Reference Memory Research Articles

Spread of pathological human Tau from neurons to oligodendrocytes and loss of high-firing pyramidal neurons in aging mice.

Intracellular aggregation of hyperphosphorylated Tau (pTau) in the brain is associated with cognitive and motor impairments, and ultimately neurodegeneration. We investigate how human pTau affects cells and network activity in the hippocampal formation of the THY-Tau22 tauopathy model mice invivo. We find that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to neurodegeneration, and we establish that pTau spreads to oligodendrocytes. During goal-directed virtual navigation in aged transgenic mice, we detect fewer high-firing prosubicular pyramidal cells, but the firing population retains its coupling to theta oscillations. Analysis of network oscillations and firing patterns of pyramidal and GABAergic neurons recorded in head-fixed and freely moving mice suggests preserved neuronal coordination. In spatial memory tests, transgenic mice have reduced short-term familiarity, but spatial working and reference memory are surprisingly normal. We hypothesize that unimpaired subcortical network mechanisms maintain cortical neuronal coordination, counteracting the widespread pTau aggregation, loss of high-firing cells, and neurodegeneration.

The Helico Maze Detects Early Impairment of Reference Memory at Three Months of Age in the 5XFAD Mouse Model of Alzheimer's Disease.

The 5XFAD model of Alzheimer's disease (AD) bearing five familial mutations of Alzheimer's disease on human APP and PSEN1 transgenes shows deposits of amyloid-β peptide (Aβ) as early as 2 months, while deficits in long-term memory can be detected at 4 months using the highly sensitive olfactory-dependent tests that we previously reported. Given that detecting early dysfunctions in AD prior to overt pathology is of major interest in the field, we sought to detect memory deficits at earlier stages of the disease in 3-month-old male 5XFAD mice. To this end, we used the Helico Maze, a behavioral task that was recently developed and patented. This device allows deeper analysis of learning and subcategories of hippocampal-dependent long-term memory using olfactory cues. Eight male 5XFAD and 6 male wild-type (WT: C57Bl6 background) mice of 3 months of age were tested in the Helico Maze. The results demonstrated, for the first time, a starting deficit of pure reference long-term memory. Interestingly, memory impairment was clearly correlated with Aβ deposits in the hippocampus. While we also found significant differences in astrogliosis between 5XFAD and WT mice, this was not correlated with memory abilities. Our results underline the efficiency of this new olfactory-dependent behavioral task, which is easy to use, with a small cohort of mice. Using the Helico Maze may open new avenues to validate the efficacy of treatments that target early events related to the amyloid-dependent pathway of the disease and AD progression.

Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice.

Tumor necrosis factor alpha (TNF-α) plays a vital role in Alzheimer’s disease (AD) pathology, and TNF-α inhibitors (TNFIs) modulate AD pathology. We fused the TNF-α receptor (TNFR), a biologic TNFI that sequesters TNF-α, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain across the blood–brain barrier (BBB). TfRMAb-TNFR was protective in 6-month-old transgenic APP/PS1 mice in our previous work. However, the effects and safety following delayed chronic TfRMAb-TNFR treatment are unknown. Herein, we initiated the treatment when the male APP/PS1 mice were 10.7 months old (delayed treatment). Mice were injected intraperitoneally with saline, TfRMAb-TNFR, etanercept (non-BBB-penetrating TNFI), or TfRMAb for ten weeks. Biologic TNFIs did not alter hematology indices or tissue iron homeostasis; however, TfRMAb altered hematology indices, increased splenic iron transporter expression, and increased spleen and liver iron. TfRMAb-TNFR and etanercept reduced brain insoluble-amyloid beta (Aβ) 1-42, soluble-oligomeric Aβ, and microgliosis; however, only TfRMAb-TNFR reduced Aβ peptides, Thioflavin-S-positive Aβ plaques, and insoluble-oligomeric Aβ and increased plaque-associated phagocytic microglia. Accordingly, TfRMAb-TNFR improved spatial reference memory and increased BBB-tight junction protein expression, whereas etanercept did not. Overall, despite delayed treatment, TfRMAb-TNFR resulted in a better therapeutic response than etanercept without any TfRMAb-related hematology- or iron-dysregulation in aged APP/PS1 mice.

