Orlandi, J. G. | bioRxiv Science

bioRxiv2021

Deficiency of the ywhaz gene, involved in neurodevelopmental disorders, alters brain activity and behaviour in zebrafish

Genetic variants in YWHAZ contribute to psychiatric disorders such as autism spectrum disorder and schizophrenia, and have been related to an impaired neurodevelopment in humans and mice. Here, we used zebrafish to further understand the mechanisms by which YWHAZ contributes to neurodevelopmental disorders. We observed that ywhaz expression was panneuronal during developmental stages and restricted to Purkinje cells in the adult cerebellum, cells that are described to be reduced in number in autistic patients. We then performed whole-brain imaging in wild-type and ywhaz CRISPR/Cas9 knockout (KO) larvae and found altered neuronal activity and connectivity in the hindbrain. Adult ywhaz KO fish display decreased levels of monoamines in the hindbrain and freeze when exposed to novel stimuli, a phenotype that can be reversed with drugs that target monoamine neurotransmission. These findings suggest an important role for ywhaz in establishing neuronal connectivity during development and modulating both neurotransmission and behaviour in adults.

neuroscience↗

bioRxiv2021

Distributed context-dependent choice information in mouse dorsal-parietal cortex

Choice information appears in the brain as distributed signals with top-down and bottom-up components that together support decision-making computations. In sensory and associative cortical regions, the presence of choice signals, their strength, and area specificity are known to be elusive and changeable, limiting a cohesive understanding of their computational significance. In this study, examining the mesoscale activity in mouse posterior cortex during a complex visual discrimination task, we found that broadly distributed choice signals defined a decision variable in a low-dimensional embedding space of multi-area activations, particularly along the ventral visual stream. The subspace they defined was near-orthogonal to concurrently represented sensory and motor-related activations, and it was modulated by task difficulty and contextually by the animals attention state. To mechanistically relate choice representations to decision-making computations, we trained recurrent neural networks with the animals choices and found an equivalent decision variable whose context-dependent dynamics agreed with that of the neural data. In conclusion, our results demonstrated an independent decision variable broadly represented in the posterior cortex, controlled by task features and cognitive demands. Its dynamics reflected decision computations, possibly linked to context-dependent feedback signals used for probabilistic-inference computations in variable animal-environment interactions.

neuroscience↗