Object Recognition Memory Test Research Articles

Brain areas interconnected to ventral pathway circuits are independently able to induce enhancement in object recognition memory and cause reversal in object recognition memory deficit.

Ventral pathway circuits are constituted by the interconnected brain areas that are distributed throughout the brain. These brain circuits are primarily involved in processing of object related information in brain. However, their role in object recognition memory (ORM) enhancement remains unknown. Here, we have studied on the implication of these circuits in ORM enhancement and in reversal of ORM deficit in aging. The brain areas interconnected to ventral pathway circuits in rat brain were activated by an expression of a protein called regulator of G-protein signaling 14 of 414 amino acids (RGS14414). RGS14414 is an ORM enhancer and therefore used here as a gain-in-function tool. ORM test and immunohistochemistry, lesions, neuronal arborization, and knockdown studies were performed to uncover the novel function of ventral pathway circuits. An activation of each of the brain areas interconnected to ventral pathway circuits individually induced enhancement in ORM; however, same treatment in brain areas not interconnected to ventral pathway circuits produced no effect. Further study in perirhinal cortex (PRh), area V2 of visual cortex and frontal cortex (FrC), which are brain areas that have been shown to be involved in ORM and are interconnected to ventral pathway circuits, revealed that ORM enhancement seen after the activation of any one of the three brain areas was unaffected by the lesions in other two brain areas either individually in each area or even concurrently in both areas. This ORM enhancement in all three brain areas was associated to increase in structural plasticity of pyramidal neurons where more than 2-fold higher dendritic spines were observed. Additionally, we found that an activation of either PRh, area V2, or FrC not only was adequate but also was sufficient for the reversal of ORM deficit in aging rats, and the blockade of RGS14414 activity led to loss in increase in dendritic spine density and failure in reversal of ORM deficit. These results suggest that brain areas interconnected to ventral pathway circuits facilitate ORM enhancement by an increase in synaptic connectivity between the local brain area circuits and the passing by ventral pathway circuits and an upregulation in activity of ventral pathway circuits. In addition, the finding of the reversal of ORM deficit through activation of an interconnected brain area might serve as a platform for developing not only therapy against memory deficits but also strategies for other brain diseases in which neuronal circuits are compromised.

Treadmill Exercise Reverses the Adverse Effects of Intermittent Fasting on Behavior and Cortical Spreading Depression in Young Rats.

Intermittent fasting (IF) and physical exercise (PE) have beneficial psychological and physiological effects, improving memory and anxiety-like behavior. However, the impact of this combination on brain electrophysiological patterns is unknown. We aimed to evaluate the behavior and parameters of a brain excitability-related phenomenon named cortical spreading depression (CSD) in young rats (31-87 days of life) submitted to IF and treadmill PE for eight weeks. Sixty-four male and female Wistar rats aged 24 days were randomized into control, IF, PE, and IF+PE groups. Behavioral tests (open field (OF), object recognition, and elevated plus maze (EPM)) were performed, and the CSD propagation features were recorded. IF caused behavioral responses indicative of anxiety (lower number of entries and time spent in the OF center and EPM open arms). IF also reduced the discrimination index for object recognition memory tests and increased the propagation velocity of CSD. PE rats displayed more entries into the OF center and lowered CSD propagation speed. Data suggest that IF worsens anxiety-like behavior and memory and accelerates CSD in young rats. In contrast, PE reverted the unfavorable effects of IF. The brain effects of IF and PE at younger ages are recommended for study.

