Negative Geotaxis Research Articles

Effects of Early Life Scarcity-Adversity on Maturational Milestones in Male and Female Rats.

Although many studies have shown a long-term negative impact of early life adversity (ELA) in rodents, literature regarding its effects on maturational milestones in rats is scarce. Available evidence suggests that ELA interferes with normal growth and development in rodents and that effects may be sex-dependent even at an early age. In accordance, we hypothesized that early life scarcity-adversity would impair physical and reflex development in male and female rats. To test this, we used an early life resource scarcity paradigm based on reducing home cage bedding during postnatal days (PND) 2-9 and assessed physical landmarks by measuring weight gain, incisor presence, fur development, and eye opening. We also evaluated the impact of early life scarcity-adversity on developmental reflexes by measuringsurface righting and grasp reflexes, negative geotaxis, cliff avoidance, bar holding, and auditory startle. Early life scarcity-adversity resulted in earlier complete lower incisor presence in males (PND 6), impaired surface righting(PND 6) and grasp reflexes (PND 8) in both sexes, and impaired cliff avoidance responses in females (PND 12). These results extend previous research examining the effects of ELA on developing male and female rodents by showing that it negatively impacts a subset of physical landmarks and developmental reflexes in a sex-dependent manner.

Enhanced Age-Dependent Motor Impairment in Males of Drosophila melanogaster Modeling Spinocerebellar Ataxia Type 1 Is Linked to Dysregulation of a Matrix Metalloproteinase

Over the past two decades, Drosophila melanogaster has proven to be successful in modeling the polyglutamine (polyQ) (caused by CAG repeats) family of neurodegenerative disorders, including the faithful recapitulation of pathological features such as polyQ length-dependent formation of protein aggregates and progressive neuronal degeneration. In this study, pan-neuronal expression of human Ataxin-1 with long polyQ repeat of 82 amino acids was driven using an elav-GAL4 driver line. This would essentially model the polyQ disease spinocerebellar ataxia type 1 (SCA1). Longevity and behavioral analysis of male flies expressing human Ataxin-1 revealed compromised lifespan and accelerated locomotor activity deficits both in diurnal activity and negative geotaxis response compared to control flies. Interestingly, this decline in motor response was coupled to an enhancement of matrix metalloproteinase 1 (dMMP1) expression together with declining expression of extracellular matrix (ECM) fibroblast growth factor (FGF) signaling by hedgehog (Hh) and branchless (bnl) and a significant decrease in expression of survival motor neuron gene (dsmn) in old (30 d) flies. Taken together, our results indicate a role for dysregulation of matrix metalloproteinase in polyQ disease with consequent impact on ECM signaling factors, as well as SMN at the neuromuscular junction causing overt physiological and behavioral deficits.

The Effect of Metoclopramide on the Antinociceptive, Locomotor and Neurobehavioral Effects of Metamizole in Mice

Abstract Combining analgesic medications with distinct pharmacodynamics may result in effective analgesia and reduced adverse effects by lowering dosages of one or both medications. The objective was to investigate the nature of interactions of metoclopramide and metamizole by measuring the antinociceptive and neurobehavioral effects in mice. The drugs were administered intraperitoneally (ip) in mice. The antinociceptive effect was determined by the up-and-down method. Isobolographic analysis was performed by simultaneous injection of the two drugs at ED50 ratios of 1:1 and 0.5:0.5. The treated mice were also subjected to an open-field behavioral test as well as dorsal immobility and negative geotaxis behavioral paradigms. The ED50 of metoclopramide and metamizole were 33.71 and 43 mg/kg ip, respectively. Lower ED50 was established for metoclopramide and metamizole by 48.44% and 47.49%, respectively when given at a ratio of 0.5:0.5, and by 35.81% and 29.88%, respectively at a ratio of 1:1. The combined dose of metoclopramide and metamizole (8 and 10 mg/kg, ip, respectively) significantly decreased the open field-activity test in mice. This was observed by lower number of squares crossing compared to the control. Additionally, the drug combination resulted in a substantial increase in the duration of dorsal immobility response and delayed the negative geotaxis task when compared with the control group. The results indicated that the interaction between metoclopramide and metamizole in lower dose ratio with ED50 50:50, was synergistic in producing analgesia in mice with reduced risk for adverse reaction but with decreased behavioral and motor neuronal activity.

