Differential Roles of Mediodorsal Nucleus of the Thalamus and Prefrontal Cortex in Decision-Making and State Representation in a Cognitive Control Task Measuring Deficits in Schizophrenia

Abstract

The mediodorsal nucleus of the thalamus (MD) is reciprocally connected with the prefrontal cortex (PFC), and although the MD has been implicated in a range of PFC-dependent cognitive functions (Watanabe and Funahashi, 2012; Mitchell and Chakraborty, 2013; Parnaudeau et al., 2018), little is known about how MD neurons in the primate participate specifically in cognitive control, a capability that reflects the ability to use contextual information (such as a rule) to modify responses to environmental stimuli. To learn how the MD-PFC thalamocortical network is engaged to mediate forms of cognitive control that are selectively disrupted in schizophrenia, we trained male monkeys to perform a variant of the AX continuous performance task, which reliably measures cognitive control deficits in patients (Henderson et al., 2012) and used linear multielectrode arrays to record neural activity in the MD and PFC simultaneously. We found that the two structures made clearly different contributions to distributed processing for cognitive control: MD neurons were specialized for decision-making and response selection, whereas prefrontal neurons were specialized to preferentially encode the environmental state on which the decision was based. In addition, we observed that functional coupling between MD and PFC was strongest when the decision as to which of the two responses in the task to execute was being made. These findings delineate unique contributions of MD and PFC to distributed processing for cognitive control and characterized neural dynamics in this network associated with normative cognitive control performance.

Mediodorsal Thalamus and Prefrontal Cortex: Specialized Partners in Cognitive Control

“…MD neurons also provide excitation to GABAergic fast-spiking (FS) interneurons to suppress cue-selective neurons in PFC that represent the irrelevant context (Schmitt et al, 2017;Rikhye et al, 2018). These data lend support to the conclusion in the study by DeNicola et al (2020) that the PFC provides important state information within the DPX task and raises the question of whether MD helps PFC represent the relevant internal state (or suppress distracting or irrelevant state information) through the recruitment of local FS interneurons in primates, a mechanism previously characterized in rodents (Delevich et al, 2015;Ferguson and Gao, 2018b).…”

“…However, little was known about how the activity of neurons in both structures regulates cognitive control. DeNicola et al (2020) recently investigated this question.…”

Prefrontal Cortex Development in Health and Disease: Lessons from Rodents and Humans

“…It is thus tempting to hypothesize that the early thalamic innervation of prefrontal layers contributes to the development of the supragranular layers. Despite the critical role of prefrontal-thalamic communication for executive functions in adult mice [87,88], and the fact that in humans prefrontal-thalamic communication is disrupted in young adults carrying a 22q11.2 deletion [77], lesions of the rodent MD in the first postnatal weeks lead to only mild cognitive impairment [86]. More thorough functional investigations of this pathway throughout development are necessary.…”

Stable thalamocortical learning between medial-dorsal thalamus and cortical attractor networks captures cognitive flexibility

“…We can apply our method to animal model of schizophrenia and see whether we can understand the reason for loss of performance when an animal model of schizophrenia is engaged in various tasks [55]. Generally, it is claimed that the way schizophrenia animal got malfunction is due to the reduction in strength of the thalamo-cortical connectivity [56,57].…”