Group I mGluRs positive allosteric modulators improved schizophrenia-related behavioral and molecular deficits in the Poly I:C rat model

RationaleMaternal polyinosinic-polycytidylic acid (Poly I:C) exposure leads to an increase in various proinflammatory cytokines and causes schizophrenia-like symptoms in offspring. In recent years, group I metabotropic glutamate receptors (mGluRs) have emerged as a potential target in the pathophysiology of schizophrenia. ObjectivesThe aim of our study was to investigate the behavioral and molecular changes by using the mGlu1 receptor positive allosteric modulator (PAM) agent RO 67-7476, and the negative allosteric modulator (NAM) agent JNJ 16259685 and the mGlu5 receptor PAM agent VU-29, and NAM agent fenobam in the Poly I:C-induced schizophrenia model in rats. MethodsFemale Wistar albino rats were treated with Poly I:C on day 14 of gestation after mating. On the postnatal day (PND) 34-35, 56-57 and 83-84, behavioral tests were performed in the male offspring. On the PND84, brain tissue was collected and the level of proinflammatory cytokines was determined by ELISA method. ResultsPoly I:C caused impairments in all behavioral tests and increased the levels of proinflammatory cytokines. While PAM agents caused significant improvements in prepulse inhibition (PPI), novel object recognition (NOR), spontaneous alternation and reference memory tests, they brought the levels of proinflammatory cytokines closer to the control group. NAM agents were ineffective on behavioral tests. It was observed that PAM agents significantly improved Poly I:C-induced disruption in behavioral and molecular analyses. ConclusionsThese results suggest that PAM agents, particularly the mGlu5 receptor VU-29, are also promising and could be a potential target in schizophrenia.

Progressive Ataxia, Memory Impairments, and Seizure Episodes in Spna2 R1098Q Mouse Variant Affecting Alpha II Spectrin’s Scaffold Stability

SPTAN1 spectrinopathies refer to a group of rare, inherited diseases associated with damage to non-erythrocytic α-II spectrin (α-II). They are linked to a range of mild to severe neuropathologies of the central and peripheral nervous systems, such as early infantile epileptic encephalopathy type 5, cerebellar ataxia, inherited peripheral neuropathy, and spastic paraplegia. Modeling human SPTAN1 encephalopathies in laboratory animals has been challenging partially because no haploinsufficiency-related phenotypes unfold in heterozygous Spna2 deficient mice nor stable transgenic lines of mice mimicking missense human SPTAN1 mutations have been created to date. Here, we assess the motor and memory performance of a dominant-negative murine Spna2 (SPTAN1) variant carrying a spontaneous point mutation replacing an arginine 1098 in the repeat 10th of α-II with the glutamine (R1098Q). By comparing groups of heterozygous R1098Q mice at different ages, we find evidence for progressive ataxia, and age-related deterioration of motor performance and muscle strength. We also document stress-induced, long-lasting seizure episodes of R1098Q mice and their poor performance in novel object recognition memory tests. Overall, we propose that the complexity of neuropathology-related phenotypes presented by the R1098Q mice recapitulates a number of symptoms observed in human patients carrying SPTAN1 mutations affecting α-II scaffold stability. This makes the R1098Q mice a valuable animal model for preclinical research.

Neurobehavioral deficits and a progressive ictogenesis in the tetrodotoxin model of epileptic spasms.

Our goal was to determine whether animals with a history of epileptic spasms have learning and memory deficits. We also used continuous (24/7) long-term electroencephalographic (EEG) recordings to evaluate the evolution of epileptiform activity in the same animals over time. Object recognition memory and object location memory tests were undertaken, as well as a matching to place water maze test that evaluated working memory. A retrospective analysis was undertaken of long-term video/EEG recordings from rats with epileptic spasms. The frequency and duration of the ictal events of spasms were quantified. Rats with a history of epileptic spasms showed impairment on the three behavioral tests, and their scores on the object recognition memory and matching to place water maze tests indicated neocortical involvement in the observed impaired cognition. Analysis of EEG recordings unexpectedly showed that the ictal events of spasms and their accompanying behaviors progressively increased in duration over a 2-week period soon after onset, after which spasm duration plateaued. At the same time, spasm frequency remained unchanged. Soon after spasm onset, ictal events were variable in wave form but became more stereotyped as the syndrome evolved. Our EEG findings are the first to demonstrate progressive ictogenesis for epileptic spasms. Furthermore, in demonstrating cognitive deficits in the tetrodotoxin model, we have met a criterion for an animal model of West syndrome. Animal models will allow in-depth studies of spasm progression's potential role in cognitive regression and may elucidate why early treatment is considered essential for improved neurodevelopmental outcomes in children.