Neuroprotective Effects of the Ethanolic Leaf Extract of Crassocephalum crepidioides (Asteracaeae) on Diazepam-Induced Amnesia in Mice.

This study aimed to evaluate the neuroprotective effects of the ethanolic leaf extract of Crassocephalum crepidioides (Cc) on diazepam-induced amnesia in mice. Thirty mice distributed into six groups of five mice each were used. The normal control and negative control groups received 2% ethanol per os, the positive control group received piracetam (150 mg/kg, p.o), and three experimental groups were treated with three doses of ethanolic leaf extract of Cc (100, 200, and 400 mg/kg, p.o). All groups except the normal control group were co-treated with diazepam (3 mg/kg, i.p) daily for 14 days. The memory effects were evaluated using the Radial Arm Maze (RAM) and the Novel Object Recognition (NOR) tests, while the anti-depressive effects were evaluated using the tail suspension test. All animals were sacrificed at the end of the study. Hippocampi, isolated from the right hemisphere, were used to prepare a homogenate for the determination of oxidative stress biomarkers. The ethanolic leaf extract of cc significantly (p < 0.001) decreased the number of working and reference memory errors in the RAM test and induced a significant (p < 0.01) increase in the time spent exploring the novel object in the NOR test. The extract also induced a significant (p < 0.001) increase in the mobility time in tail suspension. Moreover, compared to the negative control group, the extract significantly (p < 0.01) increased superoxide dismutase activity and significantly (p < 0.01) decreased malondialdehyde levels. The histopathological analysis of hippocampi showed that the cc extract increased cell density when compared with the negative control. These results suggest that the ethanolic left extract of cc could have neuroprotective properties, which could be attributed to its antioxidant properties.

Protective Effects of Shi-Zhen-An-Shen Decoction on the Cognitive Impairment in MK801-Induced Schizophrenia Model.

Cognitive dysfunction is a core feature of schizophrenia that strongly correlates to the patients' difficulties in independent living and occupational functioning. Synaptic dysfunction may result in cognitive and behavioral changes similar to what have been identified in schizophrenia. Shi-Zhen-An-Shen Decoction (SZASD) is the empirical formula of traditional Chinese medicine adopted in treating psychiatric symptoms, especially the cognitive impairment in schizophrenia patients, with proven efficacy in the long term of clinical practice in Beijing Anding Hospital, Capital Medical University. However, the mechanisms of SZASD on the cognitive improvement in schizophrenia is still unclear. Here, we aim to investigate the underlying mechanisms of the impact of SZASD on the cognitive impairment in MK801-induced schizophrenia-like rats. Six rat groups (n = 12 per group) were subjected to different treatments for 14 days. All the six groups were injected intraperitoneally with a given volume of 0.9% saline and MK801 (0.2 mg/kg) for consecutive 14 days for modelling. And the rats in the SZASD-treated groups and the clozapine-treated group were given SZASD (low, middle, and high doses) or clozapine, respectively, by intragastric administration. Then, we performed behavioral tests after the treatments, and the rats were sacrificed on the 19th day for biological analysis. Behavioral tests indicated that SZASD mitigated the aberrant motor activity and improved schizophrenia-like rats' spatial reference memory and sensory gating ability. Furthermore, SZASD significantly increased the expressions of PSD95, BDNF, and synapsin I in the hippocampus of MK801-induced schizophrenia-like rats. Our findings suggest that SZASD may ameliorate cognitive impairment by restoring the levels of synaptic proteins in the hippocampus.

Ablation of the Presynaptic Protein Mover Impairs Learning Performance and Decreases Anxiety Behavior in Mice.