Roflumilast-loaded nanostructured lipid carriers attenuate oxidative stress and neuroinflammation in Parkinson’s disease model

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with limited symptomatic treatment options. Targeting phosphodiesterase 4 (PDE4) has shown a promising result in several preclinical studies. In our study, we aim to repurpose US FDA-approved PDE4 inhibitor for PD. Through in-silico study, we identified roflumilast (ROF) as the potential candidate targeting PDE4B2. In Drosophila PD expressing the A30P mutant α-synuclein model, ROF exhibited anti-PD effects as indicated by negative geotaxis and antioxidant activities. Given the low brain distribution of ROF (<50%) at clinical doses, incorporation into nanostructured lipid carriers (NLCs) was carried out to enhanced blood-brain barrier permeability. In vitro release studies indicated sustained ROF release from NLCs (≈75%) over 24 h. Single-dose oral toxicity studies reported no mortality or toxicity signs. ROF-loaded NLCs significantly alleviated behavioural deficits, increased antioxidant parameters (p < 0.05), and reduced TNF-α and IL-6 levels (p < 0.5) in the striatum compared to pure ROF. ROF-loaded NLCs demonstrated potential anti-PD effects with high efficacy than pure ROF. Our study suggests that nanostructured lipid carriers (NLCs) can be a promising drug delivery system to overcome limitations associated with poor brain bioavailability of lipophilic drugs like ROF for PD treatment. Further investigation related to brain occupancy and underlying mechanisms of our formulation is warranted to confirm and strengthen our current findings.

Ups and downs of fossorial life: migration restlessness and geotaxis may explain overwintering emergence in the spotted salamander.

To decide whether to remain underground or to emerge from overwintering, fossorial ectotherms simultaneously process environmental, gravitational and circannual migratory cues. Here, we provide an experimental framework to study the behaviour of fossorial ectotherms during soil temperature inversion - a phenomenon that marks the transition between winter and spring - based on three non-mutually exclusive hypotheses (thermoregulation, negative geotaxis and migration restlessness). Using a vertical thermal gradient, we evaluated how temperature selection (Tsel), activity and vertical position selection differed under simulated soil temperature inversion (contrasting the active versus overwintering thermal gradients) in the spotted salamander (Ambystoma maculatum). Salamanders had different Tsel and activity levels between gradients, but selected similar heights regardless of thermal gradient orientation. Negative geotaxis may explain responses to changes in vertical thermal gradient orientation, with migratory restlessness contributing to differences in activity levels. Ultimately, our work should benefit those who aim to better understand the biology of fossorial ectotherms.

Paternal zinc deficiency alters offspring metabolic status in Drosophila melanogaster

BackgroundThis study delves into the understudied yet potentially crucial role of paternal zinc deficiency in programming offspring metabolic outcomes. By examining paternal zinc deficiency, we aim to shed light on a previously unexplored avenue with the potential to significantly impact future generations. We investigated the intergenerational effects of paternal zinc deficiency on metabolic parameters in Drosophila melanogaster. MethodsDietary zinc deficiency was induced by supplementing the diet of Drosophila F0 male flies with TPEN (N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine) from egg stage. The F0 male flies after eclosion were mated with age-matched virgin female flies from the control group, resulting in the F1 offspring generation. The F1 generation were then cultured on a standard diet for subsequent metabolic analyses, including assessments of body weight, locomotion, and levels of glucose, trehalose, glycogen, and triglycerides as well as the expression of related genes. ResultsWe observed an increase (p<0.05) in body weight in male parent flies and female offspring. Negative geotaxis performance was also impaired in the female offspring. Paternal zinc deficiency exerted distinct effects on carbohydrate and lipid metabolism, as evidenced by a significant (p<0.05) increase in trehalose and triglyceride levels in both parent and offspring. Additionally, zinc deficiency led to alterations in the expression of key metabolic genes, including significant (p<0.05) increase in DILP2 mRNA levels, highlighting potential links to insulin signaling. Also, there were reduced mRNA levels of SOD1 and CAT in both parental and offspring generations. Parental zinc deficiency also increased the expression of Eiger and UPD2 mRNA in the offspring, suggesting potential perturbations in the immune response system. ConclusionThese findings underscore the link between zinc status and various physiological and molecular processes, revealing both immediate and intergenerational impacts on metabolic, antioxidant, and inflammatory pathways and providing valuable insights on the implications of paternal zinc deficiency in Drosophila melanogaster.

