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Genetic basis of escape-related locomotor performance in a wild-introgressed sheep population.

Rapid running and jumping are core components of escape responses in prey animals and provide measurable traits for studying locomotor performance in large mammals. The genetic basis of these escape-related locomotor traits remains poorly understood in large mammals, partly because repeated, standardized phenotyping under field conditions is challenging. Here, we leveraged a sheep population carrying argali-introgressed genetic components to map genetic variations associated with running speed and jumping height. Through controlled field experiments, automated high-resolution phenotyping, whole-genome analysis, and gene-edited mouse models, we identified two loci associated with escape-related locomotor traits: one in ABCC4 (Chr10:71,849,347; p = 5.03 × 10-7) linked to maximum running speed and another in GRID2 (Chr6:32,120,477; p = 1.30 × 10-9) associated with jumping height. Functional assays in knockout mice reveal that disruption of Grid2 reduces jumping ability, whereas Abcc4 knockout and knockdown increase running speed through enhanced heart contractility under stress. These results elucidated the genetic bases of wild-derived variations in affecting locomotor performance.

Animals

Effect of a new benzodiazepine bromazepam on locomotor performance and brain monoamine metabolism.

Administration of a single dose (10 mg/kg) of a relatively new benzodiazepine, bromazepam to rats markedly suppressed their spontaneous locomotor activity. Hypomobility became apparent 15 min after the injection and remained significantly lower during the period of observation for 6 hours when locomotor activity was 27% of controls. Following 2 hours after bromazepam treatment, no change was noted in tyrosine levels and tyrosine hydroxylase activity in striatum or rate of catecholamine synthesis in synaptosomal preparation (P2 pellet). However, the endogenous levels of norepinephrine, dopamine and 5-hydroxytryptamine were significantly increased not only in several brain areas examined, but also in P2 pellet. Bromazepam failed to change 3H-norepinephrine and 3H-5-hydroxytryptamine uptake in synaptosomes suggesting that the increased levels of monoamines are not related to laterations in uptake mechanisms, but probably to a diminished release. This is supported by the data on striatal homovanillic acid and whole brain 4-hydroxy-3-methoxyphenyl glycol whose concentrations were significantly lowered following a single injection of this benzodiazepine. However, bromazepam increased 5-hydroxyindole-acetic acid levels in hypothalamus, mid-brain and pons-medulla. The present study demonstrates that bromazepam elicits its tranquilizing action by lowering the release of catecholamines in brain; however, its anti-anxiety action might be associated with a reduction in 5-hydroxytryptamine turn over. Our data also suggest that bromazepam is almost as potent as diazepam in altering the metabolism of certain putative neurotransmitters in brain.

Amines

Walking of cats on a grid: performance of locomotor task in spinal intact and hemisected cats.

We have investigated interlimb coordination during walking by observing locomotion of cats on a grid. Control cats made no error in forelimb placement on the grid, and landed their hindlimbs on the rung where each ipsilateral forelimb left moments earlier. This suggests that locomotor command signals were modified by grid information including its size and direction and affected the pattern generators of both forelimbs and hindlimbs. Hemisected cats, made both at high cervical and lower thoracic, showed deteriorated placement of the hindlimbs suggesting that interlimb coordination is carried out mainly by descending pathways from the brainstem such as ventrolateral fasciculus and dorsolateral fasciculus. Interlimb reflex pathways may play a limited role.

Animals

Potential of adult mammalian lumbosacral spinal cord to execute and acquire improved locomotion in the absence of supraspinal input.

The neural circuitry of the lumbar spinal cord can generate alternating extension and flexion of the hindlimbs. The hindlimbs of adult cats with complete transection of the spinal cord at a low thoracic level (T12-T13) can perform full weight-supporting locomotion on a treadmill belt moving at a range of speeds. Some limitations in the locomotor capacity can be associated with a deficit in the recruitment level of the fast extensors during the stance phase and the flexors during the swing phase of a step cycle. The level of locomotor performance, however, can be enhanced by daily training on a treadmill while emphasizing full weight-support stepping and by providing appropriately timed sensory stimulation, loading, and/or pharmacologic stimulation of the hindlimb neuromuscular apparatus. Furthermore, there appears to be an interactive effect of these interventions. For example, the maximum treadmill speed that a spinal adult cat can attain and maintain is significantly improved with daily full weight-supporting treadmill training, but progressive recruitment of fast extensors becomes apparent only when the hindlimbs are loaded by gently pulling down on the tail during the stepping. Stimulation of the sural nerve at the initiation of the flexion phase of the step cycle can likewise markedly improve the locomotor capability. Administration of clonidine, in particular in combination with an elevated load, resulted in the most distinct and consistent alternating bursts of electromyographic activity during spinal stepping. These data indicate that the spinal cord has the ability to execute alternating activation of the extensor and flexor musculature of the hindlimbs (stepping) and that this ability can be improved by several interventions such as training, sensory stimulation, and use of some pharmacologic agents. Thus, it appears that the spinal cord, without supraspinal input, is highly plastic and has the potential to "learn," that is, to acquire and improve its ability to execute full weight-supporting locomotion on a treadmill belt.