Early-life stress elicits peripheral and brain immune activation differently in wild type and 5xFAD mice in a sex-specific manner

BackgroundThe risk of developing Alzheimer’s disease (AD) is modulated by genetic and environmental factors. Early-life stress (ELS) exposure during critical periods of brain development can impact later brain function and health, including increasing the risk of developing AD. Microglial dysfunction and neuroinflammation have been implicated as playing a role in AD pathology and may be modulated by ELS. To complicate matters further, sex-specific effects have been noted in response to ELS and in the incidence and progression of AD.MethodsHere, we subjected male and female mice with either a wild type or 5xFAD familial AD-model background to maternal separation (MS) from postnatal day 2 to 14 to induce ELS.ResultsWe detected hippocampal neuroinflammatory alterations already at postnatal day 15. By 4 months of age, MS mice presented increased immobility time in the forced swim test and a lower discrimination index in the novel object recognition memory test compared to controls. We found altered Bdnf and Arc expression in the hippocampus and increased microglial activation in the prefrontal cortex due to MS in a sex-dependent manner. In 5xFAD mice specifically, MS exacerbated amyloid-beta deposition, particularly in females. In the periphery, the immune cell population was altered by MS exposure.ConclusionOverall, our results demonstrate that MS has both short- and long-term effects on brain regions related to memory and on the inflammatory system, both in the brain and periphery. These ELS-related effects that are detectable even in adulthood may exacerbate pathology and increase the risk of developing AD via sex-specific mechanisms.

Auricular Transcutaneous Vagus Nerve Stimulation Acutely Modulates Brain Connectivity in Mice.

Brain electrical stimulation techniques take advantage of the intrinsic plasticity of the nervous system, opening a wide range of therapeutic applications. Vagus nerve stimulation (VNS) is an approved adjuvant for drug-resistant epilepsy and depression. Its non-invasive form, auricular transcutaneous VNS (atVNS), is under investigation for applications, including cognitive improvement. We aimed to study the effects of atVNS on brain connectivity, under conditions that improved memory persistence in CD-1 male mice. Acute atVNS in the cymba conchae of the left ear was performed using a standard stimulation protocol under light isoflurane anesthesia, immediately or 3 h after the training/familiarization phase of the novel object-recognition memory test (NORT). Another cohort of mice was used for bilateral c-Fos analysis after atVNS administration. Spearman correlation of c-Fos density between each pair of the thirty brain regions analyzed allowed obtaining the network of significant functional connections in stimulated and non-stimulated control brains. NORT performance was enhanced when atVNS was delivered just after, but not 3 h after, the familiarization phase of the task. No alterations in c-Fos density were associated with electrostimulation, but a significant effect of atVNS was observed on c-Fos-based functional connectivity. atVNS induced a clear reorganization of the network, increasing the inter-hemisphere connections and the connectivity of locus coeruleus. Our results provide new insights into the effects of atVNS on memory performance and brain connectivity extending our knowledge of the biological mechanisms of bioelectronics in medicine.

Implication of thyroid hormone receptors in methamphetamine neurocognitive effects

Methamphetamine (MA) induces neurocognitive effects via several mechanisms. In the present study, we investigated the alteration of thyroid hormone receptor’s expression in the context of MA-induced memory impairment and explored the protective effects of exogenous thyroid hormones (THs). Male wistar rats, received increasing regimen of MA (1–10 mg/kg, intraperitoneal, twice a day for 10 days), were treated with T3 (40 μg/rat/day; intranasal, 2.5 μl/nostril) or T4 (20 µg/kg/day; intraperitoneal) for 7 days after MA cessation. All rats were subjected to novel object recognition memory test and then the mRNA levels of TH nuclear receptors (TRα1 and TRβ1) and seladin-1, an anti-apoptotic factor, and the protein level of TH cell surface receptor (integrin αvβ3) were measured in the hippocampus of rats. Our results showed that MA-induced memory impairment is concomitant with decreased level of TRα1 mRNA. T3 or T4 treatment significantly alleviated MA-induced memory impairment, but had no significant effect on the mRNA levels of TH nuclear receptors. However, T4 treatment significantly increased the protein level of cell surface receptor (αv subunit) in MA-treated rats. These findings suggest that MA neurocognitive effects can be associated with impaired TH signaling in the brain and introduce this pathway as a promising therapeutic approach against MA-induced memory impairment.

