Emotion dynamics as hierarchical Bayesian inference in time.

What fundamental property of our environment would be most valuable and optimal in characterizing the emotional dynamics we experience in daily life? Empirical work has shown that an accurate estimation of uncertainty is necessary for our optimal perception, learning, and decision-making. However, the role of this uncertainty in governing our affective dynamics remains unexplored. Using Bayesian encoding, decoding and computational modeling, on a large-scale neuroimaging and behavioral data on a passive movie-watching task, we showed that emotions naturally arise due to ongoing uncertainty estimations about future outcomes in a hierarchical neural architecture. Several prefrontal subregions hierarchically encoded a lower-dimensional signal that highly correlated with the evolving uncertainty. Crucially, the lateral orbitofrontal cortex (lOFC) tracked the temporal fluctuations of this uncertainty and was predictive of the participants' predisposition to anxiety. Furthermore, we observed a distinct functional double-dissociation within OFC with increased connectivity between medial OFC and DMN, while with that of lOFC and FPN in response to the evolving affect. Finally, we uncovered a temporally predictive code updating an individual's beliefs spontaneously with fluctuating outcome uncertainty in the lOFC. A biologically relevant and computationally crucial parameter in the theories of brain function, we propose uncertainty to be central to the definition of complex emotions.

Partial impairment of late-stage autophagic flux in murine splenocytes leads to sqstm1/p62 mediated nrf2-keap1 antioxidant pathway activation and induced proteasome-mediated degradation in malaria.

Splenomegaly, a major symptom in Plasmodium infection, is extensively studied for its immunopathological role in mice malaria model infected with Plasmodium berghei ANKA. The status of autophagic regulation in hosts in malaria pathogenesis remains unreported till date. This study demonstrated the autophagy, proteasomal degradation and NRF2-KEAP1 antioxidant pathway status in the host during Plasmodium infection taking murine spleen as our organ of interest. Initial staining and autophagic gene expression indicate a possibility of autophagic pathway activation. Although the conversion of LC3A to LC3B and lysosome-autophagosome fusion increases, the final degradation step remains incomplete. Resultant upregulation of p62 and its altered phosphorylated status enhances its binding to keap1 causing NRF2 translocation to the nucleus. NRF2 act as transcription factor upregulating p62 level itself leading to an autoinduction loop of p62 expression. Interestingly, enhancement of P62 interaction with proteasome subunit RPT1 indicates a possible role in transporting ubiquitinated cargo to proteasome complex. Ubiquitination level increased with subsequent upregulation of all three modes of proteasomal degradation i.e trypsin-like, caspase-like and especially chymotrypsin-like. Sqstm1/p62 plays a critical central role in regulating autophagy, proteasomal degradation, and NRF2-KEAP1 pathway. The incomplete autophagic flux in the final step may be a key therapeutic target, as autophagic degradation and subsequent pathogenic peptide presentation is of utmost necessity for downstream immune response.