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Personality Neuroscience 2023The Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines/strains were established in Rome through bidirectional selection of Wistar rats for rapid (RHA) or... (Review)
Review
The Roman high-avoidance (RHA) and low-avoidance (RLA) rat lines/strains were established in Rome through bidirectional selection of Wistar rats for rapid (RHA) or extremely poor (RLA) acquisition of a two-way active avoidance task. Relative to RHAs, RLA rats exhibit enhanced threat sensitivity, anxiety, fear and vulnerability to stress, a passive coping style and increased sensitivity to frustration. Thus, RLA rats' phenotypic profile falls well within the "internalizing" behavior spectrum. Compared with RLAs and other rat strains/stocks, RHAs present increased impulsivity and reward sensitivity, deficits in social behavior and attentional/cognitive processes, novelty-induced hyper-locomotion and vulnerability to psychostimulant sensitization and drug addiction. Thus, RHA rats' phenotypes are consistent with a "disinhibiting externalizing" profile. Many neurobiological/molecular traits differentiate both rat lines/strains. For example, relative to RLA rats, RHAs exhibit decreased function of the prefrontal cortex (PFC), hippocampus and amygdala, increased functional tone of the mesolimbic dopamine system, a deficit of central metabotropic glutamate-2 (mGlu2) receptors, increased density of serotonin 5-HT2A receptors in the PFC, impairment of GABAergic transmission in the PFC, alterations of several synaptic markers and increased density of pyramidal immature dendrític spines in the PFC. These characteristics suggest an immature brain of RHA rats and are reminiscent of schizophrenia features like hypofrontality and disruption of the excitation/inhibition cortical balance. We review evidence supporting RLA rats as a valid model of anxiety/fear, stress and frustration vulnerability, whereas RHA rats represent a promising translational model of neurodevelopmental alterations related to impulsivity, schizophrenia-relevant features and comorbidity with drug addiction vulnerability.
PubMed: 38107777
DOI: 10.1017/pen.2023.7 -
Molecular Psychiatry Dec 2023The brain's ability to associate threats with external stimuli is vital to execute essential behaviours including avoidance. Disruption of this process contributes...
The brain's ability to associate threats with external stimuli is vital to execute essential behaviours including avoidance. Disruption of this process contributes instead to the emergence of pathological traits which are common in addiction and depression. However, the mechanisms and neural dynamics at the single-cell resolution underlying the encoding of associative learning remain elusive. Here, employing a Pavlovian discrimination task in mice we investigate how neuronal populations in the lateral habenula (LHb), a subcortical nucleus whose excitation underlies negative affect, encode the association between conditioned stimuli and a punishment (unconditioned stimulus). Large population single-unit recordings in the LHb reveal both excitatory and inhibitory responses to aversive stimuli. Additionally, local optical inhibition prevents the formation of cue discrimination during associative learning, demonstrating a critical role of LHb activity in this process. Accordingly, longitudinal in vivo two-photon imaging tracking LHb calcium neuronal dynamics during conditioning reveals an upward or downward shift of individual neurons' CS-evoked responses. While recordings in acute slices indicate strengthening of synaptic excitation after conditioning, support vector machine algorithms suggest that postsynaptic dynamics to punishment-predictive cues represent behavioral cue discrimination. To examine the presynaptic signaling in LHb participating in learning we monitored neurotransmitter dynamics with genetically-encoded indicators in behaving mice. While glutamate, GABA, and serotonin release in LHb remain stable across associative learning, we observe enhanced acetylcholine signaling developing throughout conditioning. In summary, converging presynaptic and postsynaptic mechanisms in the LHb underlie the transformation of neutral cues in valued signals supporting cue discrimination during learning.
Topics: Male; Animals; Mice, Inbred C57BL; Association Learning; Habenula; Neuronal Plasticity; Punishment; Neurons; Cues; Acetylcholine; Synapses
PubMed: 37414924
DOI: 10.1038/s41380-023-02155-3 -
ELife Nov 2023Although avoidance is a prevalent feature of anxiety-related psychopathology, differences in the measurement of avoidance between humans and non-human animals hinder our...
