Up-And-Down γ-Synuclein Transcription in Dopamine Neurons Translates Into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice

The synuclein family consists of α-, β-, and γ-Synuclein (α-Syn, β-Syn, and γ-Syn), expressed in the neurons and concentrated in synaptic terminals. While α-Syn is at the center of interest due to its implication in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, limited information exists on the other members. The current study aimed at investigating the biological role of γ-Syn controlling the midbrain dopamine (DA) function. We generated two different mouse models with i) γ-Syn overexpression induced by an adeno-associated viral vector and ii) γ-Syn knockdown induced by a ligand-conjugated antisense oligonucleotide, to modify the endogenous γ-Syn transcription levels in midbrain DA neurons. The progressive overexpression of γ-Syn decreased DA neurotransmission in the nigrostriatal and mesocortical pathways. In parallel, mice evoked motor deficits in the rotarod and impaired cognitive performance as assessed by novel object recognition, passive avoidance, and Morris water maze tests. Conversely, acute γ-Syn knockdown selectively in DA neurons facilitated forebrain DA neurotransmission. Importantly, modifications in γ-Syn expression did not induce the loss of DA neurons or changes in α-Syn expression. Collectively, our data strongly suggest that DA re-lease/re-uptake processes in the nigrostriatal and mesocortical pathways are partially dependent on SNc/VTA γ-Syn transcription levels, and are linked to modulation of DA transporter function, similar to α-Syn.

The role of neutrophil gelatinase-associated lipocalin and iron homeostasis in object recognition impairment in aged sepsis-survivor rats

Older adult patients with sepsis frequently experience cognitive impairment. The roles of brain neutrophil gelatinase-associated lipocalin (NGAL) and iron in older sepsis patients remain unknown. We investigated the effects of lipopolysaccharide-induced sepsis on novel object recognition test, NGAL levels, an inflammatory mediator tumor necrosis factor-α (TNFα) levels, and iron ion levels in the hippocampus and cortex of young and aged rats. The effect of an iron chelator deferoxamine pretreatment on aged sepsis rats was also examined. Young sepsis-survivor rats did not show impaired novel object recognition, TNFα responses, or a Fe2+/Fe3+ imbalance. They showed hippocampal and cortical NGAL level elevations. Aged sepsis-survivor rats displayed a decreased object discrimination index, elevation of NGAL levels and Fe2+/Fe3+ ratio, and no TNFα responses. Pretreatment with deferoxamine prevented the reduction in the object recognition of aged sepsis-survivor rats. The elevation in hippocampal and cortical NGAL levels caused by lipopolysaccharide was not influenced by deferoxamine pretreatment. The lipopolysaccharide-induced Fe2+/Fe3+ ratio elevation was blocked by deferoxamine pretreatment. In conclusion, our findings suggest that iron homeostasis in the cortex and hippocampus contributes to the maintenance of object recognition ability in older sepsis survivors.

Effects of oral ingestion of hyoscyamine from Daturastramonium seeds on the hippocampus in adult Wistar rats (Rattusnorvegicus)

The study aimed to evaluate the effects of oral ingestion of hyoscyamine fraction of Daturastramonium seeds on the hippocampus in adult Wistar rats. Fresh seeds of D. stramonium were procured and fractionated using high-performance liquid chromatography (HPLC). Twenty-four healthy adult Wistar rats weighed 230±0.50 grams, were procured and divided equally into four groups for the experiment. The group one received an equivalent bodyweight of normal saline, while three other groups received 200, 400 and 800 mg/kgbwt of hyoscyamine fraction of D. stramonium respectively for three weeks. At the end of the experiment, the animals were subjected to memory test using Morris water maze (MWM) and Novel object recognition test (NORT) test paradigms. The data obtained were expressed as mean ± SEM and repeated measures ANOVA with Fisher’s multiple comparisons post-hoc tests were used to obtain mean differences using Minitab 17 (LLC., U.K.) statistical package software. P < 0.05 was considered statistically significant. There was a statistically significant increase in the exploration time (p = 0.031) and escape latency period (p < 0.001) in the novel object recognition and Morris water maze test between the groups in the treated compared to the control group. The CA3 region of the treated group showed significant neuronal lesions, cytoplasmic vacuolations, pyknosis and necrosis. . In conclusion, exposure to hyoscyamine fraction of D.stramonium at adulthood impaired memory in Wistar rats.

Neuroprotective effects of thymoquinone against MDMA-induced neurotoxicity

MDMA (3, 4-methylenedioxymethamphetamine) is a psychoactive substance that is associated with neurotoxicity. MDMA exposure to human results in the degeneration of neuronal cells in the hippocampus. Hence, the purpose of this study was to examine the potential of a natural compound known as thymoquinone (TQ) to protect against neuronal damage and memory impairment in rats stimulated by MDMA. The administration of TQ into MDMA-induced neuronal damage rats was carried out in male Sprague Dawley via a 1-week treatment dividing into four groups (n=36, 7-9 per group). The studied groups involved with the treatments comprise i) Control (1 mL/kg saline), ii) MDMA (10 mg/kg MDMA), iii) MDMA+TQ (10 mg/kg MDMA + 40 mg/kg TQ) and iv) TQ control (40 mg/kg TQ). A novel object recognition test (NORT) was carried out to evaluate the memory performance of the rats, followed by a histopathological assessment of the hippocampal dentate gyrus. The histopathology analysis revealed a significant increase in numbers of positive cells by Fluoro-Jade C following the effect of MDMA on neuronal damage (MDMA induced group) compared to control (P<0.05). Next, the TQ treatments observed in MDMA+TQ exhibited a decline in positive cells from Fluoro-Jade C. The index of recognition memory was found to be increased in MDMA+TQ compared to the MDMA alone (P<0.05). This study suggests that the neuronal damage inflicted by MDMA in a rat model has the potential to be treated by TQ.