Diet-induced Alzheimer's-like syndrome in the rabbit.

IntroductionAlthough mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late‐onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild‐type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3‐like isoform of apolipoprotein. We report a combined behavioral, imaging, and metabolic study using rabbit as a non‐transgenic model to examine effects of AD‐related risk factors on cognition, intrinsic functional connectivity, and magnetic resonance‐based biomarkers of neuropathology.MethodsAging rabbits were fed a diet enriched with either 2% cholesterol or 10% fat/30% fructose. Monthly tests of novel object recognition (NOR) and object location memory (OLM) were administered to track cognitive impairment. Trace eyeblink conditioning (EBC) was administered as a final test of cognitive impairment. Magnetic resonance imaging (MRI) was used to obtain resting state connectivity and quantitative parametric data (R2*).ResultsExperimental diets induced hypercholesterolemia or elevated BGL. Both experimental diets induced statistically significant impairment of OLM (but not NOR) and altered intrinsic functional connectivity. EBC was more impaired by fat/fructose diet than by cholesterol. Whole brain and regional R2* MRI values were elevated in both experimental diet groups relative to rabbits on the control diet.DiscussionWe propose that mechanisms underlying LOAD can be assessed by stressing risk factors for inducing AD and that dietary manipulations can be used to assess etiological differences in the pathologies and effectiveness of potential therapeutics against LOAD. In addition, non‐invasive MRI in awake, non‐anesthetized rabbits further increases the translational value of this non‐transgenic model to study AD.

Prenatal Poly I:C Challenge Affects Behaviors and Neurotransmission via Elevated Neuroinflammation Responses in Female Juvenile Rats.

BackgroundExposure to polyriboinosinic-polyribocytidylic acid (Poly I:C) in pregnant rats has been reported to cause schizophrenia-like behaviors and abnormal neurotransmissions in adult, particularly male, offspring. However, what is less well understood are the effects of maternal Poly I:C exposure on adolescent behaviors and neurotransmission in female juvenile rats.MethodsFemale adolescent Poly I:C offspring were constructed by treating with 5 mg/kg Poly I:C on timed pregnant rats (gestation day 15). A battery of behavioral tests was conducted during postnatal day 35–60. Neurotransmitter receptors and inflammation markers in brain regions were evaluated by RT-qPCR on postnatal day 60.ResultsOpen field, elevated plus maze, and forced swimming tests revealed that prenatal Poly I:C exposure led to elevated anxiety-like and depression-like behaviors in female adolescent offspring. Deficits in pre-pulse inhibition and social interaction were also observed. However, the Poly I:C rats had better performance than the controls in the novel object recognition memory test, which demonstrated a behavioral phenotype with improved cognitive function. Prenatal Poly I:C exposure caused brain region–specific elevation of the P2X7 receptor- and NF-κB-NLRP3-IL-1β inflammatory signaling in female juvenile rats. Prenatal Poly I:C exposure decreased expression of GABAA receptor subunits Gabrb3 in the prefrontal cortex and Gabrb1 and dopamine D2 receptor in the hippocampus, but increased NMDA receptor subunit Grin2a in the prefrontal cortex, 5-HT2A in the hippocampus, and Gabrb3 and D2 receptor in the nucleus accumben.ConclusionsPrenatal Poly I:C challenge causes behavioral deficits and brain-specific neurotransmission changes via elevated neuroinflammation responses in female adolescent offspring rats.

Skeletal muscle atrophy-induced hemopexin accelerates onset of cognitive impairment in Alzheimer's disease.

