Foot-related/walking macro-affordances are implicitly activated and preferentially guided by the framing distance of the environmental layout.

As classically captured in the notion of affordance, the natural environment presents animals with multiple opportunities for action and locomotion appears as the privileged form of action to cover distance in the extrapersonal space/environment. We have recently described a facilitation effect, known as "macro-affordance", for the execution of walking-related actions in response to distant vs. near objects/locations in the extrapersonal space. However, since the manipulation of distance was coextensive to landmark-objects contained in the environment and to the environmental layout per se, the relative contribution of these two factors remains undetermined. In addition, since the effect was originally described in the context of an incidental priming paradigm, it is still unknown whether it was specifically associated with an implicit coding of environmental distance. Here, across three experiments, we examined the degree to which the "macro-affordance" effect reflects (i) the encoding of environmental vs. landmark-objects' distance, (ii) the involvement of an implicit vs. controlled system, (iii) a foot-effector specificity. The results showed that the "macro-affordance" effect is more efficiently triggered by the framing distance of the environmental layout (far/wide/panoramic vs. near/close/restricted) rather than of isolated landmark-objects in the environment and that it only emerges when the distance dimension is implicitly processed within the incidental priming paradigm. The results additionally suggested a specificity of the effect for foot- vs. hand-related actions. The present findings suggest that macro-affordances reflect an implicit coding of spatial features of the environmental layout and viewer-environment relationships that preferentially guide a walking-related exploration of the spatial environment.

Empowering episodic memory through a model-based egocentric navigational training.

Recent works have proposed that spatial mechanisms in the hippocampal-entorhinal system might have originally developed to represent distances and positions in the physical space and successively evolved to represent experience and memory in the mental space (Bellmund et al. 2018; Bottini and Doeller 2020). Within this phylogenetic continuity hypothesis (Buzsáki and Moser 2013), mechanisms supporting episodic and semantic memory would have evolved from egocentric and allocentric spatial navigation mechanisms, respectively. Recent studies have described a specific relationship between human performance in egocentric navigation and episodic memory (Committeri et al. 2020; Fragueiro et al. 2021), representing the first behavioral support to this hypothesis. Here, we tested the causal relationship among egocentric navigation and both episodic and semantic components of declarative memory. We conducted two experiments on healthy young adults: in the first experiment, participants were submitted to a navigational training based on path integration, while in the second experiment, participants completed a control training based on visual-perceptual learning. Performance in a set of memory tasks assessing episodic, semantic and short-term memory was compared among the pre- vs. post-training sessions. The results indicated a significant improvement of the episodic memory but not of the semantic or the short-term memory performance following the navigational training. In addition, no modulations of performance across the three memory tasks were observed following the control perceptual training. Our findings provide brand-new evidence of a potential causal association between mechanisms of egocentric navigation and episodic memory, thereby further supporting the phylogenetic continuity hypothesis between navigation and memory mechanisms as well as offering new insights about possible clinical applications of navigational trainings for memory functions/dysfunctions.

Pain-like behavior in the collagen antibody-induced arthritis model is regulated by lysophosphatidic acid and activation of satellite glia cells.

Inflammatory and neuropathic-like components underlie rheumatoid arthritis (RA)-associated pain, and lysophosphatidic acid (LPA) is linked to both joint inflammation in RA patients and to neuropathic pain. Thus, we investigated a role for LPA signalling using the collagen antibody-induced arthritis (CAIA) model. Pain-like behavior during the inflammatory phase and the late, neuropathic-like phase of CAIA was reversed by a neutralizing antibody generated against LPA and by an LPA1/3 receptor inhibitor, but joint inflammation was not affected. Autotaxin, an LPA synthesizing enzyme was upregulated in dorsal root ganglia (DRG) neurons during both CAIA phases, but not in joints or spinal cord. Late-phase pronociceptive neurochemical changes in the DRG were blocked in Lpar1 receptor deficient mice and reversed by LPA neutralization. In vitro and in vivo studies indicated that LPA regulates pain-like behavior via the LPA1 receptor on satellite glia cells (SGCs), which is expressed by both human and mouse SGCs in the DRG. Furthermore, CAIA-induced SGC activity is reversed by phospholipid neutralization and blocked in Lpar1 deficient mice. Our findings suggest that the regulation of CAIA-induced pain-like behavior by LPA signalling is a peripheral event, associated with the DRGs and involving increased pronociceptive activity of SGCs, which in turn act on sensory neurons.