Animals

Effects of acute exposure to stress on subsequent aggression and locomotion performance.

Avoidance-escape deficits following certain highly stressful conditions result from changes in activity of noradrenergic or other monoaminergic neural systems. A "motor activation deficit" has been used to explain these stress-induced neurochemical changes. The present experiment showed that exposure to a stressor decreased aggression and produced deficits in locomotor performance similar to those observed after inescapable stressor conditions in the "motor activation deficit" studies and earlier "learned helplessness" studies in that (a) the animals recovered with the passage of time, (b) the decrease in aggression and locomotion was larger under conditions of inescapable as opposed to escapable shock, and (c) plasma corticosterone was higher following inescapable shock than after escapable shock. Thus, while the findings obtained are not a variance with the "motor activation deficit" hypothesis, they suggest that other mechanisms might be postulated as well to account for certain deficits in emotional behavior following inescapable stress.

Aggression

Parabacteroides goldsteinii mitigates parkinsonism in LRRK2 mutant mice by reducing neuroinflammation through Gut-Brain axis.

INTRODUCTION: Alterations in the gut microbiota accompanied by intestinal inflammation are early features of Parkinson's disease (PD). Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent a common genetic risk factor for PD and inflammatory bowel disease. Parabacteroides goldsteinii has been reported to alleviate intestinal and systemic inflammation. However, whether modulation of the gut microenvironment at early disease stage can attenuate PD progression remains unclear. OBJECTIVE: To investigate the impact of P. goldsteinii colonization prior to the onset of motor dysfunction on PD progression. METHODS: We established a germ-free PD mouse model carrying the LRRK2 G2019S mutation and administered P. goldsteinii orally at the pre-symptomatic stage to evaluate its effects on motor performance and PD-related neuropathology. Spatial and bulk RNA transcriptomic analyses of brain tissue, together with cytokine profiling, were conducted to assess central changes. To investigate gut immunomodulatory mechanisms, we performed intestinal bulk and single-cell RNA sequencing, spectral flow cytometry as well as cellular bioenergetic analyses. RESULTS: Germ-free conditions partially alleviated PD-like phenotypes in LRRK2 G2019S mice. Colonization with P. goldsteinii at 5-months of age, prior to motor symptom onset, further improved locomotor performance, reduced neuronal α-synuclein aggregations, and mitigated microglial activation and dopaminergic neurodegeneration. Neuroprotection was mediated through enhanced noncanonical neuronal IL-12 receptor-dependent neurotrophic support without activating the canonical STAT4 phosphorylation pathway, along with suppression of microglial activation and downregulation of LRRK2 kinase activity. At the intestinal level, P. goldsteinii suppressed TLR4-driven inflammation, expanded anti-inflammatory intraepithelial CD4+CD8αα+ T cells, promoted dendritic cell and macrophage differentiation, upregulated epithelial tight-junction genes, and improved mitochondrial bioenergetics in intestinal cells. CONCLUSION: P. goldsteinii colonization attenuates the progression of LRRK2-associated parkinsonism by restoring intestinal homeostasis and reducing neuroinflammation. These findings underscore the therapeutic potential of modulating the gut-immune-brain axis during the prodromal stage of PD.

Animals

[Neurobehavioral study of colliculectomized monkeys].

A battery of neurological tests was administered to normal and colliculectomized monkeys to determine the effect of the lesion on visually guided behavior, acoustically guided behavior, general locomotor performance and affective behavior. The tests were given at one week and three months post-operatively. The behaviors of the animals were filmed and the results were derived from a careful analysis of the films. The operated monkeys showed important deficits on most tests. After three months a considerable improvement was noted in many functions. However, some behaviors were still totally or partially abnormal. An attempt is made to relate the completeness of the collicular resection and the duration of some of these symptoms.