The presynaptic protein Mover/TPRGL/SVAP30 is absent in Drosophila and C. elegans and differentially expressed in synapses in the rodent brain, suggesting that it confers specific functions to subtypes of presynaptic terminals. In order to investigate how the absence of this protein affects behavior and learning, Mover knockout mice (KO) were subjected to a series of established learning tests. To determine possible behavioral and cognitive alterations, male and female 8-week-old KO and C57Bl/6J wildtype (WT) control mice were tested in a battery of memory and anxiety tests. Testing included the cross maze, novel object recognition test (NOR), the Morris water maze (MWM), the elevated plus maze (EPM), and the open field test (OF). Mover KO mice showed impaired recognition memory in the NOR test, and decreased anxiety behavior in the OF and the EPM. Mover KO did not lead to changes in working memory in the cross maze or spatial reference memory in the MWM. However, a detailed analysis of the swimming strategies demonstrated allocentric-specific memory deficits in male KO mice. Our data indicate that Mover appears to control synaptic properties associated with specific forms of memory formation and behavior, suggesting that it has a modulatory role in synaptic transmission.

Work of Memory

Film is the ‘art of time’, and film and memory’s generative affiliation is founded in this relationship. This paper will examine how this mnemonic facility is invoked through practice and how this in turn creates memories. The tension between narrative interests and memory’s imperatives can form an axis of experimentation and exploration. All films reference memory, one way or another, however not all are works of memory. Some films would evoke the idea of memory but do not risk structural and psychological instability whereas others consciously suggest memory’s presence through offering more than one temporal plain and other related signifiers. The latter categorisation includes the films suchas Muriel ou le temps d’un retour (Resnais, 1963), Tren de sombras (Guerín, 1997) and Appearances (Meter, 2000). In this work the correspondence of history and form, narrative and memory relates and develops subjective and cultural recollection. These films relate a form of filmic hybridity that emphasizes conceptual potentiality and will be the focus of this study. This examination will consider how these films’ account of memory’s evolving resonances is an act of writing and re-writing, and how these works produce new ways of seeing and thinking.

A Role for PGC-1a in the Control of Abnormal Mitochondrial Dynamics in Alzheimer's Disease.

Emerging evidence suggests that the proper control of mitochondrial dynamics provides a window for therapeutic intervention for Alzheimer’s disease (AD) progression. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1 (PGC-1a) has been shown to regulate mitochondrial biogenesis in neurons. Thus far, the roles of PGC-1a in Alzheimer’s disease and its potential value for restoring mitochondrial dysfunction remain largely unknown. In the present study, we explored the impacts of PGC-1a on AD pathology and neurobehavioral dysfunction and its potential mechanisms with a particular focus on mitochondrial dynamics. Paralleling AD-related pathological deposits, neuronal apoptosis, abnormal mitochondrial dynamics and lowered membrane potential, a remarkable reduction in the expression of PGC-1a was shown in the cortex of APP/PS1 mice at 6 months of age. By infusing AAV-Ppargc1α into the lateral parietal association (LPtA) cortex of the APP/PS1 brain, we found that PGC-1a ameliorated AD-like behavioral abnormalities, such as deficits in spatial reference memory, working memory and sensorimotor gating. Notably, overexpressed PGC-1a in LPtA rescued mitochondrial swelling and damage in neurons, likely through correcting the altered balance in mitochondrial fission–fusion and its abnormal distribution. Our findings support the notion that abnormal mitochondrial dynamics is likely an important mechanism that leading to mitochondrial dysfunction and AD-related pathological and cognitive impairments, and they indicate the potential value of PGC-1a for restoring mitochondrial dynamics as an innovative therapeutic target for AD.

Electroacupuncture modulates gut microbiota in mice: A potential target in postoperative cognitive dysfunction.