BackgroundAlzheimer's disease (AD) is an unmet medical need worldwide, and physical inactivity is a risk factor for AD. Performing physical exercise is difficult at old age, and thus, decline in physical movement may be a cause of age‐associated lowering of the brain function. This study aimed to elucidate the molecular mechanism and onset of the skeletal muscle atrophy‐induced acceleration of AD.MethodsPre‐symptomatic young 5XFAD or non‐transgenic wildtype mice were used. The bilateral hindlimbs were immobilized by placing them in casts for 14 days. Cognitive function was evaluated using the object recognition and spatial memory tests. Further, the hindlimb muscles were isolated for organ culture. Conditioned media (CM) of each muscle was separated by two‐dimensional polyacrylamide gel electrophoresis (2D‐PAGE). Protein expressions in the CM were analysed by matrix‐assisted laser desorption/ionization‐time‐of‐flight mass spectrometry analysis. The expression levels of candidate proteins were quantified using ELISA. After continuous intracerebroventricular (i.c.v.) infusion of recombinant hemopexin, cognitive function was evaluated. Gene microarray analysis of the hippocampus was performed to investigate the molecules involved in the accelerated memory deficit. Real‐time reverse transcription polymerase chain reaction and histological analysis confirmed the expression.ResultsCasting for 2 weeks reduced skeletal muscle weight. Object recognition memory in the cast‐attached 5XFAD mice (n = 7, training vs. test, P = 0.3390) was impaired than that in age‐matched wildtype (n = 7, training vs. test, P = 0.0523) and non‐cast 5XFAD mice (n = 7, training vs. test, P = 0.0473). On 2D‐PAGE, 88 spots were differentially expressed in muscle CM. The most increased spot in the cast‐attached 5XFAD CM was hemopexin. Hemopexin levels in the skeletal muscle (n = 3, P = 0.0064), plasma (n = 3, P = 0.0386), and hippocampus (n = 3, P = 0.0164) were increased in cast‐attached 5XFAD mice than those in non‐cast 5XFAD mice. Continuous i.c.v. infusion of hemopexin for 2 weeks induced memory deficits in young 5XFAD mice (n = 4, training vs. test, P = 0.6764). Lipocalin‐2 (Lcn2) messenger RNA (mRNA), neuroinflammation‐associated factor, was increased in the hippocampus in hemopexin‐infused 5XFAD mice than in control mice. LCN2 protein in the hippocampus was localized in the neurons, but not glial cells. Lcn2 mRNA levels in the hippocampus were also increased by cast‐immobilization of the hindlimbs (n = 6, P = 0.0043).ConclusionsThese findings provide new evidence indicating that skeletal muscle atrophy has an unbeneficial impact on the occurrence of memory impairment in young 5XFAD mice, which is mediated by the muscle secreted hemopexin.

Neuroprotective effects of Lepidium sativum L. on memory impairments in Wistar rat: Behavioral and neurochemical study

The present study investigated the effect of Lepidium sativum L. on Memory and on Acetylcholinesterase (AChE) activity in different brain structures among cadmium-exposed rats. Animals were divided into three groups: Control group (T): received a distilled water orally, Cadmium group (Cd): received oral administration dose of Cadmium Chloride (CdCl2) at 10 mg/kg, Protective group (Cd/LS): received CdCl2 (10mg/kg) and the aqueous extract of Lepidium sativum L. (20mg/kg) orally. The Novel Object Recognition Memory Test is used to evaluate the short and long term memory. The measure of AchE activity is realized by Ellman’s method. The results showed that subchronic Cadmium Chloride intoxication at a dose of 10 mg/kg caused a neurobehavioral impairments including: A significant decrease in the index of recognition of short-term (p<0.01) and long-term memory (p <0.05) compared to the control group. In addition, this index increase in the group (Cd/LS) compared to the group intoxicated by CdCl2. A highly significant increase in the enzymatic activity of acetylcholinesterase in hippocampus, cerebellum, and cortex (p<0.001) is registered. These results indicate that the aqueous extract of Lepidium sativum L. may modulate the toxic effect induced by cadmium and consequently improve cognition.

