaged in neuronal fueling depending on the complexity of the activity-dependent plasticity and behavior.

It has been shown in literature that East Asians are more inclined to process context information than individuals in Western cultures. Using a context memory task that requires studying object images in social contexts (i.e., rating objects in an imagined social or experiential scenario), our recent study revealed an age-invariant advantage for Chinese young and older participants compared to their Canadian counterparts in memory for encoding contexts. To examine whether this cultural difference also occurred during encoding, this follow-up report analyzed encoding performance and its relationship to subsequent memory based on the same data from the same task of the same sample. The results revealed that at encoding, Chinese participants provided higher ratings of objects, took longer to rate, and reported more vivid imagery of encoding contexts relative to their Canadian counterparts. Furthermore, only Chinese participants rated objects with recognized context at retrieval higher and slower relative to those with misrecognized context. For Chinese participants, primarily older adults, slower ratings were only related to better context memory but not item memory. Importantly, Chinese participants’ context memory advantage disappeared after controlling for encoding differences. Taken together, these results suggest that Chinese participants’ memory advantage for social contexts may have its origin in the construction of elaborative and meaningful object-context associations at encoding.

Sleep facilitates memory consolidation and gist abstraction. It has been proved that spontaneous reactivation is the mechanism of sleep dependent memory consolidation, while the reasoning suggests overlapping reactivation facilitate gist abstraction has not been tested yet. We aim to verify the necessity of ‘overlap’ using Targeted Memory Reactivation (TMR) and a declarative memory task, in which stimuli possess hidden category gist. Memories with (or without) overlapping gist will be paired with auditory cues and half will be reactivated during N2 and slow wave sleep of 90min nap. With a between-subject design, 2x2 ANOVA on performance of category gist will be conducted, with factor 1 (overlapping, non-overlapping) * factor 2 (TMR, no-TMR). The results confirm our hypothesis if a significant interaction is detected, and performance in TMR & overlapping group is better than other 3 groups, but performance in TMR & non-overlapping group is worse than no-TMR & non-overlapping group.

Accumulation of highly post-translationally modified tau proteins is a hallmark of neurodegenerative disorders known as tauopathies, the most common of which is Alzheimer’s disease. Although six tau isoforms are found in the human brain, the majority of animal and cellular tauopathy models utilize a representative single isoform. However, the six human tau isoforms present overlapping but distinct distributions in the brain and are differentially involved in particular tauopathies. These observations support the notion that tau isoforms possess distinct functional properties important for both physiology and pathology. To address this hypothesis, the six human brain tau isoforms were expressed singly in the Drosophila brain and their effects in an established battery of assays measuring neuronal dysfunction, vulnerability to oxidative stress and life span were systematically assessed comparatively. The results reveal isoform-specific effects clearly not attributed to differences in expression levels but correlated with the number of microtubule-binding repeats and the accumulation of a particular isoform in support of the functional differentiation of these tau isoforms. Delineation of isoform-specific effects is essential to understand the apparent differential involvement of each tau isoform in tauopathies and their contribution to neuronal dysfunction and toxicity.