Although avoidance is a prevalent feature of anxiety-related psychopathology, differences in the measurement of avoidance between humans and non-human animals hinder our progress in its theoretical understanding and treatment. To address this, we developed a novel translational measure of anxiety-related avoidance in the form of an approach-avoidance reinforcement learning task, by adapting a paradigm from the non-human animal literature to study the same cognitive processes in human participants. We used computational modelling to probe the putative cognitive mechanisms underlying approach-avoidance behaviour in this task and investigated how they relate to subjective task-induced anxiety. In a large online study (n = 372), participants who experienced greater task-induced anxiety avoided choices associated with punishment, even when this resulted in lower overall reward. Computational modelling revealed that this effect was explained by greater individual sensitivities to punishment relative to rewards. We replicated these findings in an independent sample (n = 627) and we also found fair-to-excellent reliability of measures of task performance in a sub-sample retested 1 week later (n = 57). Our findings demonstrate the potential of approach-avoidance reinforcement learning tasks as translational and computational models of anxiety-related avoidance. Future studies should assess the predictive validity of this approach in clinical samples and experimental manipulations of anxiety.
Topics: Animals; Humans; Avoidance Learning; Reproducibility of Results; Reinforcement, Psychology; Reward; Anxiety; Computer Simulation
PubMed: 37963085
DOI: 10.7554/eLife.87720 -
Redox Biology Nov 2023Environmental surveillance-mediated behavior integrates multiple cues through complex signaling mechanisms. In Caenorhabditis elegans, neurons coordinate perception and...
Environmental surveillance-mediated behavior integrates multiple cues through complex signaling mechanisms. In Caenorhabditis elegans, neurons coordinate perception and response through evolutionarily conserved molecular signaling cascades to mediate attraction and avoidance behaviors. However, despite lacking eyes, C. elegans was recently reported to perceive and react to the color blue. Here, we provide an explanation for this apparent color perception. We show that internally-generated reactive oxygen species (ROS) occurring in response to light are additive to exogenous sources of ROS, such as bacterial toxins or photosensitizers. Multiple sub-threshold sources of ROS are integrated to coordinate behavioral responses to the environment with internal physiologic cues, independent of color. We further demonstrate that avoidance behavior can be blocked by antioxidants, while ROS is both sufficient and scalable to phenocopy the avoidance response. Moreover, avoidance behavior in response to ROS is plastic and reversible, suggesting it may occur through a post-translation redox modification. Blue light affects C. elegans behavior through ROS generation by endogenous flavins in a process requiring the neuronal gustatory photoreceptor like protein, LITE-1. Our results demonstrate that LITE-1 is also required for ROS-mediated avoidance of pyocyanin and light-activated photosensitizers and this role is mediated through the modification of Cys44. Overall, these findings demonstrate that ROS and LITE-1 are central mediators of C. elegans foraging behavior through integration of multiple inputs, including light.
Topics: Animals; Caenorhabditis elegans; Reactive Oxygen Species; Caenorhabditis elegans Proteins; Photosensitizing Agents; Oxidation-Reduction
PubMed: 37864874
DOI: 10.1016/j.redox.2023.102934 -
Molecular Psychiatry Sep 2023The pathogenesis of schizophrenia is believed to involve combined dysfunctions of many proteins including microtubule-associated protein 6 (MAP6) and Kv3.1 voltage-gated...
The pathogenesis of schizophrenia is believed to involve combined dysfunctions of many proteins including microtubule-associated protein 6 (MAP6) and Kv3.1 voltage-gated K (Kv) channel, but their relationship and functions in behavioral regulation are often not known. Here we report that MAP6 stabilizes Kv3.1 channels in parvalbumin-positive (PV+ ) fast-spiking GABAergic interneurons, regulating behavior. MAP6 and Kv3.1 mice display similar hyperactivity and avoidance reduction. Their proteins colocalize in PV+ interneurons and MAP6 deletion markedly reduces Kv3.1 protein level. We further show that two microtubule-binding modules of MAP6 bind the Kv3.1 tetramerization domain with high affinity, maintaining the channel level in both neuronal soma and axons. MAP6 knockdown by AAV-shRNA in the amygdala or the hippocampus reduces avoidance or causes hyperactivity and recognition memory deficit, respectively, through elevating projection neuron activity. Finally, knocking down Kv3.1 or disrupting the MAP6-Kv3.1 binding in these brain regions causes avoidance reduction and hyperactivity, consistent with the effects of MAP6 knockdown. Thus, disrupting this conserved cytoskeleton-membrane interaction in fast-spiking neurons causes different degrees of functional vulnerability in various neural circuits.