Neonatal high-dose riboflavin treatment channels energy expenditure towards sensorimotor and somatic development and reduces rodent growth and weight gain by modulating NRF-1 in the hypothalamus

Metabolic adaptations early in life can drive energy expenditure towards brain and physical development, with less emphasis on body mass gain and somatic growth. Dietary or pharmacological manipulations can influence these processes, but to date, the effects provided by riboflavin have not been studied. The study aimed to evaluate the effects of neonatal treatment with different doses of riboflavin on sensorimotor and somatic development in rodents. Based on this, the following experimental groups were formed: Control (C, 0 mg/kg), Riboflavin 1 (R1, 1 mg/kg), Riboflavin 2 (R2, 10 mg/kg) and Riboflavin 3 (R3, 100 mg/kg). Treatment with 100 mg/kg riboflavin anticipated the reflex ontogeny of righting, cliff aversion, negative geotaxis, and free-fall righting. Intervention with 10 and 100 mg/kg of riboflavin anticipated the reflex maturation of vibrissae placement. Eye-opening, upper incisor eruption, and lower incisor eruption reached maturational age more quickly for animals treated with 100 mg/kg, while caudal growth and body weight gain were reduced from the second week of treatment, for groups R2 and R3. Pearson's correlation analysis indicated a positive association between the administration of high doses of riboflavin and murine growth in the first week of treatment. There was, however, a negative association between treatment with a high dose of riboflavin and growth in the second week of administration, coinciding with a reduction in body weight gain in the R3 group. Treatment with 100 mg/kg of riboflavin also reduced energy expenditure parameters in the open field and catwalk. Although high-dose treatment stimulates the physiological plasticity of the CNS and reduces weight gain, hepatic parameters were preserved, highlighting the participation of the liver in the supply of fatty acids for neural maturation. Furthermore, hypothalamic NRF-1 expression was increased in the R3 group inversely to the reduction in weight gain. Our results suggest that high-dose riboflavin stimulates sensorimotor and somatic development and reduces the energy invested in growth, body weight gain, and locomotor activity, possibly involving NRF-1 gene modulation in the hypothalamus.

Evaluation of developmental milestones and of brain measurements in rats exposed to the pesticide pyriproxyfen in prenatal period.

Pyriproxyfen is a pesticide used in Brazil to control the Aedes aegypti mosquito, vector of arboviruses like Zika and dengue. However, this pesticide is structurally similar to retinoic acid, a metabolite of vitamin A that regulates neuronal differentiation and hindbrain development during the embryonic period. Due to the similarity between pyriproxyfen and retinoic acid, studies indicate that this pesticide may have cross-reactivity with retinoid receptors. Thus, pregnant exposure to pyriproxyfen could interfere in the nervous system development of the fetal. In this context, the present study evaluated whether prenatal exposure to pyriproxyfen affects neonatal development and brain structure in rats. Wistar rat pups were divided in three experimental groups: (1) negative control (CT-)-offspring of rats that drink potable water during pregnancy; (2) pyriproxyfen (PIR)-offspring of rats exposed to Sumilarv® prenatally, a pesticide that has pyriproxyfen as active ingredient; and (3) positive control (CT+)-offspring of rats exposed to an excess of vitamin A prenatally. Only vitamin A treated-pregnant showed lower weight gain, but gestation length was similar among pregnant that received potable water, water containing vitamin A and water containing Sumilarv. In relation to the offspring, PIR group exhibits a delayed front-limb suspension response but performed early the negative geotaxis reflex. On the other hand, CT+ group exhibited lower body weight in the 1st postnatal day, delayed audio startle response, but performed early the eyelids opening and hindlimb placing response. A reduction in the maximum brain width was observed both in PIR and CT+ groups, but a reduction in the number of neurons in the M1 cortex was showed only in CT+ group. The number of glial cells in this brain area was similar between the three experimental groups studied. Although prenatal exposure to pyriproxyfen did not alter neonatal milestones in the same way as vitamin A in excess, both substances caused a reduction in the maximum width of the brain, suggesting that this pesticide can produce neurotoxic effects during the embryonic period.