Doktora Tezi, Alzheimer hastalığı (AH), günlük yaşamsal aktivitelerde azalma ve bilişsel yeteneklerde bozulma ile karakterize, nöropsikiyatrik semptomların ve davranış değişikliklerinin eşlik ettiği nörodejeneratif bir hastalıktır. AH demansın en sık görülen tipi olup prevalansı gün geçtikçe artmaktadır. Fizyopatolojisinde oluşan anormal amiloit prekursor proteinler (APP), hücre içinde nörofibril yumakları (NFY) ve senil plaklar (SP) birikmesi, sinir hücrelerinde sinaptik iletimin kaybına ve özellikle hipokampus ve serebral korteksteki nöronların ölümüne yol açmaktadır. Asetil kolin (ACh) hipokampusu serebral kortekse bağlayan nörotransmitterdir. Kolin ve asetil koA’dan ‘asetil transferaz’ enzimi ile ‘asetil kolin’ oluşur. AH’de primer defisit beyindeki kolinerjik sistemin, özellikle öğrenme ve bellek ile ilgili bölgelerde, bozulmasıdır. Plastisite geni 15 (CPG 15) olarak da bilinen nöritin, aktivite ile indüklenen glikozilfosfatidilinozitol bağımlı bir aksonal protein olup çoğunlukla merkezi sinir sisteminde eksprese edilir. İlk olarak ratların dentat girusunda, daha sonra insanda tespit edilmiştir. Nötirinin hafızayı etkileyen nörodejeneratif ve nöropsikolojik hastalıklarda da rol oynayabileceği ileri sürülmüştür. Sinirsel gelişim ve sinaptik plastisitedeki çok yönlü rolleriyle nöritin, MSS’nin nöronal bağlantılarının yeniden oluşmasında katkı sağlar. Deneysel AH modelleri birçok araştırmada AH etiyofizyopatolojisinin anlaşılması ve potansiyel tedavi seçeneklerinin etkinliğinin belirlenmesine yönelik olarak son yıllarda yoğun olarak kullanılmaktadır. Bu bağlamda MSS’de eksprese edilen yeni bir molekül olan nöritin (NRN), nörodejeneratif hastalıklarda araştırılan ümit verici bir peptittir. AH süreçlerinde NRN etkisini konu alan oldukça sınırlı sayıda araştırma bulgusu yer almaktadır. Nöritinin sıçanlardaki olası etkinliğinin davranış modelleri ve nöronal moleküler belirteçler düzeyinde etkisi ise araştırılmamıştır. Bu nedenle mevcut çalışmamızda yeni bir nörotrofik molekül olan NRN’nin AH’deki olası nöroprotektif etkinliğinin araştırılması amaçlanmıştır. Çalışmada 40 adet erkek sıçan Kontrol, demans, nöritin, demans + nöritin grupları olarak 4 gruba ayrılmıştır. Tüm hayvanlara anestezi altında stereotaksik cihaz ile ozmotik minipompa yerleştirilmiştir. Demans gruplarına streptozotosin intraserebroventriküler (İSV) yolla enjekte edilmiştir. Nöritin ve çözücüsü İSV yolla 7 gün boyunca infüze edilmiştir. 8. günde sıçanlara davranış testleri uygulanmıştır. Morris’in su labirenti testinde (MST) her bir hayvanın performansı kaydedilerek davranış parametreleri değerlendirilmiştir. Tüm sıçanlardan elde edilen serum ve beyin dokuları toplanmış ve ELISA yöntemiyle hipokampal kolinerjik aktivite analizleri gerçekleştirilmiştir. MST bulgularında NRN uygulanan gruplarda demans gruplarına kıyasla platformu bulma süresi, platforma yüzme mesafesi ve hızı açısından istatistiksel olarak olumlu sonuçlar elde edilmiştir. Moleküler analiz sonuçları istatistiksel olarak anlamlı olmasa da tedavi grubunda ChAT aktivitesinde artış tespit edilmiştir. Çalışma bulgularımız, NRN’nin AH tedavisi üzerine olan etkilerinin araştırıldığı derinlemesine çalışmaların, AH için yeni bir tedavi seçeneği olarak NRN’nin etkinliği konusunda yeni ufuklar açacağını düşündürmektedir., Alzheimer's disease (AD) has a degenerative view from the part of training, neuropsychiatric education and training with use and equipment in daily life use. AD is the most common manifestation of dementia and its prevalence is increasing day by day. Neurofibrillary tangles (NFT) and senile plaques (SP) within a cell formed in its physiopathology are considered to be acquired pathways and are detached from targets in the cerebral cortex. Acetylcholine (ACh) is the neurotransmitter that connects the hippocampus to the cerebral cortex. Acetyl choline is formed by the enzyme 'acetyl transferase' from choline and acetyl coA. The primary deficit in AD is the disruption of the cholinergic system in the brain, especially in regions related to learning and memory. Neuritin, also known as plasticity gene 15 (CPG 15), is an activity-induced glycosylphosphatidylinositol-dependent axonal protein and is mostly expressed in the central nervous system. It was first detected in the dentate gyrus of rats and later in humans. It has been suggested that neutirine may also play a role in neurodegenerative and neuropsychological diseases that affect memory. With its versatile roles in neural development and synaptic plasticity, neuritin contributes to the regeneration of neuronal connections of the CNS. Experimental AD models have been used extensively in many studies in recent years to understand the etiophysiopathology of AD and to determine the effectiveness of potential treatment options. In this context, neuritin (NRN), a new molecule expressed in the CNS, is a promising peptide investigated in neurodegenerative diseases. There are very limited research findings on the effect of NRN in AD processes. The possible effect of neuritis in rats at the level of behavioral patterns and neuronal molecular markers has not been investigated. Therefore, in our current study, it was aimed to investigate the possible neuroprotective activity of NRN, a new neurotrophic molecule, in AD. In the study, 40 male rats were divided into 4 groups as control, dementia, neuritin, dementia + neuritin groups. All animals were placed under anesthesia with a stereotaxic device and an osmotic minipump. Streptozotocin was injected intracerebroventricularly (ICV) to dementia groups. Neuritin and its solvent were infused by ISV for 7 days. Behavioral tests were applied to the rats on the 8th day. In Morris' water maze test (MWM), the performance of each animal was recorded and behavioral parameters were evaluated. Serum and brain tissues obtained from all rats were collected and hippocampal cholinergic activity analyzes were performed by ELISA method. In the MST findings, statistically positive results were obtained in terms of time to find the platform, swimming distance to the platform and speed in the NRN applied groups compared to the dementia groups. Although the results of the molecular analysis were not statistically significant, an increase in ChAT activity was detected in the treatment group. Our study findings suggest that in-depth studies investigating the effects of NRN on the treatment of AD will open new horizons for the effectiveness of NRN as a new treatment option for AD.