Neuroprotective Potential of Synthetic Mono-Carbonyl Curcumin Analogs Assessed by Molecular Docking Studies

Cognitive decline in dementia is associated with deficiency of the cholinergic system. In this study, five mono-carbonyl curcumin analogs were synthesized, and on the basis of their promising in vitro anticholinesterase activities, they were further investigated for in vivo neuroprotective and memory enhancing effects in scopolamine-induced amnesia using elevated plus maze (EPM) and novel object recognition (NOR) behavioral mice models. The effects of the synthesized compounds on the cholinergic system involvement in the brain hippocampus and their binding mode in the active site of cholinesterases were also determined. Compound h2 (p < 0.001) and h3 (p < 0.001) significantly inhibited the cholinesterases and reversed the effects of scopolamine by significantly reducing TLT (p < 0.001) in EPM, while (p < 0.001) increased the time exploring the novel object. The % discrimination index (DI) was significantly increased (p < 0.001) in the novel object recognition test. The mechanism of cholinesterase inhibition was further validated through molecular docking study using MOE software. The results obtained from the in vitro, in vivo and ex vivo studies showed that the synthesized curcumin analogs exhibited significantly higher memory-enhancing potential, and h3 could be an effective neuroprotective agent. However, more study is suggested to explore its exact mechanism of action.

Amifostine (WR-2721) Mitigates Cognitive Injury Induced by Heavy Ion Radiation in Male Mice and Alters Behavior and Brain Connectivity

The deep space environment contains many risks to astronauts during space missions, such as galactic cosmic rays (GCRs) comprised of naturally occurring heavy ions. Heavy ion radiation is increasingly being used in cancer therapy, including novel regimens involving carbon therapy. Previous investigations involving simulated space radiation have indicated a host of detrimental cognitive and behavioral effects. Therefore, there is an increasing need to counteract these deleterious effects of heavy ion radiation. Here, we assessed the ability of amifostine to mitigate cognitive injury induced by simulated GCRs in C57Bl/6J male and female mice. Six-month-old mice received an intraperitoneal injection of saline, 107 mg/kg, or 214 mg/kg of amifostine 1 h prior to exposure to a simplified five-ion radiation (protons, 28Si, 4He, 16O, and 56Fe) at 500 mGy or sham radiation. Mice were behaviorally tested 2–3 months later. Male mice that received saline and radiation exposure failed to show novel object recognition, which was reversed by both doses of amifostine. Conversely, female mice that received saline and radiation exposure displayed intact object recognition, but those that received amifostine prior to radiation did not. Amifostine and radiation also had distinct effects on males and females in the open field, with amifostine affecting distance moved over time in both sexes, and radiation affecting time spent in the center in females only. Whole-brain analysis of cFos immunoreactivity in male mice indicated that amifostine and radiation altered regional connectivity in areas involved in novel object recognition. These data support that amifostine has potential as a countermeasure against cognitive injury following proton and heavy ion irradiation in males.

The effect of binge-like ethanol exposure on adolescent performance in non-spatial and spatial forms of the novel object recognition paradigm

<p>Previous research has demonstrated that ethanol produces differential effects on non-spatial or recognition memory and spatial memory; spatial memory deficits were consistently found to be more persistent than non-spatial memory deficits. Ethanol-produced deficits have also been found to be dependent on age at exposure, and exposure during adolescence produced more persistent deficits than when exposure was experienced by older subjects. The current study investigated the effects of a “binge-like’ 5 day episode of ethanol exposure (1.0g/kg x 5) on performance in non-spatial and spatial forms of the novel object recognition (NOR) task. Subjects were exposed either during adolescence or following maturity. Tests were conducted 2 or 9 days following exposure. NOR was tested following inter-trial intervals of 1, 3, or 5 minutes. Data from mature rats could not be obtained or analysed due to procedural issues that precluded NOR measurement. Control rats failed to demonstrate NOR at any of the time intervals. Reasons for these negative findings are discussed.</p>

The effect of binge-like ethanol exposure on adolescent performance in non-spatial and spatial forms of the novel object recognition paradigm

<p>Previous research has demonstrated that ethanol produces differential effects on non-spatial or recognition memory and spatial memory; spatial memory deficits were consistently found to be more persistent than non-spatial memory deficits. Ethanol-produced deficits have also been found to be dependent on age at exposure, and exposure during adolescence produced more persistent deficits than when exposure was experienced by older subjects. The current study investigated the effects of a “binge-like’ 5 day episode of ethanol exposure (1.0g/kg x 5) on performance in non-spatial and spatial forms of the novel object recognition (NOR) task. Subjects were exposed either during adolescence or following maturity. Tests were conducted 2 or 9 days following exposure. NOR was tested following inter-trial intervals of 1, 3, or 5 minutes. Data from mature rats could not be obtained or analysed due to procedural issues that precluded NOR measurement. Control rats failed to demonstrate NOR at any of the time intervals. Reasons for these negative findings are discussed.</p>

Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome

The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.