The detailed mechanism of inflammation in postoperative cognitive dysfunction (POCD) is unclear. This study aimed to determine whether electroacupuncture (EA) ameliorates POCD by modulating gut microbial dysbiosis. Compared to the control group, mice in the EA group were treated at the acupoints Zusanli (ST36), Quchi (L111), Baihui (GV20), and Dazhui (GV14) 1 week before appendectomy. Novel object recognition and the Morris water maze tests were used to assess learning and spatial reference memory deficits, whereas hippocampus samples and stool samples were collected for central inflammatory tests and 16S-rRNA sequencing of intestinal flora, respectively. In amyloid precursor protein/presenilin 1 (APP/PS1) mice, EA enhanced spatial memory and learning deficits. The fecal microbial community was altered in APP/PS1 mice in the absence of EA following surgery. Among them, Coprococcus and Bacteroidetes were more abundant in the EA groups than in the control groups; however, Actinobacteriota, Helicobacteraceae, and Escherichia/shigella constitute the minor bacterial colonization in the EA groups. Furthermore, we found a significant negative correlation between Firmicutes and escape latency (Pearson correlation coefficient - 0.551, p < 0.01) and positive correlation between Proteobacteria and escape latency (Pearson correlation coefficient 0.462, p < 0.05). Electron microscopy revealed signs of blood-brain barrier (BBB) impairments and immunofluorescence images showed glial cells activated in the hippocampus of APP/PS mice without EA, and serum diamine oxidase levels were increased in these mice; whereas EA treatment significantly relieved the above pathological changes. Our findings implied that EA decreases hippocampal inflammation ofAPP/PS1 by upregulating benificial gut microbiota, reducing BBB and intestinal barrier dysfunction, thus alleviates postoperative cognitive dysfunction. This may provide a novel target in POCD management.

Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females

The TgF344 rat model of Alzheimer’s disease (AD) provides a comprehensive neuropathology presentation, with age-dependent development of tau tangles, amyloid-beta (A{beta}) plaques, neuronal loss, and increased gliosis. The behavioral trajectory of this model, particularly relating to spatial learning and memory, has yet to be fully characterized. The current experiment evaluated spatial working and reference memory performance, as well as several physiological markers of health, at 3 key age points in female TgF344-AD rats: 6-months, 9-months, and 12-months. At 6 months of age, indications of working and reference memory impairments were observed in transgenic (Tg) rats on the water radial-arm maze, a complex task that requires working and reference memory simultaneously; at 12 months old, Tg impairments were observed for two working memory measures on this task. Notably, no impairments were observed at the 9-month timepoint on this maze. For the Morris maze, a measure of spatial reference memory, Tg rats demonstrated significant impairment relative to wildtype (WT) controls at all 3 age-points. Frontal cortex, entorhinal cortex, and dorsal hippocampus were evaluated for A{beta}1–42 expression via western blot in Tg rats only. Analyses of A{beta}1–42 expression revealed age-dependent increases in all 3 regions critical to spatial learning and memory. Measures of physiological health, including heart, uterine, and body weights, revealed unique age-specific outcomes for female Tg rats, with the 9-month timepoint identified as critical for further research within the trajectory of AD-like behavior, physiology, and pathology.

The dorsal hippocampal CA3 regulates spatial reference memory through the CtBP2/GluR2 pathway.

The dorsal hippocampus plays a pivotal role in spatial memory. However, the role of subregion-specific molecular pathways in spatial cognition remains unclear. We observed that the transcriptional coregulator C-terminal binding protein 2 (CtBP2) presented CA3-specific enrichment in expression. RNAi interference of CtBP2 in the dorsal CA3 (dCA3) neurons, but not the ventral CA3 (vCA3), specifically impaired spatial reference memory and reduced the expression of GluR2, the calcium permeability determinant subunit of AMPA receptors. Application of an antagonist for GluR2-absent calcium permeable AMPA receptors rescued spatial memory deficits in dCA3 CtBP2 knockdown animals. Transcriptomic analysis suggest that CtBP2 may regulate GluR2 protein level through post-translational mechanisms, especially by the endocytosis pathway which regulates AMPA receptor sorting. Consistently, CtBP2 deficiency altered the mRNA expression of multiple endocytosis-regulatory genes, and CtBP2 knockdown in primary hippocampal neurons enhanced GluR2-containing AMPA receptor endocytosis. Together, our results provide evidence that the dCA3 regulates spatial reference memory by the CtBP2/GluR2 pathway through the modulation of calcium permeable AMPA receptors.

