Halassa Lab

Project 1

Cross-Species Interrogation of Thalamocortical Substrates for Hierarchical Reasoning and their Perturbations in Schizophrenia

Cognitive deficits are a prominent and debilitating feature of schizophrenia and remain largely resistant to current treatments in part because the circuit mechanisms that underlie these impairments are still poorly understood.  Progress has also been limited by marked patient heterogeneity and by the difficulty of developing tractable tasks that can isolate individual computations and link them back to their underlying neural substrates.  These challenges underscore the need for novel cross-species frameworks that can bridge clinically relevant behavioral variation in humans with mechanistically precise circuit perturbations in animals.  To address this, we developed a cross-species decision-making task in humans and animals, together with a computational model to dissect the latent processes that support hierarchical reasoning.

Using this framework, we aim to trace behavioral impairments in patients to specific algorithmic deficits, and then link those same algorithmic signatures to thalamocortical circuit-level perturbations in mice.  This work is motivated by converging evidence that interactions between the mediodorsal thalamus and prefrontal cortex support reasoning under uncertainty and that dysfunction in this same circuit is linked to executive deficits in schizophrenia (Mukherjee et al. 2021, Huang et al. 2024, Lam et al. 2025). By pairing computational phenotyping with task-engaged fMRI in humans and optogenetic inactivation in mice, we aim to identify the specific neural networks and circuits responsible for implementing these computations.  This translational cross-species framework provides a path toward identifying mechanistically grounded subtypes of cognitive impairment and ultimately toward more precise, subtype-informed treatment strategies in schizophrenia.  This work is done in collaboration with Neil Woodward’s group at Vanderbilt University.

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