Active Inference, Novelty and Neglect

In this chapter, we provide an overview of the principles of active inference. We illustrate how different forms of short-term memory are expressed formally (mathematically) through appealing to beliefs about the causes of our sensations and about the actions we pursue. This is used to motivate an approach to active vision that depends upon inferences about the causes of 'what I have seen' and learning about 'what I would see if I were to look there'. The former could manifest as persistent 'delay-period' activity - of the sort associated with working memory, while the latter is better suited to changes in synaptic efficacy - of the sort that underlies short-term learning and adaptation. We review formulations of these ideas in terms of active inference, their role in directing visual exploration and the consequences - for active vision - of their failures. To illustrate the latter, we draw upon some of our recent work on the computational anatomy of visual neglect

Characterization of the impact of proteins linked to neurodegenerative diseases in the yeast Saccharomyces cerevisiae

Our society will have to face an estimated of about 65 million cases of dementia in 2030 and 115 million cases by the year 2050. Alzheimer's Disease represents the majority of these cases. Despite tremendous efforts of the research community to unravel the disease mechanisms, there is still a lack of insight in disease pathogenesis. This disorder is substantially heterogeneous, both at the level of genetics as well as at the level of clinical and neuropathological presentation. The aim of this thesis was to investigate the impact of proteins involved in neurodegenerative diseases, especially Aβ, α-Synuclein and tau, on cellular processes. Neurodegenerative Diseases, such as Alzheimer's, or Parkinson's disease, are complex, multifactorial pathologies. Over the last decades, large efforts have been made to pinpoint the causative mechanisms and to develop effective treatments against these diseases. However, these aims have not been reached yet, and although progress has been made in understanding some aspects of the disease onset and progression, the underlying mechanisms of Alzheimer's and Parkinson's disease are still not known, and there are no potent treatments available today. To shed light on these issues, firstly, a yeast model was created to study the impact of Aβ on biochemical pathways and intracellular organelles. By making use of clinical as well as synthetic Aβ mutants, not only previous reports that Aβ acts on mitochondria to induce cellular stress could be confirmed, but it could be also demonstrated that it impairs vesicular trafficking and membrane repair events. The Endosomal Sorting Complex Required for Transport (ESCRT) factor Bro1 was identified to be crucial for this process. Furthermore, toxic Aβ species disturb the lipid metabolism and lead to the aggregation of the endoplasmic reticulum. In collaboration with Roel Van Assche, who expressed Aβ and tau in C. elegans, and subsequently performed metabolomics, the kynurenine pathway has been identified as a potential link to Aβ-toxicity. The kynurenine-factor Bna1 seems to play a crucial role in mediating Aβ-toxicity and modulating synergistic effects between Aβ and tau or α-Synuclein in yeast. Previous studies suggest, that the microtubule-binding K18-domain of tau has a propensity to aggregate. Here, we modulated, optimized, and characterized yeast-based prion-detection systems for further investigation of the aggregation and prion propensities of the K18-domain.status: publishe

Nocturnal asthma. Beta 2-adrenoceptors on peripheral mononuclear leukocytes, cAMP- and cortisol-plasma concentrations

To evaluate pathophysiologic mechanisms of the predominantly nocturnal complaints in atopic bronchial asthma, the expression and function of beta 2-adrenoceptors on peripheral mononuclear leukocytes (pMNL), the cAMP--as well as the cortisol--plasma concentrations were studied in eight healthy men and ten so far untreated male asthmatic patients at 4-h intervals for 24 h. No difference was seen in the beta 2-adrenoceptor density (Bmax) on pMNL between healthy and asthmatic men (24-h means +/- SE: 908 +/- 59 sites per cell and 821 +/- 54 sites per cell, respectively). The equilibrium dissociation constant (Kd), however, was significantly higher in the asthmatic patients (24-h mean +/- SE: 8.8 +/- 1.2 pmol/L vs 3.0 +/- 0.2 pmol/L in healthy men, p less than 0.0001), which is equivalent to a lower affinity of the beta 2-adrenoceptors for the radioligand 125iodocyanopindolol. Bmax showed a statistically significant circadian variation, but Kd did not. The circadian variation in Bmax was reflected in the basal intracellular cyclic adenosine-monophosphate (cAMP) content of the cells investigated. High Kd values (equivalent to low receptor affinities) tended to be associated with small increases of the intracellular cAMP content after in vitro stimulation by 10(-7) mol/L isoprenaline (isoproterenol) (24-h mean +/- SE: 1.4 +/- 0.2 pmol/10(6) cells; r = -0.529, p = 0.05 at r = -0.549, n = 10). Plasma cAMP concentrations were found to be significantly lower in the asthmatic patients (24-h means +/- SE: 22.9 +/- 1.3 nmol/L vs 29.1 +/- 1.1 nmol/L, p less than 0.0001). Plasma cortisol concentrations were significantly higher in the asthmatic patients (24-h means +/- SE: 0.500 +/- 0.084 mumol/L vs 0.319 +/- 0.063 mumol/L). The results support the hypothesis that a lesion of the beta-adrenergic system contributes to the pathophysiology of atopic bronchial asthma. In the patients investigated in this study, such a lesion could be demonstrated in the affinity rather than in the number of beta 2-adrenoceptors expressed on peripheral cells of the immune system (pMNL). According to present-day knowledge of adrenergic effects on pMNL, such an affinity decrease of beta 2-adrenoceptors could account for overshooting immune responses. In association with other factors influencing respiratory function, it could be responsible for the predominantly nocturnal complaints in atopic bronchial asthma. Plasma cortisol concentrations did not appear to be related to the principal cause of "nocturnal asthma;" they rather reflected an endogenous defense mechanism to the disease