Topics: Mice; Animals; Neurons; Potassium Channels, Voltage-Gated; Cytoskeleton; Microtubules; Emotions; Shaw Potassium Channels
PubMed: 37833406
DOI: 10.1038/s41380-023-02286-7 -
Nutrients Aug 2023Eating disorders (EDs) are mental health diseases characterized by dysfunctional eating patterns, including restrictive eating, avoidance of foods, binge eating, and...
Eating disorders (EDs) are mental health diseases characterized by dysfunctional eating patterns, including restrictive eating, avoidance of foods, binge eating, and compensative behaviors to avoid weight increases and promote thinness (purging, vomiting, laxative/diuretics misuse, and compulsive exercise) [...].
Topics: Humans; Feeding and Eating Disorders; Behavior, Addictive; Binge-Eating Disorder; Bulimia; Diuretics
PubMed: 37686749
DOI: 10.3390/nu15173718 -
Journal of Safety Research Dec 2023In recent years, as novel micromobility vehicles (MMVs) have hit the market and rapidly gained popularity, new challenges in road safety have also arisen. There is an...
INTRODUCTION
In recent years, as novel micromobility vehicles (MMVs) have hit the market and rapidly gained popularity, new challenges in road safety have also arisen. There is an urgent need for validated models that comprehensively describe the behavior of such novel MMVs. This study aims to compare the longitudinal and lateral control of bicycles and e-scooters in a collision-avoidance scenario from a top-down perspective, and to propose appropriate quantitative models for parameterizing and predicting the trajectories of the avoidance-braking and steering-maneuvers.
METHOD
We compared a large e-scooter and a light e-scooter with a bicycle (in assisted and non-assisted modes) in field trials to determine whether these new vehicles have different maneuverability constraints when avoiding a rear-end collision by braking and/or steering.
RESULTS
Braking performance in terms of deceleration and jerk varies among the different types of vehicles; specifically, e-scooters are not as effective at braking as bicycles, but the large e-scooter demonstrated better braking performance than the light one. No statistically significant difference was observed in the steering performance of the vehicles. Bicycles were perceived as more stable, maneuverable, and safe than e-scooters. The study also presents arctangent kinematic models for braking and steering, which demonstrate better accuracy and informativeness than linear models.
CONCLUSIONS
This study demonstrates that the new micromobility solutions have some maneuverability characteristics that differ significantly from those of bicycles, and even within their own kind. Steering could be a more efficient collision-avoidance strategy for MMVs than braking under certain circumstances, such as in a rear-end collision. More complicated modeling for MMV kinematics can be beneficial but needs validation.
PRACTICAL APPLICATIONS
The proposed arctangent models could be used in new advanced driving assistance systems to prevent crashes between cars and MMV users. Micromobility safety could be improved by educating MMV riders to adapt their behavior accordingly. Further, knowledge about the differences in maneuverability between e-scooters and bicycles could inform infrastructure design, and traffic regulations.
Topics: Humans; Accidents, Traffic; Protective Devices; Automobiles; Biomechanical Phenomena
PubMed: 38081697
DOI: 10.1016/j.jsr.2023.09.019 -
The Science of the Total Environment Nov 2023Agrochemicals represent prominent anthropogenic stressors contributing to the ongoing global insect decline. While their impact is generally assessed in terms of...