(1) Background: Exercise exerts many neuroprotective effects in diabetes-induced brain disorders. In this study, we investigated the effect of high-intensity interval training (HIIT) on brain molecular changes and cognitive and anxiety-like behaviors in rats with type 2 diabetes. (2) Methods: Twenty-eight adult male rats were divided into four groups (n = 7): control (C), exercise + control (C+EX), diabetes (DM), and diabetes + exercise (DM+EX). Diabetes was induced using a two-month high-fat diet and a single dose of streptozotocin (35 mg/kg) in the DM and DM+EX groups. After, the C+EX and DM+EX groups performed HIIT for eight weeks (five sessions per week, running at 80–100% of VMax, 4–10 intervals) on a motorized treadmill. Then, the elevated plus maze (EPM) and open field test (OFT) were performed to evaluate anxiety-like behaviors. The Morris water maze (MWM) and shuttle box were used to assess cognitive function. The hippocampal levels of beta-amyloid and tau protein were also assessed using Western blot. (3) Results: The hippocampal levels of beta-amyloid and tau protein were increased in the DM group, but HIIT restored these changes. While diabetes led to a significant decrease in open arm time percentage (%OAT) and open arm enters percentage (%OAE) in the EPM, indicating anxiety-like behavior, HIIT restored them. In the OFT, grooming was decreased in diabetic rats, which was restored by HIIT. No significant difference between groups was seen in the latency time in the shuttle box or for learning and memory in the MWM. (4) Conclusions: HIIT-induced hippocampal molecular changes were associated with anxiety-like behavior improvement but not cognitive function in rats with type 2 diabetes.

Maternal separation (MS) is a key contributor to neurodevelopmental disorders, including learning disabilities. To test the hypothesis that dopamine signaling is a major factor in this, an atypical new dopamine transporter (DAT) inhibitor, CE-123, was assessed for its potential to counteract the MS-induced spatial learning and memory deficit in male and female rats. Hence, neonatal rats (postnatal day (PND)1 to 21) were exposed to MS (180 min/day). Next, the acquisition of spatial learning and memory (Barnes maze task) and the expression of dopamine D1 receptor, dopamine transporter (DAT), and the neuronal GTPase, RIT2, which binds DAT in the vehicle-treated rats were evaluated in the prefrontal cortex and hippocampus in the adolescent animals. The results show that MS impairs the acquisition of spatial learning and memory in rats, with a more severe effect in females. Moreover, the MS induced upregulation of DAT and dopamine D1 receptors expression in the prefrontal cortex and hippocampus in adolescent rats. Regarding RIT2, the expression was decreased in the hippocampus for both the males and females, however, in the prefrontal cortex, reduction was found only in the females, suggesting that there are region-specific differences in DAT endocytic trafficking. CE-123 ameliorated the behavioral deficits associated with MS. Furthermore, it decreased the MS-induced upregulation of D1 receptor expression level in the hippocampus. These effects were more noted in females. Overall, CE-123, an atypical DAT inhibitor, is able to restore cognitive impairment and dopamine signaling in adolescent rats exposed to MS—with more evident effect in females than males.