Animals

Integrated Transcriptomic and Proteomic Analysis Elucidates the Mechanisms of Huperzine A Injection Against Cerebral Ischemia/Reperfusion Injury.

BACKGROUND: After recanalization in acute ischemic stroke, cerebral ischemia/reperfusion injury (CI/RI) drives a cascade of pathophysiological events that worsen clinical outcomes, yet effective therapeutic options remain limited. Given the neuroprotective potential of Huperzine A (HupA), the efficacy of HupA injection (HAI, a major clinical formulation of HupA) against CI/RI and its underlying molecular basis warrant investigation. METHODS: In a mouse model of CI/RI, neurological performance, locomotor ability, cerebral infarction, histopathological alterations, and apoptotic neurons were jointly used to assess the anti-CI/RI effect of HAI at two different doses. An integrated transcriptomic and proteomic strategy was adopted to decipher the key anti-CI/RI mechanisms of HAI and then validated experimentally. RESULTS: Compared with vehicle&#x2011;treated CI/RI mice, HAI intervention significantly alleviated neurobehavioral deficits, decreased infarct size, mitigated histopathological damage, and suppressed neuronal apoptosis (P < 0.01). Both separate and combined transcriptomic and proteomic analyses highlighted that the complement and coagulation cascades, together with inflammation, were strongly correlated with HAI's beneficial action in preventing CI/RI. Indeed, HAI treatment effectively normalized the dysregulated mRNA and protein levels of pivotal targets within the complement and coagulation cascades, including C3, C5, C9, CFB, MASP2, F7, F10, F12, and SERPINE1, in the damaged cortical tissues of CI/RI mice (P < 0.05). Moreover, this intervention markedly attenuated the abnormally elevated expression of multiple inflammatory mediators, including TLR2, TLR4, TNF-&#x3b1;, IL-1&#x3b2;, IL-6, CCL2, CCL5, CXCL1, ICAM1, S100A9, LCN2, MMP8, and MMP9, at both the mRNA and protein levels (P < 0.01). CONCLUSION: Collectively, our data suggest that HAI may confer efficacy against CI/RI by modulating the complement and coagulation cascades and orchestrating the inflammatory response. Although further investigation is warranted, these preliminary findings provide a foundation for accelerating the clinical translation of HAI as a novel neuroprotectant against CI/RI in ischemic stroke.

Animals

A model of the mechanism controlling neuromuscular activation during ambulation based on feedback control hypothhesis.

As tested by many investigators, locomotor performance at steady state does not involve high conscious systems but takes place almost automatically. A great number of experiments on animals seem to demonstrate that the afferent proprioceptive signals play an important role in locomotion and that the higher nervous centers act in order to activate the lower control systems. On the basis of previous findings, we hypothesized that the descending signal from the higher nervous centers can lower the threshold of intervention of the proprioceptive signals on the alpha-motoneurons. The influences of the afferent signals on the various muscles enable them to realize the pattern of the basic muscular activity that we can record from walking subjects. A simulation of the model of human locomotion has been implemented on a digital computer and the theoretical results are compared with the experimental findings.

Afferent Pathways

Recovery of amnestic effect of alpha-amanitin by post-training administration of d-amphetamine in the rat.

alpha-Amanitin, an inhibitor of RNA polymerase II, given intraventricularly 6 or 24 h before training, impaired consolidation of both passive and active avoidance responses in rats. Administration of d-amphetamine sulfate (0.5 mg/kg intraperitoneally) immediately after training produced a clear-cut antiamnestic effect in alpha-amanitin-injected rats without modifying consolidation in control animals. Examination of several parameters of conditioning enabled the authors to rule out an impairment in locomotor performance of alpha-amanitin-treated rats both in training and in test sessions. The amnestic effect of alpha-amanitin and recovery by means of d-amphetamine were discussed in relation to RNA synthesis inhibition and a possible restoring effect of d-amphetamine upon alpha-amanitin-induced decrease of brain RNA content.

Amanitins

Quantifying the control laws governing terminal attack in lions.