Inhibition of return in time-lapse: Brain Rhythms during grip force control for spatial attention.

The inhibition of return (IoR) is the observable slowed response to a target at a cued position for cue-target intervals of longer than 300 ms; when there has been enough time to disengage from a previously-cued location, an inhibitory after-effect can be observed. Studies aimed at understanding whether mechanisms underlying IoR act at a perceptual/attentional or a later response-execution stage have offered divergent results. Though focusing on the brain's responses to cue-target intervals can offer significant information on the nature of IoR, few studies have investigated neural activity during this interval; these studies suggest the generation of inhibitory tags on the spatial coordinates of the previously attended position which, in turn, inhibit motor programming toward that position. As such, a cue-target task was administered in this study; the rhythmic activity of EEG signals on the entire cue-target interval was measured to determine whether IoR is referred to early or late response processing stages. A visually-guided force variation during isometric contraction, instead of a key press response, was required to reduce the effect of motor response initiation. Our results indicated the prominent involvement of the fronto-parietal and occipital cortical areas post-cue appearance, with a peculiar theta band modulation characterizing the posterior parietal cortex. Theta activity in this region was enhanced post-cue onset, decreased over time, and was enhanced again when a target appeared in an unexpected location rather than in a cued position. This suggests that the mechanism that generates IoR sequentially affects perceptual/attentional processing and motor preparation rather than response execution.

Travel in the Physical and Mental Space: A Behavioral Assessment of the Phylogenetic Continuity Hypothesis Between Egocentric Navigation and Episodic Memory.

Based on the neuro-functional association between navigation in the physical and the mental space at the level of the hippocampal-entorhinal system, Buzsáki and Moser (2013) have hypothesized a phylogenetic continuity between spatial navigation and declarative memory functions. According to this proposal, mechanisms of episodic and semantic memory would have evolved from mechanisms of self-based and map-based navigation in the physical space, respectively. Using classic versions of path integration and item recognition tasks in human subjects, we have recently described a correlation and a predictive relationship between abilities in egocentric navigation and episodic memory. Here we aim at confirming and extending this association to the dynamic component of sequential updating in the physical (egocentric navigation) and mental (episodic memory) space, and at investigating the relationship of these self-centered abilities with semantic memory. To this aim, we developed three new experimental tasks in which the dynamic component of updating information is particularly emphasized in the spatial, the temporal, and the semantic domain. The contribution of visual short-term memory to the three tasks was also controlled by including an additional task. The results confirmed the existence of a direct and predictive relationship between self-based spatial navigation and episodic memory. We also found a significant association between egocentric navigation and semantic memory, but this relationship was explained by short-term memory abilities and was mediated by episodic memory functions. Our results support the hypothesis of an evolutionary link between mechanisms that allow spatial navigation in the physical space and time travel in the mental space.

Automatic coding of environmental distance for walking-related locomotion in the foot-related sensory-motor system: A TMS study on macro-affordances.