Lactate administration causes long-term neuroprotective effects following neonatal hypoxia-ischemia

Neonatal hypoxia-ischemia (HI) is one of the main causes of mortality and long-term disabilities in newborns, and the only clinical approach to treat this condition is therapeutic hypothermia, which shows some limitations. Thus, putative neuroprotective agents have been tested in animal models of HI. Lactate is a preferential metabolic substrate of the neonatal brain and has already been shown to produce beneficial neuroprotective outcomes in neonatal animals exposed to HI. Here, we administered lactate as a treatment in neonatal rats previously exposed to HI and evaluated the impact of this treatment in adulthood. Seven-day-old (P7) male and female Wistar rats underwent permanent common right carotid occlusion combined with an exposition to a hypoxic atmosphere (8% oxygen) for 60 min. Animals were assigned to one of four experimental groups: HI, HI+LAC, SHAM, SHAM+LAC. Lactate was administered intraperitoneally 30 min and 2 h after hypoxia in HI+LAC and SHAM+LAC groups, whereas HI and SHAM groups received vehicle. Animals were tested in the behavioral tasks of negative geotaxis and righting reflex (P8), cylinder test (P24), and the modified neurological severity score was calculated (P25). Open field (OF), and novel object recognition (NOR) were evaluated in adulthood. Animals were killed at P60, and the brains were harvested and processed to evaluate the volume of brain injury. Our results showed that lactate administration reduced the volume of brain lesion and improved sensorimotor and cognitive behaviors in neonatal, juvenile, and adult life in HI animals from both sexes. Thus, lactate administration might be considered as a potential neuroprotective strategy for the treatment of neonatal HI, which is a prevalent disorder affecting newborns.

Knockout of Hsp70 genes significantly affects locomotion speed and gene expression in leg skeletal muscles of Drosophila melanogaster.

The functions of the heat shock protein 70 (Hsp70) genes were studied using a line of Drosophila melanogaster with a knockout of 6 of these genes out of 13. Namely, the effect of knockout of Hsp70 genes on negative geotaxis climbing (locomotor) speed and the ability to adapt to climbing training (0.5-1.5 h/day, 7 days/wk, 19 days) were examined. Seven- and 23-day-old Hsp70- flies demonstrated a comparable reduction (twofold) in locomotor speed and widespread changes in leg skeletal muscle transcriptome (RNA sequencing) compared with w1118 flies. To identify the functions of genes related to decreased locomotor speed, the overlapped differentially expressed genes at both time points were analyzed: the upregulated genes encoded extracellular proteins, regulators of drug metabolism, and the antioxidant response, whereas downregulated genes encoded regulators of carbohydrate metabolism and transmembrane proteins. In addition, in Hsp70- flies, activation of transcription factors related to disruption of the fibril structure and heat shock response (Hsf) was predicted, using the position weight matrix approach. In control flies, adaptation to chronic exercise training was associated mainly with gene response to a single exercise bout, whereas the predicted transcription factors were related to stress/immune (Hsf, NF-κB, etc.) and early gene response. In contrast, Hsp70- flies demonstrated no adaptation to training as well as a significantly impaired gene response to a single exercise bout. In conclusion, the knockout of Hsp70 genes not only reduced physical performance but also disrupted adaptation to chronic physical training, which is associated with changes in the leg skeletal muscle transcriptome and impaired gene response to a single exercise bout.NEW & NOTEWORTHY Knockout of six heat shock protein 70 (Hsp70) genes in Drosophila melanogaster reduced locomotion (climbing) speed that is associated with genotype-specific differences in leg skeletal muscle gene expression. Disrupted adaptation of Hsp70- flies to chronic exercise training is associated with impaired gene response to a single exercise bout.