Alzheimer’s disease (AD) is associated with cognitive impairments and age-dependent memory deficits which have been studied using genetic models of AD. Whether the processes for modulating memory persistence are more vulnerable to the influence of amyloid pathology than the encoding and consolidation of the memory remains unclear. Here, we investigated whether early amyloid pathology would affect peri-learning novelty in promoting memory, through a process called behavioral tagging and capture (BTC). AppNL-G-F/NL-G-F mice and wild-type littermates were trained in an appetitive delayed matching-to-place (ADMP) task which allows for the assessment of peri-learning novelty in facilitating memory. The results show that novelty enabled intermediate-term memory in wild-type mice, but not in AppNL-G-F/NL-G-F mice in adulthood. This effect preceded spatial memory impairment in the ADMP task seen in middle age. Other memory tests in the Barnes maze, Y-maze, novel object or location recognition tasks remained intact. Together, memory modulation through BTC is impaired before apparent deficits in learning and memory. Relevant biological mechanisms underlying BTC and the implication in AD are discussed., This work was supported by Alzheimer’s Research UK and the Masonic Trust (SRF2018B-009 and PhD2018-040), and the Biotechnology and Biological Sciences Research Council (BB/M025128/1).

Rho GTPases are a class of G-proteins involved in several aspects of cellular biology, including the regulation of actin cytoskeleton. The most studied members of this family are RHOA and RAC1 that act in concert to regulate actin dynamics. Recently, Rho GTPases gained much attention as synaptic regulators in the mammalian central nervous system (CNS). In this context, ARHGAP22 protein has been previously shown to specifically inhibit RAC1 activity thus standing as critical cytoskeleton regulator in cancer cell models; however, whether this function is maintained in neurons in the CNS is unknown. Here, we generated a knockout animal model for arhgap22 and provided evidence of its role in the hippocampus. Specifically, we found that ARHGAP22 absence leads to RAC1 hyperactivity and to an increase in dendritic spine density with defects in synaptic structure, molecular composition, and plasticity. Furthermore, arhgap22 silencing causes impairment in cognition and a reduction in anxiety-like behavior in mice. We also found that inhibiting RAC1 restored synaptic plasticity in ARHGAP22 KO mice. All together, these results shed light on the specific role of ARHGAP22 in hippocampal excitatory synapse formation and function as well as in learning and memory behaviors.

Older adults show both age-related decreases in resting state functional connectivity and diminished sensorimotor function. Exercise has emerged as an intervention that may mitigate or even reverse these age-related declines. Here we sought to understand whether exercise impacts resting state functional connectivity, and motor acquisition and learning in older adults. Forty-two healthy older adults rested or completed 3 sets of high-intensity interval exercise (3 minutes at 75% maximal power output and 3 minutes light intensity) for a total of 23 minutes, then immediately practiced a complex, implicit motor task with their non-dominant hand across five separate sessions. Participants completed resting stage functional MRI before the first and after the fifth day of practice; they also returned 24-hours and 35-days following their fifth day of practice to complete short- and long-term retention tests to assess motor learning. Independent component analysis of resting state functional MRI revealed increased connectivity in the frontoparietal, the dorsal attentional, and cerebellar networks in the exercise group relative to the rest group. Seed-based analysis showed strengthened connectivity between the limbic system and right cerebellum, and between the right cerebellum and bilateral middle temporal gyri. There was no motor learning advantage for the exercise group; both rest and exercise groups demonstrated motor learning as measured at the short- and long-term retention tests. Our data suggest that exercise paired with a challenging implicit motor learning task in older adults can augment resting state functional connectivity without enhancing behaviour beyond that stimulated by skilled motor practice.