We have recently described a facilitation effect for the execution of a walking-related action in response to distant objects/locations in the extrapersonal space. Based on the parallelism with the well-known effect of "micro-affordance", observed during the execution of functionally appropriate hand-related actions towards manipulable objects, we have referred to this effect in terms of "macro-affordance". Here we used transcranical magnetic stimulation (TMS) to investigate whether a foot-related region located in the human dorsal precuneate cortex plays a causal role in the generation and maintenance of such behavioral effect. This question was addressed by comparing the magnitude of the facilitation effect during an incidental go/no-go task, i.e. advantage for walking-related actions to pictures framing an environment from a far vs. near distance, during three different TMS conditions. The three TMS conditions were collected in all subjects in a randomized order and included stimulation of: i. a foot-related region in the anterior precuneus, ii. a control region in the middle intraparietal sulcus (mIPS), and iii. a sham condition. Enrollment in the TMS protocol was based on analysis of individual performance during a preliminary session conducted using a sham stimulation. TMS was administered at a low frequency range before the beginning of each condition. The results showed that stimulation of the foot-related region in the anterior precuneus produced a significant reduction of the walking-related facilitation effect as compared to both stimulation of the active-control region and the non-active sham stimulation. These findings suggest that the foot-related sensory-motor system directly participates in the process of extraction of the spatial features (i.e. distance) from an environmental scene that are useful for locomotion. More in general, these findings support an automatic coding of environmental affordance or "macro-affordances" in the walking-related sensory-motor system.

Class inclusion versus quantifiers comprehension tasks: an experimental study with school-aged children.

Literature in developmental psychology pays special attention to the difficulties met by preschool children when confronted with (universal vs. existential) quantified sentences. According to the pivotal Piagetian view, the difficulties exhibited in quantifier comprehension during the preoperational period (age 2-6) derive from the same limitations in logical reasoning that cause bad performance outcomes in class inclusion problems. Nevertheless, as far as we know, a direct comparison between the two tasks has never been produced. In this research we tested the logical hypotheses concerning the failure in quantifier comprehension of preschool children by administering a sentence-picture matching task to two groups of children (5-6 vs. 7-8 years old). Pictures, obtained by partially pairing two entity sets, one of which outnumbers the other, were presented to participants. After each picture, children were asked to answer questions involving quantified versus class inclusion contents. Main findings showed that younger children performed the quantifier task worse than older children and their performance in that task was also worse with respect to the class inclusion task. This difference was not observed with older children who obtained better results than younger children in both tasks. These findings suggest that the specific abilities involved in solving the two problems evolve independently from each other during cognitive development. The results have been discussed in the light of the recent developmental theories.

Parsing the Flanker task to reveal behavioral and oscillatory correlates of unattended conflict interference.

Stimulus-Response conflict is generated by an overlap between stimulus and response dimensions, but the intrinsic nature of this interaction is not yet deeply clarified. In this study, using a modified Eriksen flanker task, we have investigated how flankers have to be incongruent to target in order to produce an interference and whether and how this interference interacts with the one produced by Stimulus features overlap. To these aims, an Eriksen-like task employing oriented hands\arrows has been designed to distinguish between two types of Stimulus-Response (S-R) interferences: one derived by a short-term association and one based on automatic processes. Stimulus-Stimulus (S-S) conflict has been also included in the same factorial design. Behavioral, Event Related Potential (ERP) and oscillatory activity data have been measured. Results revealed distinct S-S and automatic S-R effects on behavioral performance. ERP and Theta band power modulation results suggested an early frontal S-S conflict processing followed by a posterior simultaneous S-S and automatic S-R conflict processing. These findings provide evidence that, in presence of different conflicts, the sequence of stimulus identification and response selection could not move forward in a linear serial direction, but it may involve further effort, mirrored in posterior late components and response time prolongation.

The right hemisphere contribution to semantic categorization: a TMS study.

A large amount of evidence suggests an involvement of the right hemisphere in lexical-semantic processing, but its specific contribution compared to the left hemisphere is not entirely clear. The present study investigated the contribution of both hemispheres to the semantic categorization process of words referring to typical and atypical exemplars. Transcranial Magnetic Stimulation (TMS) was used to interfere with the online activity of Wernicke's area and its right homologue during a verbal category membership task. The TMS delayed the responses to typical member nouns compared to the control condition, over both areas of interest. On the contrary, a delay in the responses to atypical member nouns was observed only when the right Wernicke's area was stimulated. Overall, these results indicate that while both hemispheres are involved in the categorization of typical exemplars, the right hemisphere specifically contributes to semantic categorization of atypical ones.

