Synthetic Spatial Foraging With Active Inference in a Geocaching Task

Humans are highly proficient in learning about the environments in which they operate. They form flexible spatial representations of their surroundings that can be leveraged with ease during spatial foraging and navigation. To capture these abilities, we present a deep Active Inference model of goal-directed behavior, and the accompanying belief updating. Active Inference rests upon optimizing Bayesian beliefs to maximize model evidence or marginal likelihood. Bayesian beliefs are probability distributions over the causes of observable outcomes. These causes include an agent's actions, which enables one to treat planning as inference. We use simulations of a geocaching task to elucidate the belief updating-that underwrites spatial foraging-and the associated behavioral and neurophysiological responses. In a geocaching task, the aim is to find hidden objects in the environment using spatial coordinates. Here, synthetic agents learn about the environment via inference and learning (e.g., learning about the likelihoods of outcomes given latent states) to reach a target location, and then forage locally to discover the hidden object that offers clues for the next location

The neurobiology of functional neurological disorders characterised by impaired awareness

We review the neurobiology of Functional Neurological Disorders (FND), i.e., neurological disorders not explained by currently identifiable histopathological processes, in order to focus on those characterised by impaired awareness (functionally impaired awareness disorders, FIAD), and especially, on the paradigmatic case of Resignation Syndrome (RS). We thus provide an improved more integrated theory of FIAD, able to guide both research priorities and the diagnostic formulation of FIAD. We systematically address the diverse spectrum of clinical presentations of FND with impaired awareness, and offer a new framework for understanding FIAD. We find that unraveling the historical development of neurobiological theory of FIAD is of paramount importance for its current understanding. Then, we integrate contemporary clinical material in order to contextualise the neurobiology of FIAD within social, cultural, and psychological perspectives. We thus review neuro-computational insights in FND in general, to arrive at a more coherent account of FIAD. FIAD may be based on maladaptive predictive coding, shaped by stress, attention, uncertainty, and, ultimately, neurally encoded beliefs and their updates. We also critically appraise arguments in support of and against such Bayesian models. Finally, we discuss implications of our theoretical account and provide pointers towards an improved clinical diagnostic formulation of FIAD. We suggest directions for future research towards a more unified theory on which future interventions and management strategies could be based, as effective treatments and clinical trial evidence remain limited

Reduced grid-like theta modulation in schizophrenia

The hippocampal formation has been implicated in the pathophysiology of schizophrenia, with patients showing impairments in spatial and relational cognition, structural changes in entorhinal cortex, and reduced theta coherence with medial prefrontal cortex. Both the entorhinal cortex and medial prefrontal cortex exhibit a six-fold (or 'hexadirectional') modulation of neural activity during virtual navigation that is indicative of grid cell populations and associated with accurate spatial navigation. Here, we examined whether these grid-like patterns are disrupted in schizophrenia. We asked 17 participants with diagnoses of schizophrenia and 23 controls (matched for age, sex and IQ) to perform a virtual reality spatial navigation task during magnetoencephalography. The control group showed stronger 4-10 Hz theta power during movement onset, as well as hexadirectional modulation of theta band oscillatory activity in the right entorhinal cortex whose directional stability across trials correlated with navigational accuracy. This hexadirectional modulation was absent in patients, with a significant difference between groups. These results suggest that impairments in spatial and relational cognition associated with schizophrenia may arise from disrupted grid firing patterns in entorhinal cortex

Markov Blankets in the Brain

Recent characterisations of self-organising systems depend upon the presence of a Markov blanket: a statistical boundary that mediates the interactions between what is inside of and outside of a system. We leverage this idea to provide an analysis of partitions in neuronal systems. This is applicable to brain architectures at multiple scales, enabling partitions into single neurons, brain regions, and brain-wide networks. This treatment is based upon the canonical micro-circuitry used in empirical studies of effective connectivity, so as to speak directly to practical applications. This depends upon the dynamic coupling between functional units, whose form recapitulates that of a Markov blanket at each level. The nuance afforded by partitioning neural systems in this way highlights certain limitations of modular perspectives of brain function that only consider a single level of description.Comment: 25 pages, 5 figures, 1 table, Glossar

Graphene-based nanomaterials for peripheral nerve regeneration

Emerging nanotechnologies offer numerous opportunities in the field of regenerative medicine and have been widely explored to design novel scaffolds for the regeneration and stimulation of nerve tissue. In this review, we focus on peripheral nerve regeneration. First, we introduce the biomedical problem and the present status of nerve conduits that can be used to guide, fasten and enhance regeneration. Then, we thoroughly discuss graphene as an emerging candidate in nerve tissue engineering, in light of its chemical, tribological and electrical properties. We introduce the graphene forms commonly used as neural interfaces, briefly review their applications, and discuss their potential toxicity. We then focus on the adoption of graphene in peripheral nervous system applications, a research field that has gained in the last years ever-increasing attention. We discuss the potential integration of graphene in guidance conduits, and critically review graphene interaction not only with peripheral neurons, but also with non-neural cells involved in nerve regeneration; indeed, the latter have recently emerged as central players in modulating the immune and inflammatory response and accelerating the growth of new tissue