Nuclear Factor [Erythroid-derived 2]-like 2 and Mitochondrial Transcription Factor A Contribute to Moderate-intensity Swimming Effectiveness against Memory Impairment in Young Mice Induced by Concomitant Exposure to a High-calorie Diet during the Early Life Period

Increased energy food consumption during early-life has been associated with memory impairment. Swimming training has been reported to improve memory processes in rodent models. This study aimed to evaluate whether moderate-intensity swimming training counteracts learning and memory impairment in young mice fed a high-calorie diet during the early-life period. The contribution of hippocampal oxidative stress, as well as nuclear factor [erythroid-derived 2]-like 2/Kelch-like ECH-associated protein (NRF2/Keap-1/HO-1) and peroxisome proliferator-activated receptor gamma co-activator 1-alpha/mitochondrial transcription factor A (PCG-1α/mtTFA) signaling, in memory effects was also investigated. Three-week-old male Swiss mice received a high-calorie diet (20% fat; 20% carbohydrate enriched) or a standard diet from 21 to 49 postnatal days. Mice performed a moderate-intensity swimming protocol (5 days/week) and behavioral tests predictive of memory function. Mice fed a high-calorie diet and subjected to the swimming protocol performed better on short- and long-term spatial and object recognition memory tests than those fed a high-calorie diet. The swimming protocol modulated the hippocampal NRF2/Keap-1/HO-1 and mtTFA pathways in mice fed a high-calorie diet. Swimming training positively affected location and long-term memory, fat mass content, as well as NRF2/Keap-1/HO-1 and mtTFA proteins of control‐diet‐fed mice. In conclusion, a moderate-intensity swimming training evoked an adaptive response in mice fed a high-calorie diet by restoring different types of memory-impaired and hippocampal oxidative stress as well as upregulated the NRF2/Keap-1/HO-1 and mtTFA pathways.

Interplay of Prenatal and Postnatal Risk Factors in the Behavioral and Histological Features of a "Two-Hit" Non-Genetic Mouse Model of Schizophrenia.

Schizophrenia is a multifactorial developmental neuropsychiatric disorder. This study examined the interplay of maternal infection and postweaning social isolation, which are prenatal and postnatal risk factors, respectively. Pregnant mice received poly I:C or saline injection on gestation day 9 and the pups were weaned at postnatal day 28. After weaning, male offspring were randomly assigned into group-rearing and isolation-rearing groups. In their adulthood, we performed behavioral tests and characterized the histochemical features of their mesocorticolimbic structures. The sociability and anxiety levels were not affected by either manipulation, but synergistic effects of the two hits on stress-coping behavior was observed. Either of the single manipulations caused defects in sensorimotor gating, novel object recognition and spatial memory tests, but the combination of the two hits did not further exacerbate the disabilities. Prenatal infection increased the number of dopaminergic neurons in midbrain, whereas postweaning isolation decreased the GABAergic neurons in cortex. Single manipulation reduced the dendritic complexity and spine densities of neurons in the medial prefrontal cortex (mPFC) and dentate gyrus. Our results support the current perspective that disturbances in brain development during the prenatal or postnatal period influence the structure and function of the brain and together augment the susceptibility to mental disorders, such as schizophrenia.

Implications of night-party environment on emotional, physiological, and anatomical features in mammals: A simulation based study on Swiss mice

Audiovisual superstimuli at night parties have been concerning parents and public health authorities, mainly when it comes to the risk of drug abuse and violence. However, the effects of such stimuli on the mental health of night-party goers are little known. Thus, the aim of the present study was to evaluate whether Swiss mice exposure to night-party environment simulations induces locomotor damages and predictive behavioral changes such as anxiety and memory deficit. Animals were exposed to audiovisual stimuli simulating a night-party environment for five consecutive days (6 h/day). Based on the collected data, the locomotor activity and the emotional state of animals subjected to audiovisual superstimuli [group sound (S) + light (L)] did not differ from the records of animals exposed to sound (group S) or visual (group V) stimulus in separate, or even from those of animals in the control group (C). Serum cortisol levels and results of histological analyses applied to the suprarenal glands suggested that the animals did not suffer stress due to the exposure procedure. However, mice in the S + L group recorded lower recognition index than the ones in the control group in the object recognition memory test, as well as lower latency to descend the platform in the inhibitory avoidance test. Therefore, the audiovisual superstimuli affected the short-term memory, which is related to object recognition and to aversive memory recall. To the best of our knowledge, the present study is novel in developing an apparatus and an exposure protocol to simulate a night-party environment to be used in further laboratory trials. In addition, results have shown that cognitive processes linked to short-term and aversive memory can be affected by audiovisual superstimuli; therefore, the current research warns about mental damages likely caused by night-party environments.