Rank perception and self-evaluation in eating disorders.

OBJECTIVES: Heightened sensitivity to social comparison and negative self-evaluation have been implicated in the development and maintenance of eating disorders (EDs). This study used behavioral tasks, as well as self-report measures, to examine processing of social rank-related cues and implicit self-concept in participants with EDs. METHOD: Fifty healthy participants (HCs), 46 people with an ED, and 22 people recovered from an ED (REC) undertook an attentional bias task using social rank-related cues and an implicit self-evaluation task. In addition, they completed self-report measures of social comparison, submissive behavior, and shame. RESULTS: People with EDs showed vigilance toward social rank-related stimuli and lower implicit positive self-evaluation than HCs. Self-report data confirmed the behavioral findings and showed that people with EDs had higher levels of unfavorable social comparison, submissive behaviors, and external and internal shame than HCs. People who had recovered from an ED showed an intermediate profile between the two groups. DISCUSSION: People with EDs have heightened sensitivity to social rank-related cues and impaired self-evaluation at an automatic level of processing. Some of these biases remain in people who have recovered. Interventions which aim to remediate social threat sensitivity and negative bias about self and others might be of benefit in EDs.

The representation of conceptual knowledge: visual, auditory, and olfactory imagery compared with semantic processing.

Two experiments comparing imaginative processing in different modalities and semantic processing were carried out to investigate the issue of whether conceptual knowledge can be represented in different format. Participants were asked to judge the similarity between visual images, auditory images, and olfactory images in the imaginative block, if two items belonged to the same category in the semantic block. Items were verbally cued in both experiments. The degree of similarity between the imaginative and semantic items was changed across experiments. Experiment 1 showed that the semantic processing was faster than the visual and the auditory imaginative processing, whereas no differentiation was possible between the semantic processing and the olfactory imaginative processing. Experiment 2 revealed that only the visual imaginative processing could be differentiated from the semantic processing in terms of accuracy. These results showed that the visual and auditory imaginative processing can be differentiated from the semantic processing, although both visual and auditory images strongly rely on semantic representations. On the contrary, no differentiation is possible within the olfactory domain. Results are discussed in the frame of the imagery debate.

Social reward and rejection sensitivity in eating disorders: an investigation of attentional bias and early experiences.

OBJECTIVES: People with eating disorders (EDs) have difficulties with social functioning. One explanatory mechanism is a problem with over-sensitivity to rejection and/or low sensitivity to social reward. The aim of this study is to investigate attentional bias to facial stimuli in people with a lifetime diagnosis of EDs and healthy controls (HCs) and to test whether these attentional biases are linked to adverse early experiences. METHODS: Forty-six participants with a current diagnosis of EDs (29 with anorexia nervosa (AN) and 17 with bulimia nervosa (BN)), 22 participants recovered from an eating disorder (13 with past AN and nine with past BN) and 50 HCs completed a dot-probe task with faces expressing rejection and acceptance. Participants reported on parental style and adverse early experiences. RESULTS: People with a lifetime diagnosis of EDs show an attentional bias to rejecting faces and a difficulty disengaging attention from these stimuli. Also, they had a sustained attentional avoidance of accepting faces. HCs demonstrated the opposite attentional pattern. The attentional bias to rejection was correlated with adverse childhood experiences. CONCLUSIONS: People with an EDs show vigilance to rejection and avoidance of social reward. This may contribute to the causation or maintenance of the illness.

Blockage of lysophosphatidic acid signaling improves spinal cord injury outcomes.

Evidence suggests a proinflammatory role of lysophosphatidic acid (LPA) in various pathologic abnormalities, including in the central nervous system. Herein, we describe LPA as an important mediator of inflammation after spinal cord injury (SCI) in zebrafish and mice. Furthermore, we describe a novel monoclonal blocking antibody raised against LPA that potently inhibits LPA's effect in vitro and in vivo. This antibody, B3, specifically binds LPA, prevents it from interacting with its complement of receptors, and blocks LPA's effects on the neuronal differentiation of human neural stem/progenitor cells, demonstrating its specificity toward LPA signaling. When administered systemically to mice subjected to SCI, B3 substantially reduced glial inflammation and neuronal death. B3-treated animals demonstrated significantly more neuronal survival upstream of the lesion site, with some functional improvement. This study describes the use of anti-LPA monoclonal antibody as a novel therapeutic approach for the treatment of SCI.