The majority of smokers relapse even after successfully quitting because of the craving to smoking after unexpectedly re-exposed to smoking-related cues. This conditioned craving is mediated by reward memories that are frequently experienced and stubbornly resistant to treatment. Reconsolidation theory posits that well-consolidated memories are destabilized after retrieval, and this process renders memories labile and vulnerable to amnestic intervention. This study tests the retrieval reconsolidation procedure to decrease nicotine craving among people who smoke. In this study, 52 male smokers received a single dose of propranolol (n = 27) or placebo (n = 25) before the reactivation of nicotine-associated memories to impair the reconsolidation process. Craving for smoking and neural activity in response to smoking-related cues served as primary outcomes. Functional magnetic resonance imaging was performed during the memory reconsolidation process. The disruption of reconsolidation by propranolol decreased craving for smoking. Reactivity of the postcentral gyrus in response to smoking-related cues also decreased in the propranolol group after the reconsolidation manipulation. Functional connectivity between the hippocampus and striatum was higher during memory reconsolidation in the propranolol group. Furthermore, the increase in coupling between the hippocampus and striatum positively correlated with the decrease in craving after the reconsolidation manipulation in the propranolol group. Propranolol administration before memory reactivation disrupted the reconsolidation of smoking-related memories in smokers by mediating brain regions that are involved in memory and reward processing. These findings demonstrate the noradrenergic regulation of memory reconsolidation in humans and suggest that adjunct propranolol administration can facilitate the treatment of nicotine dependence. The present study was pre-registered at ClinicalTrials.gov (registration no. ChiCTR1900024412).

BackgroundThe anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive, as is the ventral hippocampus in rodent models for schizophrenia risk. Hyperactive ventral hippocampal projections to extrahippocampal brain regions contribute to schizophrenia symptoms, but less is known about the functional effects of hyperactive projections within the hippocampal formation long axis. We approached this question by testing whether hyperactivation of ventral dentate gyrus (DG) mossy cells (MCs), which densely project intrahippocampally to the dorsal DG, influences spatial memory, a cognition dependent on intact dorsal DG function.MethodsIn CD-1 mice, we targeted dorsal DG-projecting ventral DG MCs using an adeno-associated virus intersectional strategy. In vivo fiber photometry recording of ventral DG MCs was performed during exploratory behaviors. We targeted excitatory chemogenetic constructs to ventral DG MCs and tested whether their hyperactivation impaired encoding in a spatial memory task.ResultsVentral DG MCs were activated during behavior related to environmental information gathering (rearing) but not during non-exploratory motor behaviors. Ventral DG MCs made functional monosynaptic inputs to dorsal DG granule cells, with chemogenetic activation of ventral DG MCs leading to increased activity of dorsal DG granule cells. Finally, chemogenetic activation of ventral DG MCs during the encoding phase of an object location memory task impaired retrieval 24 hours later, without effects on locomotion or other exploratory behaviors.ConclusionsThese data suggest that localized hippocampal hyperactivity may have longitudinal intrahippocampal functional consequences, supporting study of longitudinal circuits as targets to mitigate cognitive deficits associated with schizophrenia.

Oligodendrocyte precursor cells (OPCs) originate in localized germinal zones in the embryonic neural tube, then migrate and proliferate to populate the entire central nervous system, both white and gray matter. They divide and generate myelinating oligodendrocytes (OLs) throughout postnatal and adult life. OPCs express NG2 and platelet-derived growth factor receptor alpha subunit (PDGFRα), two functionally important cell surface proteins, which are also widely used as markers for OPCs. The proliferation of OPCs, their terminal differentiation into OLs, survival of new OLs, and myelin synthesis are orchestrated by signals in the local microenvironment. We discuss advances in our mechanistic understanding of paracrine effects, including those mediated through PDGFRα and neuronal activity-dependent signals such as those mediated through AMPA receptors in OL survival and myelination. Finally, we review recent studies supporting the role of new OL production and “adaptive myelination” in specific behaviours and cognitive processes contributing to learning and long-term memory formation. Our article is not intended to be comprehensive but reflects the authors’ past and present interests.

