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1. Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models

   https://doi.org/10.1186/s13229-022-00492-8  

   Klibaite, Ugne ; Kislin, Mikhail ; Verpeut, Jessica L. ; Bergeler, Silke ; Sun, Xiaoting ; Shaevitz, Joshua W. ; Wang, Samuel S. -H. ( March 2022 , Molecular Autism)

   Repetitive action, resistance to environmental change and fine motor disruptions are hallmarks of autism spectrum disorder (ASD) and other neurodevelopmental disorders, and vary considerably from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we observed male and female C57BL/6J mice to methodically catalog adaptive movement over multiple days and examined two rodent models of developmental disorders against this dynamic baseline. We then investigated the behavioral consequences of a cerebellum-specific deletion in Tsc1 protein and a whole-brain knockout in Cntnap2 protein in mice. Both of these mutations are found in clinical conditions and have been associated with ASD.

   We used advances in computer vision and deep learning, namely a generalized form of high-dimensional statistical analysis, to develop a framework for characterizing mouse movement on multiple timescales using a single popular behavioral assay, the open-field test. The pipeline takes virtual markers from pose estimation to find behavior clusters and generate wavelet signatures of behavior classes. We measured spatial and temporal habituation to a new environment across minutes and days, different types of self-grooming, locomotion and gait.

   Both Cntnap2 knockouts and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants and Cntnap2 knockouts showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure to adapt took the form of maintained ambling, turning and locomotion, and an overall decrease in grooming. However, adaptation in these traits was similar between wild-type mice and Cntnap2 knockouts. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy.

   Genetic risk factors for autism are numerous, and we tested only two. Our pipeline was only done under conditions of free behavior. Testing under task or social conditions would reveal more information about behavioral dynamics and variability.

   Our automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics. The reported deficits indicate that deep phenotyping constitutes a robust set of ASD symptoms that may be considered for implementation in clinical settings as quantitative diagnosis criteria.

    

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2. Sources of predictive information in dynamical neural networks

   https://doi.org/10.1038/s41598-020-73380-x  

   Candadai, Madhavun ; Izquierdo, Eduardo J. ( December 2020 , Scientific Reports)

   null (Ed.)

   Abstract Behavior involves the ongoing interaction between an organism and its environment. One of the prevailing theories of adaptive behavior is that organisms are constantly making predictions about their future environmental stimuli. However, how they acquire that predictive information is still poorly understood. Two complementary mechanisms have been proposed: predictions are generated from an agent’s internal model of the world or predictions are extracted directly from the environmental stimulus. In this work, we demonstrate that predictive information, measured using bivariate mutual information, cannot distinguish between these two kinds of systems. Furthermore, we show that predictive information cannot distinguish between organisms that are adapted to their environments and random dynamical systems exposed to the same environment. To understand the role of predictive information in adaptive behavior, we need to be able to identify where it is generated. To do this, we decompose information transfer across the different components of the organism-environment system and track the flow of information in the system over time. To validate the proposed framework, we examined it on a set of computational models of idealized agent-environment systems. Analysis of the systems revealed three key insights. First, predictive information, when sourced from the environment, can be reflected in any agent irrespective of its ability to perform a task. Second, predictive information, when sourced from the nervous system, requires special dynamics acquired during the process of adapting to the environment. Third, the magnitude of predictive information in a system can be different for the same task if the environmental structure changes. 

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3. Epigenetic tuning of brain signal entropy in emergent human social behavior

   https://doi.org/10.1186/s12916-020-01683-x  

   Puglia, Meghan H. ; Krol, Kathleen M. ; Missana, Manuela ; Williams, Cabell L. ; Lillard, Travis S. ; Morris, James P. ; Connelly, Jessica J. ; Grossmann, Tobias ( December 2020 , BMC Medicine)

   null (Ed.)

