Computational Core

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Project summary The aim of Core B is to provide an adequately detailed biophysical model of thalamocortical interactions to allow the model to guide experiments of the Thalamus Conte Center, especially Projects P1-P3. The Center is proposing to understand the function of higher-order thalamus in tasks involving attention and decision making, particularly when there are uncertainties in sensory input or context. The Center hypothesis is that higher-order thalamic nuclei in the primate brain, particularly the mediodorsal nucleus (MD) and the pulvinar (PUL), play a fundamental role in integrating and gating cortical activity and coordinating information flow across large-scale cortical networks. Indeed, we propose that an understanding of the functioning of cortical cognitive networks in the primate brain is not possible without understanding the interactions of cortex and thalamus. The experiments to be done in P1-P3 involve non-human primates and tree shrews in a way that will constrain circuit models of both dynamics and function. In addition, the group will also investigate animal models of schizophrenia (SZ) (P3). In both the normal and SZ animal models, the experimentalist will gather information about brain rhythms and spike timing need for the model. Our model will also be informed by network data from healthy humans (P4) and Schizophrenia patients (P5). The computational model to be constructed in core B will use the detailed physiological framework of Hodgkin-Huxley equations, constrained by currently available and future data. The model will be built with multiple modules, each with multiple cell types, each producing multiple kinds of dynamics that can themselves change rhythmically on a slow time scale. Each of these modules can change with effects of neuromodulation, and the functional connections among them are also subject to modulation. Such a complex model needs to be highly constrained, and we will make use of a novel methodology in which each module is constrained by known physiology plus the multiple dynamical behaviors that it must produce with different inputs. The anatomy of the model is partly motivated by earlier work with Kastner explaining the roles of multiple brain rhythms in a spatial attention task and showing that those frequencies are functionally important. Indeed, the current work, in which the tasks require us to consider similarly complex interactions, raises the very general and important question: Is such biological complexity important for function, and in what ways? We hypothesize that the known complex rhythms are essential to function; in the proposed work of Core B, we aim to spell out in what ways those dynamics are important in the context of tasks requiring attention, decision making and rule changing. In Aim 1, we investigate the effects of cortical dynamics on pulvinar and MD. In Aim 2, we consider the changes in dynamics when there is uncertainty about which is the cue and there is switching in the rule. In Aim3, in the context of schizophrenia, we consider how dysfunctions in thalamic rhythms and in inhibitory function can lead to cognitive deficits, using the work of Aims 1 and 2. This work is expected to contribute to answers to the question of why the higher order thalamus is needed for cognition.