Systemic Effects of Photoactivated 5,10,15,20-tetrakis(N-methylpyridinium-3-yl) Porphyrin on Healthy Drosophila melanogaster.

Porphyrins are frequently employed in photodynamic therapy (PDT), a non-invasive technique primarily utilized to treat subcutaneous cancers, as photosensitizing agents (PAs). The development of a new PA with improved tissue selectivity and efficacy is crucial for expanding the application of PDT for the management of diverse cancers. We investigated the systemic effects of 5,10,15,20-tetrakis(N-methylpyridinium-3-yl)-porphyrin (TMPyP3) using Drosophila melanogaster adult males. We established the oral administration schedule and demonstrated that TMPyP3 was absorbed and stored higher in neuronal than in non-neuronal extracts. Twenty-four hours after oral TMPyP3 photoactivation, the quantity of hydrogen peroxide (H2O2) increased, but exclusively in the head extracts. Regardless of photoactivation, TMPyP3 resulted in a reduced concentration of H2O2 after 7 days, and this was linked with a decreased capacity to climb, as indicated by negative geotaxis. The findings imply that systemic TMPyP3 therapy may disrupt redox regulation, impairing cellular signaling and behavioral outcomes in the process. To determine the disruptive effect of porphyrins on redox homeostasis, its duration, and the mechanistic variations in retention across various tissues, more research is required.

Comparative Evaluation of Neuroprotective Activity of Tryptanthrin and Its Oxime in Middle Cerebral Artery Occlusion in Rats.

The neuroprotective activity of tryptanthrin and its oxime was compared in male Wistar rats with a model of intraluminal occlusion of the middle cerebral artery. Neurobehavioral tests were performed 4, 24, and 48 h after focal cerebral infarction (FCI) using a modified neurological severity score (mNSS); additionally, the horizontal stability test, the plantar sensitivity test of the fore and hind limbs, holding on the tilted cage top test, and negative geotaxis test were performed. The size of FCI and the severity of brain tissue swelling were examined on day 2 after occlusion. Tryptanthrin and its oxime were administered at a dose of 10 mg/kg intraperitoneally during FCI, then daily for 2 days. In the control group, the mean score of neurological deficit remained at a high level for 2 days. FCI size was 43.8±3.4% of hemisphere area, and the hemisphere volume increased by 18.5±2.0% due to brain tissue swelling and edema. Administration of tryptanthrin and its oxime significantly decreased neurological deficits at all control points and reduced FCI size (by 24.2 and 30.4%, respectively) and brain tissue swelling of the affected hemisphere (by 64.9 and 62.7%, respectively). Therefore, the neuroprotective effect of tryptanthrine and its oxime in the acute period of FCI is largely determined by their anti-inflammatory activity.

Synergistic Enhancement of Motor Function by Curcumin and Piperine in Alpha-Synuclein Expressing Drosophila Models

Parkinson’s disease (PD) is a neurodegenerative disease characterized by Lewy body formation mainly phosphorylated and aggregated α-synuclein, with subsequent neurotoxicity and death of dopaminergic neurons in the basal ganglia. The neuroprotective action of curcumin and piperine has been reported. We used the GAL4/UAS bipartite system for targeted expression of α-synuclein pan-neuronal and dopamine neurons to create genetically induced PD. Hence, in this study we assessed the ameliorative effect of curcumin and piperine on α-synuclein-induced dopaminergic neuron degeneration and photoreceptor degeneration in the Drosophila melanogaster model of PD. Male Drosophila melanogaster (upstream activating sequence (UAS) linked to synuclein (SNCA) flies were crossed with virgin wild-type Can-ton-S, DDC-GAL4 or GMR-GAL4 female flies) cultured on either medium containing graded concentrations of curcumin and/or piperine (5, 10, and 50 μM) or vehicle. The parameters measured included fecundity, larval motility, negative geotaxis, and lifespan. Vehicle, curcumin, or piperine supplementation in SNCA&gt;Cs, SNCA&gt;DDC, or SNCA&gt;GMR flies did not affect fecundity or larval motility, but piperine (5 μM and 10 μM but not 50 μM) supplementation reduced fecundity. SNCA&gt;DDC flies significantly reduced climbing performance and lifespan, peaked in week 4, ameliorated by the curcumin and piperine combination. Moreover, the increased aggregation of synuclein, as evidenced in ommatidial degeneration in SNCA&gt;GMR flies’ eyes, was attenuated by the curcumin and piperine combination. Findings from the present study further reinforced the potential benefit of curcumin and piperine in the management of PD.