Agrochemicals represent prominent anthropogenic stressors contributing to the ongoing global insect decline. While their impact is generally assessed in terms of mortality rates, non-lethal effects on fitness are equally important to insect conservation. Glyphosate, a commonly used herbicide, is toxic to many animal species, and thought to impact a range of physiological functions. In this study, we investigate the impact of long-term exposure to glyphosate on locomotion, phototaxis and learning abilities in bumblebees, using a fully automated high-throughput assay. We find that glyphosate exposure had a very slight and transient impact on locomotion, while leaving the phototactic drive unaffected. Glyphosate exposure also reduced attraction towards UV light when blue was given as an alternative and, most strikingly, impaired learning of aversive stimuli. Thus, glyphosate had specific actions on sensory and cognitive processes. These non-lethal perceptual and cognitive impairments likely represent a significant obstacle to foraging and predator avoidance for wild bumblebees exposed to glyphosate. Similar effects in other species could contribute to a widespread reduction in foraging efficiency across ecosystems, driven by the large-scale application of this herbicide. The high-throughput paradigm presented in this study can be adapted to investigate sublethal effects of other agrochemicals on bumblebees or other important pollinator species, opening up a critical new avenue for the study of anthropogenic stressors.
PubMed: 37451452
DOI: 10.1016/j.scitotenv.2023.165527 -
Nature Communications Aug 2023The modulation of dopamine release from midbrain projections to the striatum has long been demonstrated in reward-based learning, but the synaptic basis of aversive...
The modulation of dopamine release from midbrain projections to the striatum has long been demonstrated in reward-based learning, but the synaptic basis of aversive learning is far less characterized. The cerebellum receives axonal projections from the locus coeruleus, and norepinephrine release is implicated in states of arousal and stress, but whether aversive learning relies on plastic changes in norepinephrine release in the cerebellum is unknown. Here we report that in mice, norepinephrine is released in the cerebellum following an unpredicted noxious event (a foot-shock) and that this norepinephrine release is potentiated powerfully with fear acquisition as animals learn that a previously neutral stimulus (tone) predicts the aversive event. Importantly, both chemogenetic and optogenetic inhibition of the locus coeruleus-cerebellum pathway block fear memory without impairing motor function. Thus, norepinephrine release in the cerebellum is modulated by experience and underlies aversive learning.
Topics: Mice; Animals; Avoidance Learning; Norepinephrine; Locus Coeruleus; Cerebellum; Mesencephalon
PubMed: 37563141
DOI: 10.1038/s41467-023-40548-8 -
BioRxiv : the Preprint Server For... Aug 2023Chronic stress induces changes in the periphery and the central nervous system (CNS) that contribute to neuropathology and behavioral abnormalities associated with...
Chronic stress induces changes in the periphery and the central nervous system (CNS) that contribute to neuropathology and behavioral abnormalities associated with psychiatric disorders. In this study, we examined the impact of peripheral and central inflammation during chronic social defeat stress (CSDS) in female mice. Compared to male mice, we found that female mice exhibited heightened peripheral inflammatory response and identified C-C motif chemokine ligand 5 (CCL5), as a stress-susceptibility marker in females. Blocking CCL5 signaling in the periphery promoted resilience to CSDS. In the brain, stress-susceptible mice displayed increased expression of C-C chemokine receptor 5 (CCR5), a receptor for CCL5, in microglia in the prefrontal cortex (PFC). This upregulation was associated with microglia morphological changes, their increased migration to the blood vessels, and enhanced phagocytosis of synaptic components and vascular material. These changes coincided with neurophysiological alterations and impaired blood-brain barrier (BBB) integrity. By blocking CCR5 signaling specifically in the PFC were able to prevent stress-induced physiological changes and rescue social avoidance behavior. Our findings are the first to demonstrate that stress-mediated dysregulation of the CCL5-CCR5 axis triggers excessive phagocytosis of synaptic materials and neurovascular components by microglia, resulting in disruptions in neurotransmission, reduced BBB integrity, and increased stress susceptibility. Our study provides new insights into the role of cortical microglia in female stress susceptibility and suggests that the CCL5-CCR5 axis may serve as a novel sex-specific therapeutic target for treating psychiatric disorders in females.
PubMed: 37662400
DOI: 10.1101/2023.08.18.553789