Enriched Environment Ameliorates Cognitive Deficits and Locomotor Sensitization in Morphine-Withdrawn Rats Receiving Methadone Maintenance Treatment

Objective: This study was designed to examine whether enriched environments (EE) would attenuate object recognition and spatial learning and memory deficits and locomotor sensitization induced by methadone maintenance treatment (MMT) in morphine-withdrawn rats. Methods: Male Wistar rats (170 ± 10 g) were injected with bi-daily doses (10 mg/kg, 12-h intervals) of morphine for 14 days. Rats receiving MMT were reared in the standard environment (SE) or EE during 30 days of morphine withdrawal. Then, the rats were tested for object recognition (the object recognition memory test, ORMT) and spatial learning and memory (the water maze) and then challenged with morphine (1 mg/kg, i.p.) and evaluated for locomotor activity (open-field box). Results: The results revealed that the dependent/saline/EE (D/Sal/EE) and D/methadone/EE (D/Meth/EE) rats exhibited significant preference for the new object (p = 0.006 and p = 0.049), spent more time in the target zone (p = 0.045 and p = 0.005) on the water maze, and displayed a lower level of distance traveled (p = 0.002 and p = 0.0001) compared to their control groups reared in SE. Conclusions: We conclude that exposure to EE could ameliorate the object recognition and spatial memory deficits and also decrease locomotor sensitivity in morphine-withdrawn rats receiving MMT. Thus, EE may be beneficial in the treatment of addiction during MMT.

Aβ oligomer induced cognitive impairment and evaluation of ACU193-MNS-based MRI in rabbit.

IntroductionAmyloid‐beta oligomers (AβOs) accumulate in Alzheimer's disease and may instigate neuronal pathology and cognitive impairment. We examined the ability of a new probe for molecular magnetic resonance imaging (MRI) to detect AβOs in vivo, and we tested the behavioral impact of AβOs injected in rabbits, a species with an amino acid sequence that is nearly identical to the human sequence.MethodsIntracerebroventricular (ICV) injection with stabilized AβOs was performed. Rabbits were probed for AβO accumulation using ACUMNS (an AβO‐selective antibody [ACU193] coupled to magnetic nanostructures). Immunohistochemistry was used to verify AβO presence. Cognitive impairment was evaluated using object location and object recognition memory tests and trace eyeblink conditioning.ResultsAβOs in the entorhinal cortex of ICV‐injected animals were detected by MRI and confirmed by immunohistochemistry. Injections of AβOs also impaired hippocampal‐dependent, but not hippocampal‐independent, tasks and the area fraction of bound ACUMNs correlated with the behavioral impairment.DiscussionAccumulation of AβOs can be visualized in vivo by MRI of ACUMNS and the cognitive impairment induced by the AβOs can be followed longitudinally with the novel location memory test.

Maternal Deprivation Induces Memory Deficits That Are Reduced by One Aerobic Exercise Shot Performed after the Learning Session.

