Elsevier

Biological Psychiatry

Volume 83, Issue 8, 15 April 2018, Pages 648-656
Biological Psychiatry

Review
The Mediodorsal Thalamus: An Essential Partner of the Prefrontal Cortex for Cognition

https://doi.org/10.1016/j.biopsych.2017.11.008Get rights and content

Abstract

Deficits in cognition are a core feature of many psychiatric conditions, including schizophrenia, where the severity of such deficits is a strong predictor of long-term outcome. Impairment in cognitive domains such as working memory and behavioral flexibility has typically been associated with prefrontal cortex (PFC) dysfunction. However, there is increasing evidence that the PFC cannot be dissociated from its main thalamic counterpart, the mediodorsal thalamus (MD). Since the causal relationships between MD-PFC abnormalities and cognitive impairment, as well as the neuronal mechanisms underlying them, are difficult to address in humans, animal models have been employed for mechanistic insight. In this review, we discuss anatomical, behavioral, and electrophysiological findings from animal studies that provide a new understanding on how MD-PFC circuits support higher-order cognitive function. We argue that the MD may be required for amplifying and sustaining cortical representations under different behavioral conditions. These findings advance a new framework for the broader involvement of distributed thalamo-frontal circuits in cognition and point to the MD as a potential therapeutic target for improving cognitive deficits in schizophrenia and other disorders.

Section snippets

Anatomy of MD-PFC Circuits

Based on anatomical and functional data, dorsal thalamic nuclei have been categorized into two types (14). First-order thalamic nuclei are characterized by their functional response patterns to sensory stimuli or motor activity, consistent with their close connectivity with the sensory periphery and primary motor pathways. In contrast, higher-order thalamic nuclei receive few or no sensory inputs from the periphery but can be anatomically defined by its driving afferents from the cortex (14).

Thalamo-frontal Circuits and Working Memory: Behavioral and Electrophysiological Studies

Patients with thalamic lesions often exhibit amnesic syndromes similar to those observed in patients with hippocampal lesions, likely due to damage to the mammillothalamic tract or anterior thalamic nucleus 18, 19. However, lesions more circumscribed to the MD have been associated with deficits in executive functions, similar to those deficits observed in patients with frontal lobe dysfunction 19, 20, 21. Unfortunately, patients often exhibit damage to several thalamic areas, thus limiting

The Role of the MD in Behavioral Flexibility

Behavioral flexibility reflects the ability of an individual to respond and adjust to changes in the environment. It can be tested using reversal-learning or set-shifting tasks. Both behaviors require adaptation by switching stimulus-outcome and/or response-outcome associations, yet both have been shown to depend on distinct prefrontal areas. Reversal learning has been linked to lateral OFC function. OFC lesions in primates and rodents 67, 68, 69, 70, 71 generally induce perseveration in

Distinct MD-PFC Circuits for Distinct Cognitive Functions

Overall, work over the past 15 years demonstrates a role for the MD in distinct cognitive behaviors that rely on different prefrontal regions. As such, we described above that in rodents, MD inhibition alters both working memory and reversal learning, functions that are supported by the mPFC and the OFC, respectively. Based on the predominately parallel nature of thalamo-frontal circuits, it may be inferred that OFC function is tightly linked to the central MD (magnocellular MD in monkey),

Relevance for Clinical Research

Numerous studies have found anatomical and/or functional abnormalities in either the thalamus or thalamo-cortical circuits of patients with psychiatric disorders such as major depressive disorder 93, 94, obsessive-compulsive disorder (95), eating disorder (96), posttraumatic stress disorder (97), bipolar disorder and schizophrenia 13, 98. Cognitive dysfunction is a common feature of most if not all psychiatric diseases (99).

In schizophrenia, cognitive symptoms are considered core to the disease

Acknowledgments and Disclosures

This work was supported by the Centre National de Recherche Scientifique (SP), Institut National de la Santé et de la Recherche Médicale (SP), the University Pierre et Marie Curie (SP), LabEx Bio-Psy, and the Agence Nationale pour la Recherche (Grant No. ANR-14-CE35-0029-01 to SP); the National Institute of Mental Health (Grant No. NIMH F31 MH102041 to SSB); and the Irma T. Hirschl Foundation.

The authors report no biomedical financial interests or potential conflicts of interest.

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