Processing Italian relative clauses: working memory span and word order effects on RTs.

In this study, the authors aim to clarify whether the subject-object asymmetry in relative clause comprehension is due to the use of parsing strategies (Active Filler Theory) or to a greater memory load generated by object sentences. Two experiments investigate how individual differences in working memory span may influence the reading times of relative sentences in Italian, a language characterized by a flexible structure. The results of Experiment 1 indicate that object extraction is more complex than subject extraction when sentences have a canonical structure. Furthermore, low-span participants have particular difficulties with object relative sentence comprehension. The results of Experiment 2 show that subject-relative clauses with uncanonical structures are more complex to understand than object-relative clauses, and low-span participants have more difficulties than high-span participants in elaborating both subject and object relative clauses. These data seem to be coherent with the Active Filler Theory.

Production and characterization of monoclonal anti-sphingosine-1-phosphate antibodies.

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid involved in multiple physiological processes. Importantly, dysregulated S1P levels are associated with several pathologies, including cardiovascular and inflammatory diseases and cancer. This report describes the successful production and characterization of a murine monoclonal antibody, LT1002, directed against S1P, using novel immunization and screening methods applied to bioactive lipids. We also report the successful generation of LT1009, the humanized variant of LT1002, for potential clinical use. Both LT1002 and LT1009 have high affinity and specificity for S1P and do not cross-react with structurally related lipids. Using an in vitro bioassay, LT1002 and LT1009 were effective in blocking S1P-mediated release of the pro-angiogenic and prometastatic cytokine, interleukin-8, from human ovarian carcinoma cells, showing that both antibodies can out-compete S1P receptors in binding to S1P. In vivo anti-angiogenic activity of all antibody variants was demonstrated using the murine choroidal neovascularization model. Importantly, intravenous administration of the antibodies showed a marked effect on lymphocyte trafficking. The resulting lead candidate, LT1009, has been formulated for Phase 1 clinical trials in cancer and age-related macular degeneration. The anti-S1P antibody shows promise as a novel, first-in-class therapeutic acting as a "molecular sponge" to selectively deplete S1P from blood and other compartments where pathological S1P levels have been implicated in disease progression or in disorders where immune modulation may be beneficial.

Thrombin receptor and RhoA mediate cell proliferation through integrins and cysteine-rich protein 61.

A subset of G-protein coupled receptors (GPCRs), including the thrombin receptor (PAR1), elicits mitogenic responses. Thrombin also activates Ras homolog gene family member A (RhoA) and activating protein (AP-1) -mediated gene expression in 1321N1 astrocytoma cells, whereas the nonmitogenic agonist carbachol does not. Transcriptomic analysis was used to explore differential gene induction by these agonists and revealed that the matricellular protein cysteine-rich 61 (Cyr61/CCN1) is selectively induced by thrombin. The ability of GPCR agonists to induce Cyr61 parallels their ability to activate RhoA; agonist-stimulated Cyr61 expression is inhibited by C3 toxin. When Cyr61 is down-regulated using short interfering RNA (siRNA) or short-hairpin RNA (shRNA), thrombin-induced DNA synthesis is significantly attenuated. When Cyr61 expression is induced, it appears in the extracellular compartment and on the cell surface. Extracellular Cyr61 interacts with alpha(5), alpha(6), and beta(1) integrins on these cells, and monoclonal antibodies directed against alpha(5) and beta(1) integrins inhibit thrombin-induced DNA synthesis. Functional blockade of Cyr61 with soluble heparin or anti-Cyr61 antibodies also inhibits thrombin-induced DNA synthesis. Thus Cyr61 is a highly inducible, secreted extracellular factor through which GPCR and RhoA signaling pathways engage integrins that contribute to GPCR-mediated proliferation.