Although the cannabinoid receptor 2 (CB2R) is often thought to play a role mainly outside the brain several publications unequivocally showed the presence of CB2R on hippocampal principal neurons. Activation of CB2R produced a long-lasting membrane potential hyperpolarization, altered the input/output function of CA2/3 principal neurons and produced alterations in gamma oscillations. However, other cellular, molecular and behavioral consequences of hippocampal CB2R signaling have not been studied in detail. Here we demonstrate that the deletion of CB2 leads to a highly significant increase in hippocampal synapsin-I expression levels and particle density, as well as increased vesicular GABA transporter (vGAT) levels. This phenotype was restricted to females and not observed in males. Furthermore, we demonstrate an impairment of social memory in CB2 deficient mice. Our results thus demonstrate that the lack of CB2R leads to changes in the hippocampal synaptic landscape and reveals an important sex-specific difference in endocannabinoid signaling. This study supports a significant role of the CB2R in modulation of different types of memory despite its low expression levels in the brain and provides more insight into a sex-specific role of CB2R in synaptic architecture.

Aging affects individuals of every species, with sometimes detrimental effects on memory and cognition. The simultaneous-chaining task, a sequential-learning task, requires subjects to select items in a predetermined sequence, putting demands on memory and cognitive processing capacity. It is thus a useful tool to investigate age-related differences in these domains. Pigeons of three age groups (young, adult and aged) completed a locomotor adaptation of the task, learning a list of four items. Training began by presenting only the first item; additional items were added, one at a time, once previous items were reliably selected in their correct order. Although memory capacity declined noticeably with age, not all aged pigeons showed impairments compared to younger pigeons, suggesting that inter-individual variability emerged with age. During a subsequent free-recall memory test in the absence of reinforcement, when all trained items were presented alongside novel distractor items, most pigeons did not reproduce the trained sequence. During a further forced-choice test, when pigeons were given a choice between only two of the trained items, all three age groups showed evidence of an understanding of the ordinal relationship between items by choosing the earlier item, indicating that complex cognitive processing, unlike memory capacity, remained unaffected by age.

Slowed processing speed is considered a hallmark feature of cognitive decline in cerebral small vessel disease (SVD); however, it is unclear whether SVD’s association with slowed processing might be due to its association with overall declining general cognitive ability. We quantified the total MRI-visible SVD burden of 540 members of the Lothian Birth Cohort 1936 (age: 72.6 ± 0.7 years; 47% female). Using latent growth curve modelling, we tested associations between total SVD burden at mean age 73 and changes in general cognitive ability, processing speed, verbal memory and visuospatial ability, measured at age 73, 76, 79 and 82. Covariates included age, sex, vascular risk and childhood cognitive ability. In the fully adjusted models, greater SVD burden was associated with greater declines in general cognitive ability (standardised β: −0.201; 95% CI: [−0.36, −0.04]; pFDR = 0.022) and processing speed (−0.222; [−0.40, −0.04]; pFDR = 0.022). SVD burden accounted for between 4 and 5% of variance in declines of general cognitive ability and processing speed. After accounting for the covariance between tests of processing speed and general cognitive ability, only SVD’s association with greater decline in general cognitive ability remained significant, prior to FDR correction (−0.222; [−0.39, −0.06]; p = 0.008; pFDR = 0.085). Our findings do not support the notion that SVD has a specific association with declining processing speed, independent of decline in general cognitive ability (which captures the variance shared across domains of cognitive ability). The association between SVD burden and declining general cognitive ability supports the notion of SVD as a diffuse, whole-brain disease and suggests that trials monitoring SVD-related cognitive changes should consider domain-specific changes in the context of overall, general cognitive decline.