Intercepting an evasive, maneuvering target is among the most computationally demanding tasks a predator performs: in the terminal phase of a chase, it must continuously convert sensory information about the target into steering and speed commands, subject to its own biomechanical limits. How terrestrial predators solve this in real time has remained difficult to quantify. Here, we combine drone videography with AI-based markerless pose estimation to reconstruct the kinematics of 67 lion (Panthera leo) attacks on a mechanized lure programmed to move unpredictably. Lion steering is described by a combination of proportional navigation and proportional pursuit, which is a mixed guidance law previously identified only in the aerial pursuit of Harris's hawks (Parabuteo unicinctus), and speed is regulated within a defined kinematic envelope during turns, which declines at close range where the cost of overshooting is greatest. These findings reveal shared guidance principles across aerial and terrestrial pursuit, thus providing a quantitative framework for comparing pursuit strategies across species.

computational ethology

Assessing the aversiveness of intracranial stimulation.

A comparison was made between rats' performance to escape intracranial stimulation in a shuttle-box, two-lever box and a single-lever Sidman avoidance situation. The former two tasks also provided concurrent rate-independent measures of the rewarding properties of ICS. The rate-independent measures of aversion (latency to escape ICS) obtained in the shuttle-box and two-lever task were significantly correlated with each other but were not significantly correlated with the lever-press rates on Sidman avoidance. A number of animals that would not lever-press to initiate ICS would perform the locomotor response very vigorously to initiate the same ICS suggesting that even rate-independent lever-press measures may not accurately reflect the motivational characteristics of ICS. These data are discussed in the context of the problem as to why animals escape rewarding ICS and it is suggested that the escape behaviour is an independent phenomenon which merits further study in its own right.

Animals

Modification of ethanol intoxication by dopamine agonists and antagonists.

The effects of ethanol on locomotor activity and rotarod performance were measured in the rat. Apomorphine (4 mg/kg s.c.) antagonized and pimozide (0.75 - 1.50 mg/kg s.c.) enhanced the effects of a 2 g/kg dose of ethanol on rotarod performance. No such interaction was seen with pentobarbital, 25 mg/kg, a dose sufficiency to produce an equivalent motor performance deficit. Animals with 6-hydroxydopamine lesions of the substantia nigra were more sensitive to the ethanol-induced impairment of rotarod performance and suppression of locomotor activity than shamoperated controls. The pattern of dopamine depletion in lesioned animals indicated a degree of selectivity of the lesion for the nigrostriatal pathway. The results are compatible with the hypothesis that ethanol interferes with dopaminergic transmission, and that such an interference may be involved in the behavioral effects of ethanol.

Alcoholic Intoxication

Effect of physical exercise upon nystagmus and locomotor dysequilibrium after labyrinthectomy in experimental primates.

Spontaneous nystagmus and locomotor equilibrium function were repeatedly tested before and after unilateral labyrinthectomy in 12 squirrel monkeys in order to study the effect of physical exercise on the vestibulo-oculomotor and vestibulo-locomotor compensation. Post-operatively, 6 of the monkeys received forced physical exercise in the rotating cage, while the other 6 did not. The provocation of post-operative spontaneous nystagmus was less in the exercise group. The statistical studies showed a certain contribution of physical exercise toward the oculomotor balance compensation and maintenance, probably at the level of the brain stem. Statistical comparison of the locomotor equilibrium performance did not depict a significant difference between the exercise and non-exercise groups; however, there was a possibility that the present testing maneuver which involves physically advanced tasks might have concealed the effect of the physical exercise.

Animals

Terrain preferences in the play behavior of Siberian ibex kids (Capra ibex sibirica).

Play behavior was studied in a captive group of Siberian ibex at the Chicago Zoological Park. The hypothesis that physical training effects were at least partially responsible for the evolution of play in this species was tested by noting the amounts of play which occurred on flat and on sloped surfaces. The kids showed a clear preference for play on sloped terrain, even though this choice resulted in considerably greater risks. The danger involved in highly active locomotor play performed on steeply sloped areas is presumably outweighed by the physical training benefit for an adult life spent moving in precipitious areas.

Animals

Divergent selection on locomotor activity in Drosophila melanogaster. II. Test for reproductive isolation between selected lines.

Tests for reproductive isolation between lines selected for locomotor activity were performed. Three sets of selection lines were used, each consisting of lines selected for low and high locomotor activity from the same base population. Females preferred high-activity males in almost every case. However, in one of the sets temporary sexual isolation was found between flies of the high and low lines. This was accompanied in the low-activity females with a higher fertility when they were mated with their own males. After further selection the partial isolation disappeared.

Animals