Validation of an anti-sphingosine-1-phosphate antibody as a potential therapeutic in reducing growth, invasion, and angiogenesis in multiple tumor lineages.

S1P has been proposed to contribute to cancer progression by regulating tumor proliferation, invasion, and angiogenesis. We developed a biospecific monoclonal antibody to S1P to investigate its role in tumorigenesis. The anti-S1P mAb substantially reduced tumor progression and in some cases eliminated measurable tumors in murine xenograft and allograft models. Tumor growth inhibition was attributed to antiangiogenic and antitumorigenic effects of the antibody. The anti-S1P mAb blocked EC migration and resulting capillary formation, inhibited blood vessel formation induced by VEGF and bFGF, and arrested tumor-associated angiogenesis. The anti-S1P mAb also neutralized S1P-induced proliferation, release of proangiogenic cytokines, and the ability of S1P to protect tumor cells from apoptosis in several tumor cell lines, validating S1P as a target for therapy.

Dynamics of male sexual arousal: distinct components of brain activation revealed by fMRI.

The peripheral mechanisms of male sexual arousal are well known. Recently, neuroimaging techniques, such as PET or fMRI, allowed the investigation of the subjacent cerebral mechanisms. In ten healthy subjects, we have simultaneously recorded fMRI images of brain activation elicited by viewing erotic scenes, and the time course of penile tumescence by means of a custom-built MRI-compatible pneumatic cuff. We have compared activation elicited by video clips with a long duration, that led to sexual arousal and penile erection, and activation elicited by briefly presented still images, that did induce sexual arousal without erection. This comparison and the use of the time course of penile tumescence in video clips allowed to perform a time resolved data analysis and to correlate different patterns of brain activation with different phases of sexual response. The activation maps highlighted a complex neural circuit involved in sexual arousal. Of this circuit, only a few areas (anterior cingulate, insula, amygdala, hypothalamus, and secondary somatosensory cortices) were specifically correlated with penile erection. Finally, these areas showed distinct dynamic relationships with the time course of sexual response. These differences might correspond to different roles in the development and appraisal of the sexual response. These findings shed light on the psychophysiology of male sexuality and open new perspectives for the diagnosis, therapy, and possible rehabilitation of sexual dysfunction.

Rho-mediated cytoskeletal rearrangement in response to LPA is functionally antagonized by Rac1 and PIP2.

G-protein-coupled receptors signal through Rho to induce actin cytoskeletal rearrangement. We previously demonstrated that thrombin stimulates Rho-dependent process retraction and rounding of 1321N1 astrocytoma cells. Surprisingly, while lysophosphatidic acid (LPA) activated RhoA in 1321N1 cells, it failed to produce cell rounding. Thrombin, unlike LPA, decreased Rac1 activity, and activated (GTPase-deficient) Rac1 inhibited thrombin-stimulated cell rounding, while expression of dominant-negative Rac1 promoted LPA-induced rounding. LPA and thrombin receptors appear to differ in coupling to Gi, as LPA but not thrombin-stimulated 1321N1 cell proliferation was pertussis toxin-sensitive. Blocking Gi with pertussis toxin enabled LPA to induce cell rounding and to decrease activated Rac1. These data support the hypothesis that Rac1 and Gi activation antagonize cell rounding. Thrombin and LPA receptors also differentially activated Gq pathways as thrombin but not LPA increased InsP3 formation and reduced phosphatidylinositol 4,5-bisphosphate (PIP2) levels. Microinjection of the plekstrin homology domain of phospholipase C (PLC)delta1, which binds PIP2, enabled LPA to elicit cell rounding, consistent with a requirement for PIP2 reduction. We suggest that Rho-mediated cytoskeletal responses are enhanced by concomitant reductions in cellular levels of PIP2 and Rac1 activation and thus effected only by G-protein-coupled receptors with appropriate subsets of G protein activation.