   Abstract Background How the brain develops accurate models of the external world and generates appropriate behavioral responses is a vital question of widespread multidisciplinary interest. It is increasingly understood that brain signal variability—posited to enhance perception, facilitate flexible cognitive representations, and improve behavioral outcomes—plays an important role in neural and cognitive development. The ability to perceive, interpret, and respond to complex and dynamic social information is particularly critical for the development of adaptive learning and behavior. Social perception relies on oxytocin-regulated neural networks that emerge early in development. Methods We tested the hypothesis that individual differences in the endogenous oxytocinergic system early in life may influence social behavioral outcomes by regulating variability in brain signaling during social perception. In study 1, 55 infants provided a saliva sample at 5 months of age for analysis of individual differences in the oxytocinergic system and underwent electroencephalography (EEG) while listening to human vocalizations at 8 months of age for the assessment of brain signal variability. Infant behavior was assessed via parental report. In study 2, 60 infants provided a saliva sample and underwent EEG while viewing faces and objects and listening to human speech and water sounds at 4 months of age. Infant behavior was assessed via parental report and eye tracking. Results We show in two independent infant samples that increased brain signal entropy during social perception is in part explained by an epigenetic modification to the oxytocin receptor gene ( OXTR ) and accounts for significant individual differences in social behavior in the first year of life. These results are measure-, context-, and modality-specific: entropy, not standard deviation, links OXTR methylation and infant behavior; entropy evoked during social perception specifically explains social behavior only; and only entropy evoked during social auditory perception predicts infant vocalization behavior. Conclusions Demonstrating these associations in infancy is critical for elucidating the neurobiological mechanisms accounting for individual differences in cognition and behavior relevant to neurodevelopmental disorders. Our results suggest that an epigenetic modification to the oxytocin receptor gene and brain signal entropy are useful indicators of social development and may hold potential diagnostic, therapeutic, and prognostic value. 

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4. Distributed Neural Systems Support Flexible Attention Updating during Category Learning

   https://doi.org/10.1162/jocn_a_01882  

   Weichart, Emily R. ; Evans, Daniel G. ; Galdo, Matthew ; Bahg, Giwon ; Turner, Brandon M. ( January 2022 , Journal of Cognitive Neuroscience)

   Abstract To accurately categorize items, humans learn to selectively attend to the stimulus dimensions that are most relevant to the task. Models of category learning describe how attention changes across trials as labeled stimuli are progressively observed. The Adaptive Attention Representation Model (AARM), for example, provides an account in which categorization decisions are based on the perceptual similarity of a new stimulus to stored exemplars, and dimension-wise attention is updated on every trial in the direction of a feedback-based error gradient. As such, attention modulation as described by AARM requires interactions among processes of orienting, visual perception, memory retrieval, prediction error, and goal maintenance to facilitate learning. The current study explored the neural bases of attention mechanisms using quantitative predictions from AARM to analyze behavioral and fMRI data collected while participants learned novel categories. Generalized linear model analyses revealed patterns of BOLD activation in the parietal cortex (orienting), visual cortex (perception), medial temporal lobe (memory retrieval), basal ganglia (prediction error), and pFC (goal maintenance) that covaried with the magnitude of model-predicted attentional tuning. Results are consistent with AARM's specification of attention modulation as a dynamic property of distributed cognitive systems. 

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5. The eyes reflect an internal cognitive state hidden in the population activity of cortical neurons

   https://doi.org/10.1093/cercor/bhab418  

   Johnston, Richard ; Snyder, Adam C ; Khanna, Sanjeev B ; Issar, Deepa ; Smith, Matthew A ( December 2021 , Cerebral Cortex)

   Abstract Decades of research have shown that global brain states such as arousal can be indexed by measuring the properties of the eyes. The spiking responses of neurons throughout the brain have been associated with the pupil, small fixational saccades, and vigor in eye movements, but it has been difficult to isolate how internal states affect the eyes, and vice versa. While recording from populations of neurons in the visual and prefrontal cortex (PFC), we recently identified a latent dimension of neural activity called “slow drift,” which appears to reflect a shift in a global brain state. Here, we asked if slow drift is correlated with the action of the eyes in distinct behavioral tasks. We recorded from visual cortex (V4) while monkeys performed a change detection task, and PFC, while they performed a memory-guided saccade task. In both tasks, slow drift was associated with the size of the pupil and the microsaccade rate, two external indicators of the internal state of the animal. These results show that metrics related to the action of the eyes are associated with a dominant and task-independent mode of neural activity that can be accessed in the population activity of neurons across the cortex. 

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