The effects of inactivated SARS-CoV-2 vaccination and subsequent infection of pregnant mice on the behaviors of offspring.

The mass inoculation of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccines to induce herd immunity is one of the most effective measures we can deploy in the fight against coronavirus disease 2019 (COVID‐19). Pregnant women are prone to a higher risk of COVID‐19, and maternal infection is a risk factor for a range of neurological disorders leading to abnormal behavior in adulthood. However, there are limited clinical data to support whether vaccination or infection post‐immunization in pregnant women can affect the behavioral cognition of fetuses in adulthood. In this study, human angiotensin‐converting enzyme 2 pregnant mice (F0 generation) were immunized with CoronaVac and then infected with SARS‐CoV‐2. Subsequently, we analyzed the behavioral cognition of their adult offspring (F1 generation) using the open‐field test and Morris water maze test. The adult F1 generation did not exhibit any impairments in spontaneous locomotor activity or spatial reference memory.

Nanoparticles and nanomaterials as inevitable modern toxic agents. Review. Part 3. Influence of nanoparticles on brain and behavior. Conclusions and unsolved problems

The final part of the review focuses on the existing methods and results of studying the effects of nanoparticles (NPs) on the brain and behavior. The types of behavioral tests used to assess changes in the behavior of NP-treated animals are described. The data accumulated in the literature on the negative influence of NPs on animal brains exposed to NPs in adulthood are considered. The signs of different cellular and tissue damage are presented, such as development of oxidative stress in the brain, inflammation and swelling, disturbances in the structure of cells, and an increase in the permeability of the bloodbrain barrier. Disturbances in spatial memory, working, and long-term reference memory, decreased propensity for social interactions, inhibition of exploratory behavior, depression and anxiety, and impaired motor coordination, were found after various types and duration of contact of animals with NPs. The accumulated information about the negative consequences of prenatal and early postnatal, during lactation, for example, contact with NPs for mature offspring, is also described. Various cellular and tissue damage is found in the brain of young animals, such as the inhibition of cell proliferation, an increase in the number of cells undergoing apoptosis, edema and vascular degeneration, a decrease in the expression of genes associated with neurogenesis, and numerous signs of the development of oxidative stress. Behavioral disturbances in adult animals that had contact with NPs in early ontogenesis are considered, such as manifestations of depressive behavior or increased anxiety and suppression of spatial and short-term memory. Contradictory results of studies about contact with NPs in both adulthood and early ontogenesis are also presented. In conclusion, unresolved issues are highlighted, and general conclusions on the review are given.

5-HT5A Receptor Antagonist ASP5736 Ameliorates Several Abnormal Behaviors in an Fmr1-Targeted Transgenic Male Rat Model of Fragile X Syndrome

BackgroundFragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS.MethodsWe evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats.Results Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03–0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment.ConclusionsASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.

Resuscitation with epinephrine worsens cerebral capillary no-reflow after experimental pediatric cardiac arrest: An in vivo multiphoton microscopy evaluation

Epinephrine is the principal resuscitation therapy for pediatric cardiac arrest (CA). Clinical data suggest that although epinephrine increases the rate of resuscitation, it fails to improve neurological outcome, possibly secondary to reductions in microvascular flow. We characterized the effect of epinephrine vs. placebo administered at resuscitation from pediatric asphyxial CA on microvascular and macrovascular cortical perfusion assessed using in vivo multiphoton microscopy and laser speckle flowmetry, respectively, and on brain tissue oxygenation (PbO2), behavioral outcomes, and neuropathology in 16–18-day-old rats. Epinephrine-treated rats had a more rapid return of spontaneous circulation and brisk immediate cortical reperfusion during 1–3 min post-CA vs. placebo. However, at the microvascular level, epinephrine-treated rats had penetrating arteriole constriction and increases in both capillary stalling (no-reflow) and cortical capillary transit time 30–60 min post-CA vs. placebo. Placebo-treated rats had increased capillary diameters post-CA. The cortex was hypoxic post-CA in both groups. Epinephrine treatment worsened reference memory performance vs. shams. Hippocampal neuron counts did not differ between groups. Resuscitation with epinephrine enhanced immediate reperfusion but produced microvascular alterations during the first hour post-resuscitation, characterized by vasoconstriction, capillary stasis, prolonged cortical transit time, and absence of compensatory cortical vasodilation. Targeted therapies mitigating the deleterious microvascular effects of epinephrine are needed.

SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice

SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function.

Deeper cerebral hypoperfusion leads to spatial cognitive impairment in mice

BackgroundVascular cognitive impairment (VCI) is the second-leading cause of dementia worldwide, which is caused by cerebrovascular diseases or relevant risk factors. However, there are no appropriate animal models, which can...

A 5-HT6R agonist alleviates cognitive dysfunction after traumatic brain injury in rats by increasing BDNF expression

Effective treatment for cognitive dysfunction after traumatic brain injury (TBI) is lacking in clinical practice. Increased brain-derived neurotrophic factor (BDNF) expression in cognitive circuits can significantly alleviate cognitive dysfunction in animal models of TBI. Selective 5-hydroxytryptamine receptor 6 (5-HT6R) agonists significantly increase BDNF expression and improve cognitive function. Therefore, we evaluated the protective effect of a highly selective 5-HT6R agonist, WAY-181187, on cognitive dysfunction after TBI. We established a controlled cortical impact model of moderate TBI in rats and performed drug intervention for five consecutive days. Rats had spatial reference memory impairment in the Morris water maze one and four weeks after TBI. BDNF expression in the medial prefrontal cortex (mPFC) and hippocampus decreased two and five weeks after TBI. Additionally, five weeks after TBI, decreases in neuronal dendritic spine density and the proportion of thin, mushroom-shaped dendritic spines and an increased proportion of stubby-type dendritic spines were observed. WAY-181187 administration (3 mg/kg) for five consecutive days after TBI significantly alleviated cognitive dysfunction at one and four weeks (P < 0.001 and P < 0.01), upregulated BDNF expression in the mPFC and hippocampus at two (P < 0.01 and P < 0.05) and five (P < 0.01 and P < 0.001) weeks and increased the dendritic spine density and the proportions of thin, mushroom-shaped dendrites in the mPFC (P < 0.05, P < 0.001 and P < 0.01) and hippocampus (P < 0.05, P < 0.001 and P < 0.05) at five weeks after TBI. Our results confirm that WAY-181187 administration (3 mg/kg) in the acute phase alleviated cognitive dysfunction after TBI, possibly by upregulating BDNF expression in the mPFC and hippocampus, enhancing neuroplasticity.

Memory-enhancing, Antioxidant, and Anticholinesterase Effects of Inhaled Achillea pseudoaleppica Essential Oil on Scopolamine-induced Amnesic Rats

Achillea species are used for therapeutic purposes in many countries. This study demonstrated the memory-enhancing, antioxidant, and anticholinesterase effects of Achillea pseudoaleppica essential oil in scopolamine-induced amnesia. The GC/FID-GC/MS system revealed camphor as the major compound in the oil. The application of the essential oil (1% and 3%) was performed on the rats by inhalation for 21 consecutive days before the performance of the behavioral tests (Y-maze and radial-arm maze tests). The essential oil application increased the spontaneous alternation behavior in scopolamine-induced rats in the Y-maze task. Furthermore, essential oil administration decreased working memory errors and reference memory errors in scopolamine-treated rats in the radial-arm maze test. Therefore, Achillea pseudoaleppica essential oil inhalation improved memory in scopolamine-treated rats. In addition, acetylcholinesterase and antioxidant profiles of the hippocampal tissues of the rats were examined. Essential oil administration decreased acetylcholinesterase and superoxide dismutase specific activities and malondialdehyde levels while increasing the total content of reduced glutathione in the rat hippocampus in scopolamine-treated rats. Therefore, in this study, the combination of scopolamine and Achillea pseudoaleppica essential oil improved memory formation and increased the activities of antioxidants and anticholinesterase.

A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions.

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson’s and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.