Emodin attenuates hypoxic-ischemic brain damage by inhibiting neuronal apoptosis in neonatal mice

Neonatal hypoxic-ischemic brain damage (HIBD) can lead to mortality and severe neurological dysfunction. Emodin is a natural anthraquinone derivative that is easy to obtain and has good neuroprotective effects. This study aimed to investigate the neuroprotective effect of emodin on neonatal mouse HIBD. The modified Rice–Vannucci method was used to induce HIBD in mouse pups. Eighty postnatal 7-day (P7) C57BL/6 neonatal mice were randomly divided into the sham group (sham), vehicle group (vehicle), and emodin group (emodin). TTC staining and whole-brain morphology were used to evaluate the infarct volume and morphology of the brain tissue. The condition of the neurons was observed through Nissl staining, HE staining, FJC staining, immunofluorescence and Western blot for NeuN, IBA-1, and GFAP. The physiological status of the mice was evaluated using weight measurements. The neural function of the mice was assessed using the negative geotaxis test, righting reflex test, and grip test. TUNEL staining was used to detect apoptosis in brain cells. Finally, Western blot and immunofluorescence were used to detect the expression levels of apoptosis-related proteins, such as P53, cleaved caspase-3, Bax and Bcl-2, in the brain. Experiments have shown that emodin can reduce the cerebral infarct volume, brain oedema, neuronal apoptosis, and degeneration and improve the reconstruction of brain tissue morphology, neuronal morphology, physiological conditions, and neural function. Additionally, emodin inhibited the expression of proapoptotic proteins such as P53, Bax and cleaved caspase-3 and promoted the expression of the antiapoptotic protein Bcl-2. Emodin attenuates HIBD by inhibiting neuronal apoptosis in neonatal mice.

Persisting neurobehavioral consequences of daily or intermittent paternal cannabis administration in F1 and F2 Rats

Repeated paternal preconception exposure to Δ9-tetrahydrocannabinol (Δ9-THC) alone or together with the other constituents in a cannabis extract has been shown in our earlier studies in rats to cause significant neurobehavioral impairment in their offspring. In the current study, we compared the effects of daily cannabis extract (CE) exposure to cannabis on two consecutive days per week, modeling weekend cannabis use in human. The CE contained Δ9-THC as well as cannabidiol and cannabinol. We also extended the investigation of the study to cross-generational effects of grand-paternal cannabis exposure on the F2 generation and included testing the effects of paternal cannabis exposure on responding for opiate self-administration in F1 and F2 generation offspring. We replicated the findings of neurobehavioral impairment in F1 offspring of male rats exposed to cannabis extract containing 4 mg/kg/day of Δ9-THC daily for four weeks prior to mating with drug naïve females. The 4-week cannabis extract exposure caused a significant decrease in weight gain in the male rats exposed daily. In contrast, their offspring showed significantly greater body weights and anogenital distances (AGD) in the third to fourth weeks after birth. The behavioral effects seen in the F1 generation were increased habituation of locomotor activity in the figure-8 maze in female offspring and increased lever pressing for the opiate drug remifentanil in male offspring. The F2 generation showed significantly impaired negative geotaxis and an elimination of the typical sex-difference in locomotor activity, with effects not seen in the F1 generation. This study shows that daily paternal cannabis exposure for four weeks prior to mating causes significant neurobehavioral impairment in the F1 and F2 offspring. Intermittent exposure on two consecutive days per week for four weeks caused comparable neurobehavioral impairment. In sum, there should be concern about paternal as well as maternal exposure to cannabis concerning neurobehavioral development of their offspring.

Prenatal restraint stress affects early neurobehavioral response and oxidative stress in mice pups.