Human TrkAR649W mutation impairs nociception, sweating and cognitive abilities: a mouse model of HSAN IV

A functional nerve growth factor (NGF)-TrkA system is an essential requisite for the generation and maintenance of long-lasting thermal and mechanical hyperalgesia in adult mammals. Indeed, mutations in the gene encoding for TrkA are responsible for a rare condition, named Hereditary Sensory and Autonomic Neuropathy type IV (HSAN IV), characterized by the loss of response to noxious stimuli, anhidrosis and cognitive impairment. However, to date, there is no available mouse model to properly understand how the NGF-TrkA system can lead to pathological phenotypes that are distinctive of HSAN IV. Here, we report the generation of a knock-in mouse line carrying the HSAN IV TrkAR649W mutation. First, by in vitro biochemical and biophysical analyses, we show that the pathological R649W mutation leads to kinase-inactive TrkA also affecting its membrane dynamics and trafficking. In agreement with the HSAN IV human phenotype, TrkAR649W/m mice display a lower response to thermal and chemical noxious stimuli, correlating with reduced skin innervation, in addition to decreased sweating in comparison to TrkAh/m controls. Moreover, the R649W mutation decreases anxiety-like behavior and compromises cognitive abilities, by impairing spatial-working and social memory. Our results further uncover unexplored roles of TrkA in thermoregulation and sociability. In addition to accurately recapitulating the clinical manifestations of HSAN IV patients, our findings contribute to clarify the involvement of the NGF-TrkA system in pain sensation

Gestational Diabetes Mellitus pregnancy by pregnancy. early, late and nonrecurrent GDM

Aims: To assess the GDM recurrence rate in a cohort of pregnant women with prior GDM, to compare two consecutive pregnancies complicated by GDM, to compare women with nonrecurrent and recurrent GDM and to stratify the latter in women with early and late recurrent GDM.Methods: Retrospective study including 113 women with GDM in an index pregnancy (G1), at least a postindex pregnancy (G2) and normal glucose tolerance in between. The GDM recurrence rate was assessed, and maternal and neonatal outcomes and pancreatic beta cell function of the index pregnancy were compared with those of the postindex pregnancy (G1 vs. G2). Women with nonrecurrent GDM were compared with those with recurrent GDM.Results: The GDM recurrence rate was 83.2% and the minimum prevalence of early recurrent GDM was 43,4%. The pregravid BMI of women with recurrent GDM increased between the two pregnancies (27.3 +/- 5.98 vs. 28.1 +/- 6.19 kg/m(2), p < 0.05). Women with recurrent GDM had a higher prepregnancy BMI than those with nonrecurrent GDM either at the index (27.3 +/- 5.98 vs. 23.1 +/- 4.78 kg/m(2), p < 0.05) or the postindex pregnancy (27 +/- 6vs.24 +/- 4,4 kg/m2, p < 0.05).Conclusions: GDM shows a high recurrence rate in our cohort of slightly overweight women, with an early GDM minimum prevalence of 43.4%

Axonal plasticity in response to active forces generated through magnetic nano-pulling

Mechanical force is crucial in guiding axon outgrowth before and after synapse formation. This process is referred to as "stretch growth." However, how neurons transduce mechanical input into signaling pathways remains poorly understood. Another open question is how stretch growth is coupled in time with the intercalated addition of new mass along the entire axon. Here, we demonstrate that active mechanical force generated by magnetic nano-pulling induces remodeling of the axonal cytoskeleton. Specifically, the increase in the axonal density of microtubules induced by nano-pulling leads to an accumulation of organelles and signaling vesicles, which, in turn, promotes local translation by increasing the probability of assembly of the "translation factories." Modulation of axonal transport and local translation sustains enhanced axon outgrowth and synapse maturation

Structural and functional interactions between six-transmembrane mu-opioid receptors and beta(2)-adrenoreceptors modulate opioid signaling

The primary molecular target for clinically used opioids is the mu-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with beta(2)-adrenergic receptors (beta(2)-ARs) through an interaction with the fifth and sixth helices of beta(2)-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective beta(2)-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and beta(2)-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with beta(2)-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by beta(2)-AR antagonists, providing a new avenue for opioid therapy.Peer reviewe