During the neonatal period, the brain is susceptible to external influences. Exposure to stressful events during this phase of life influences brain development and impacts adult life. In animals, the maternal deprivation (MD) model is effective in mimicking stress in the early stages of development. In contrast, physical exercise seems to be able to prevent deficits in memory consolidation. Although the effects of chronic exercise in cognition are already well established, little is known about the effects of acute aerobic exercise. Here, male Wistar rats divided into deprived (MD) and nondeprived (NMD) rats were submitted to the object recognition (OR) memory test. Immediately after OR training, some of the rats were submitted to a single aerobic exercise session for 30 minutes. Memory consolidation and persistence were evaluated by retention tests performed 24 h and 7, 14, and 21 days after OR training. We show that a single physical exercise session is able to modulate learning by promoting memory consolidation and persistence in rats with cognitive deficits induced by MD. Hippocampal dopamine levels, measured by HPLC, were not altered after OR training in rats that performed and in rats that did not perform an exercise session; on the other hand, while OR training promoted increase of hippocampal norepinephrine in NMD rats, the MD rats did not present this increase, regardless of the practice or not of exercise.

Neurobehavioral effects of selected tobacco constituents in rodents following subchronic administration

Bidirectional correlations between cigarette smoking and affective disorders, such as depression, anxiety, and schizophrenia, are well documented. These findings have led to substantial investigations into the effects of the major tobacco alkaloid, nicotine, and to a lesser extent, of other tobacco constituents, on the central nervous system (CNS). However, systematic profiling of the neuropharmacological effects of tobacco constituents is limited. To elucidate the effects of selected tobacco constituents on the CNS, we used the SmartCube® system, which captures and classifies behavioral features of compound-treated mice, to profile the psychiatric drugs-like properties of previously reported neuroactive tobacco compounds in mice. Daily intraperitoneal injection of nicotine (0.5 and 1 mg/kg/day) and anatabine (5 mg/kg/day) for 7 days produced antidepressant-like behavioral SmartCube® signatures in mice, and these results were supported by the improved active coping responses in the forced swim tests. Conversely, ferulic acid did not show any identifiable class signatures in the SmartCube® tests, but rather displayed subclass signatures associated with acetylcholinesterase inhibitors. In novel object recognition memory test in rats, ferulic acid improved memory after 7 days of subcutaneous injection at 0.3 or 3 mg/kg/day. These results support previous findings showing the antidepressant drug-like effects of nicotine and the nootropic effects of ferulic acid. This is also the first report on the antidepressant drug-like effects of anatabine in rodents. This study provides a systemic behavioral evaluation of tobacco alkaloids and further insights into the association between affective disorders and smoking incidence.

Intergenerational Inheritance of the Effects of Exercise on Novel Object Recognition Memory and Pattern Separation Performance in Mice

It is known that intergenerational inheritance can be induced by environmental changes in parents. These studies usually focus on negative stressors that affect the offspring adversely. There is increasing evidence that exercise improves learning and memory in humans and mice. These beneficial effects could be mediated by enhanced hippocampal neurogenesis. Whether these effects could be inherited by future generations remains to be seen. This study analysed if paternal exercise training could facilitate hippocampal‐dependent novel object recognition memory and pattern separation performance in offspring. Firstly, male progenitors were subjected to a forced moderate exercise protocol for eight weeks before mating. All male experimental animals underwent the following behavioural protocols: an activity cage and two different protocols of a novel object recognition memory test and a pattern separation test, both protocols differing in the level of difficulty. Regarding basal motor activity, no differences were found between experimental groups in a known environment. As for the novel object recognition and pattern separation tests, only male progenitors that had undergone the exercise protocol were able to discriminate the novel object and the change of pattern in the difficult protocols. No significant differences were found in postnatal behaviour. However, the behavioural outcomes in adulthood showed that only the offspring of male progenitors that had undergone physical exercise displayed facilitation in novel object recognition memory and pattern separation performance. In order to assess adult hippocampal neurogenesis, immunohistochemistry against different neurogenesis markers was performed. Furthermore, whole‐genome sequence analyses showed differential gene expression among experimental groups. These results suggest that beneficial effects of exercise training on learning and memory can be inherited.Support or Funding InformationWork was supported by project grants from Spanish Ministry of Economy and Competitiveness BFU2013‐48907‐R and BFU2016‐77162‐R (to J.L.T.). A.F. was funded by a JaE‐DOC CSIC grant, I.L.T. was funded by an FPI grant, and K.R.McG. was funded by a contract associated with the project grants above mentioned (to J.L.T.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.