Evidence suggests that selective serotonin reuptake inhibitors (SSRIs) reorganize neural networks via a transient window of neuroplasticity. While previous findings support an effect of SSRIs on intrinsic functional connectivity, little is known regarding the influence of SSRI-administration on connectivity during sequence motor learning. To investigate this, we administered 20 mg escitalopram or placebo for 1-week to 60 healthy female participants undergoing concurrent functional magnetic resonance imaging and sequence motor training in a double-blind randomized controlled design. We assessed task-modulated functional connectivity with a psycho-physiological interaction (PPI) analysis in the thalamus, putamen, cerebellum, dorsal premotor, primary motor, supplementary motor, and dorsolateral prefrontal cortices. Comparing an implicit sequence learning condition to a control learning condition, we observed decreased connectivity between the thalamus and bilateral motor regions after 7 days of escitalopram intake. Additionally, we observed a negative correlation between plasma escitalopram levels and PPI connectivity changes, with higher escitalopram levels being associated with greater thalamo-cortico decreases. Our results suggest that escitalopram enhances network-level processing efficiency during sequence motor learning, despite no changes in behaviour. Future studies in more diverse samples, however, with quantitative imaging of neurochemical markers of excitation and inhibition, are necessary to further assess neural responses to escitalopram.

Steroid hormones play important roles in brain development and function. The signaling of steroid hormones depends on the interaction between steroid receptors and their coactivators. Although the function of steroid receptor coactivators has been extensively studied in other tissues, their functions in the central nervous system are less well investigated. In this study, we addressed the function of steroid receptor coactivator 3 (SRC3) – a member of the p160 SRC protein family that is expressed predominantly in the hippocampus. While hippocampal development was not altered in Src3+/− mice, hippocampus-dependent functions such as short-term memory and spatial memory were impaired. We further demonstrated that the deficient learning and memory in Src3+/− mice was strongly associated with the impairment of long-term potentiation (LTP) at Schaffer Collateral-CA1 synapses. Mechanistic studies indicated that Src3+/− mutation altered the composition of N-methyl-D-aspartate receptor subunits in the postsynaptic densities of hippocampal neurons. Finally, we showed that SRC3 regulated synaptic plasticity and learning mainly dependent on its lysine acetyltransferase activity. Taken together, these results reveal previously unknown functions of SRC3 in the hippocampus and thus may provide insight into how steroid hormones regulate brain function.

Auditory-cued goal-oriented behaviors requires the participation of cortical and subcortical brain areas, but how neural circuits associate sensory-based decisions with goal locations through learning remains poorly understood. The hippocampus is critical for spatial coding, suggesting its possible involvement in transforming sensory inputs to the goal-oriented decisions. Here, we developed an auditory discrimination task in which rats learned to navigate to goal locations based on the frequencies of auditory stimuli. Using in vivo calcium imaging in freely behaving rats over the course of learning, we found that dentate granule cells became more active, spatially tuned, and responsive to task-related variables as learning progressed. Furthermore, only after task learning, the activity of dentate granule cell ensembles represented the navigation path and predicts auditory decisions as early as when rats began to approach the goals. Finally, chemogenetic silencing of dentate gyrus suppressed task learning. Our results demonstrate that dentate granule cells gain task-relevant firing pattern through reinforcement learning and could be a potential link of sensory decisions to spatial navigation.

Objective: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with impaired cognitive skills and learning and memory dysfunctions. It has been suggested that pelargonidin (PG), as an antioxidant agent, has a neuroprotective effect. PG could prevent damaging effects of amyloid-beta (Aβ) deposition. The aim of this study was to determine the chronic effect of PG on hippocampal neurons and memory processes in a rat model of AD. Materials and Methods: Twenty-eight male adult rats were divided into sham, AD, AD+PG (5 μg, intracerebroventricular), and PG (5 μg, intracerebroventricular) groups. Intracerebroventricular (ICV) injection of Aβ peptides (6 μg) was done using stereotaxic surgery. ICV administration of PG or saline was performed daily for 28 consecutive days. Behavioral analysis was performed using the novel object recognition (NOR) and passive avoidance tests. Neuronal apoptosis was detected using TUNEL assay in the hippocampus. Results: The ICV injection of Aβ reduced step-through latency and discrimination index in behavioral tests (p