Prenatal stress (PS), in both humans and animals, presents a potential risk to the mother and her fetus throughout gestation. PS is always associated with physiological changes that alter embryonic development and predispose the individual to lifelong health problems, including susceptibility to mental illness. This study aims to identify the harmful effects of prenatal restraint stress (PRS), commonly employed to induce stress painlessly and without any lasting debilitation during gestation. This stress is applied to pregnant Swiss albino mice from E7.5 to delivery for three hours daily. Our results show that PS affects dams' weight gain during the gestational period; moreover, the PS dams prefer passive nursing, exhibit a lower percentage of licking and grooming, and impair other maternal behaviors, including nesting and pup retrieval. Concerning the offspring, this stress induces neurobehavioral impairments, including a significant increase in the time of recovery of the young stressed pups in the surface righting reflex, the latency to avoid the cliff in the cliff avoidance test, longer latencies to accomplish the task in negative geotaxis, and a lower score in swimming development. These alterations were accompanied by increased Malondialdehyde activity (MDA) at PND17 and 21 and downregulation of AchE activity in the whole brain of pups on postnatal days 7 and 9. These findings demonstrated that PS causes deleterious neurodevelopmental impairments that can alter various behaviors later in life.

Diverse memory paradigms in Drosophila reveal diverse neural mechanisms.

In this review, we aggregated the different types of learning and memory paradigms developed in adult Drosophila and attempted to assess the similarities and differences in the neural mechanisms supporting diverse types of memory. The simplest association memory assays are conditioning paradigms (olfactory, visual, and gustatory). A great deal of work has been done on these memories, revealing hundreds of genes and neural circuits supporting this memory. Variations of conditioning assays (reversal learning, trace conditioning, latent inhibition, and extinction) also reveal interesting memory mechanisms, whereas mechanisms supporting spatial memory (thermal maze, orientation memory, and heat box) and the conditioned suppression of innate behaviors (phototaxis, negative geotaxis, anemotaxis, and locomotion) remain largely unexplored. In recent years, there has been an increased interest in multisensory and multicomponent memories (context-dependent and cross-modal memory) and higher-order memory (sensory preconditioning and second-order conditioning). Some of this work has revealed how the intricate mushroom body (MB) neural circuitry can support more complex memories. Finally, the most complex memories are arguably those involving social memory: courtship conditioning and social learning (mate-copying and egg-laying behaviors). Currently, very little is known about the mechanisms supporting social memories. Overall, the MBs are important for association memories of multiple sensory modalities and multisensory integration, whereas the central complex is important for place, orientation, and navigation memories. Interestingly, several different types of memory appear to use similar or variants of the olfactory conditioning neural circuitry, which are repurposed in different ways.

Neuroprotective Effect of Grewia carpinifolia Extract against Behavioral Impairments Induced by Vanadium

Vanadium is a heavy metal that has been reported to cause toxicity in the central nervous system resulting in various behavioral alterations. This is characterized by the generation of reactive oxygen species. The present study was designed to investigate the probability of Grewia carpinifolia ethanol extract in preventing behavioral impairments following acute vanadium toxicity in mice. Twenty five Swiss albino mice (25–27g) were randomized into 5 groups (A–E) of 5 animals each. Group A received distilled water and served as a control; group B received vitamin E (500mg·kg−1 b.w. every 72 hours), a known antioxidant orally along with a daily dose of sodium metavanadate intraperitoneally (i.p.) for 7 days; group C and group D received Grewia carpinifolia leaf extract at 100 and 200mg·kg−1 b.w orally respectively, along with the sodium metavanadate i.p. for 7 days; while group E received sodium metavanadate i.p. only for 7 days. The behavioral and motor functions were analyzed by the open field, negative geotaxis, and hanging wire tests; the daily body and brain weights were recorded. Grewia carpinifolia ethanol extracts significantly reduced the number of grooming, stretched attend posture, and freezing time that were significantly increased in the vanadium only group and also enhanced the vestibular functions. Furthermore, the latent time spent on the hanging wire in groups simultaneously administered with the extract and vanadium compared positively (P&gt;0.05) with the control groups but a decrease in latent time was observed in the vanadium only group. The results suggest that acute vanadium toxicity results in various behavioral impairments and support a possible role of Grewia carpinifolia as a protective agent against acute vanadium-toxicity with a better result at 200mg·kg−1 b.w. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Alpha-ketoglutarate supplementation in long-lived Drosophila melanogaster: Impact on lifespan and metabolic responses.

Studies on antiaging remedies in insect models sometimes show discrepancies in results. These discrepancies could be explained by different responses of short- and long-lived strains on the antiaging remedies. The purpose of the study was to test whether life-prolonging effects of alpha-ketoglutarate (AKG), observed in nematodes and fruit flies, would be reproduced in long-lived Drosophila melanogaster flies. Lifespan was assayed in flies kept in demographic cages. Fecundity, proportion of flies capable of negative geotaxis, starvation resistance, time of heat coma onset, levels of triacyglycerols, body glucose, glycogen, activities of glutamate dehydrogenase, catalase, glutathione-S-transferase, hexokinase, phosphofructokinase, pyruvate kinase, lactate, and glutamate dehydrogenases were assessed. Dietary AKG did not affect fly lifespan on the diet with 5% yeast and 5% sucrose (5Y:5S) and on the diet with 9% yeast and 1% sucrose (9Y:1S), but increased lifespan on the low-protein diet (1Y:9S). Twenty-five-day-old female flies fed a 5Y:5S diet with 10 mM AKG for 3 weeks, did not differ from the control group (without AKG) in climbing activity, resistance to heat stress, and starvation. The levels of glucose and glycogen were unaffected but the levels of triacylglycerols were lower in AKG-fed female flies. No differences in activities of glycolytic enzymes, NADPH-producing enzymes, glutamate dehydrogenase, oxygen consumption, and levels of oxidative stress markers were observed between the control and AKG-fed flies. However, AKG-fed flies had lower activities of catalase and glutathione-S-transferase. These results suggest that potential antiaging remedies, such as AKG, may not extend lifespan in long-living organisms despite influencing several metabolic parameters.

Improved therapeutic approach for spinal muscular atrophy via ubiquitination-resistant survival motor neuron variant.

Zolgensma is a gene-replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre-symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination-resistant variant of survival motor neuron (SMN), SMNK186R, has improved therapeutic effects for SMA compared with wild-type SMN (SMNWT). A severe SMA mouse model, SMA type 1.5 (Smn-/-; SMN2+/+; SMN∆7+/-) mice, was used to compare the differences in therapeutic efficacy between AAV9-SMNWT and AAV9-SMNK186R. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle. AAV9-SMNK186R-treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9-SMNWT-treated mice. Lifespan increased by more than 10-fold in AAV9-SMNK186R-treated mice (144.8±26.11days) as compared with AAV9-SMNWT-treated mice (26.8±1.41days). AAV9-SMNK186R-treated mice showed an ascending weight pattern, unlike AAV9-SMNWT-treated mice, which only gained weight until P20 up to 5g on average. Several motor function tests showed the improved therapeutic efficacy of SMNK186R. In the negative geotaxis test, AAV9-SMNK186R-treated mice turned their bodies in an upward direction successfully, unlike AAV9-SMNWT-treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9-SMNK186R-treated mice, unlike AAV9-SMNWT-treated mice that showed clasping phenotype for more than 20 out of 30s. At this point, the number of motor neurons (1.5-fold) and the size of myofibers (2.1-fold) were significantly increased in AAV9-SMNK186R-treated mice compared with AAV9-SMNWT-treated mice without prominent neurotoxicity. AAV9-SMNK186R had fewer liver defects compared with AAV9-SMNWT, as judged by increased proliferation of hepatocytes (P<0.0001) and insulin-like growth factor-1 production (P<0.0001). Especially, low-dose AAV9-SMNK186R (nine-fold) also reduced clasping time compared with SMNWT. SMNK186R will provide improved therapeutic efficacy in patients with severe SMA with insufficient therapeutic efficacy. Low-dose treatment of SMA patients with AAV9-SMNK186R can reduce the adverse events of Zolgensma. Collectively, SMNK186R has value as a new treatment for SMA that improves treatment effectiveness and reduces adverse events simultaneously.