The mediodorsal nucleus of the thalamus (MD) has been implicated in executive functions (such as planning, cognitive control, working memory, and decision-making) because of its significant interconnectivity with the prefrontal cortex (PFC). Yet, whilst the roles of the PFC have been extensively studied, how the MD contributes to these cognitive functions remains relatively unclear. Recently, causal evidence in monkeys has demonstrated that in everyday tasks involving rapid updating (e.g., while learning something new, making decisions, or planning the next move), the MD and frontal cortex are working in close partnership. Furthermore, researchers studying the MD in rodents have been able to probe the underlying mechanisms of this relationship to give greater insights into how the frontal cortex and MD might interact during the performance of these essential tasks. This review summarizes the circuitry and known neuromodulators of the MD, and considers the most recent behavioral, cognitive, and neurophysiological studies conducted in monkeys and rodents; in total, this evidence demonstrates that MD makes a critical contribution to cognitive functions. We propose that communication occurs between the MD and the frontal cortex in an ongoing, fluid manner during rapid cognitive operations, via the means of efference copies of messages passed through transthalamic routes; the conductance of these messages may be modulated by other brain structures interconnected to the MD. This is similar to the way in which other thalamic structures have been suggested to carry out forward modeling associated with rapid motor responding and visual processing. Given this, and the marked thalamic pathophysiology now identified in many neuropsychiatric disorders, we suggest that changes in the different subdivisions of the MD and their interconnections with the cortex could plausibly give rise to a number of the otherwise disparate symptoms (including changes to olfaction and cognitive functioning) that are associated with many different neuropsychiatric disorders. In particular, we will focus here on the cognitive symptoms of schizophrenia and suggest testable hypotheses about how changes to MD-frontal cortex interactions may affect cognitive processes in this disorder.

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HighlightsEarly insult of the mediodorsal thalamus (MD) disturbed cognitive behaviors.Early MD damage decreased locomotor activity, and reduced social interactions.Early insult of the MD disturbed postnatal maturation of affective behavior.The MD is important for prefrontal cortex function during brain maturation.

Distributed brain networks govern adaptive decision-making, new learning and rapid updating of information. However, the functional contribution of the rhesus macaque monkey parvocellular nucleus of the mediodorsal thalamus (MDpc) in these key higher cognitive processes remains unknown. This study investigated the impact of MDpc damage in cognition. Preoperatively, animals were trained on an object-in-place scene discrimination task that assesses rapid learning of novel information within each session. Bilateral neurotoxic (NMDA and ibotenic acid) MDpc lesions did not impair new learning unless the monkey had also sustained damage to the magnocellular division of the MD (MDmc). Contralateral unilateral MDpc and MDmc damage also impaired new learning, while selective unilateral MDmc damage produced new learning deficits that eventually resolved with repeated testing. In contrast, during food reward (satiety) devaluation, monkeys with either bilateral MDpc damage or combined MDpc and MDmc damage showed attenuated food reward preferences compared to unoperated control monkeys; the selective unilateral MDmc damage left performance intact. Our preliminary results demonstrate selective dissociable roles for the two adjacent nuclei of the primate MD, namely, MDpc, as part of a frontal cortical network, and the MDmc, as part of a frontal-temporal cortical network, in learning, memory and the cognitive control of behavioural choices after changes in reward value. Moreover, the functional cognitive deficits produced after differing MD damage show that the different subdivisions of the MD thalamus support distributed neural networks to rapidly and fluidly incorporate task-relevant information, in order to optimise the animals' ability to receive rewards.

Early postnatal damage to the mediodorsal thalamus (MD) produces deficits in cognition and behavior believed to be associated with early prefrontal cortical maldevelopment. We assessed the role of MD afferents during development on the morphological and functional maturation of the prefrontal cortex (PFC) and the basolateral amygdala (BLA). Sprague-Dawley rat pups (n = 56) received a bilateral electrolytic lesion of the MD or a MD Sham lesion on postnatal day 4. 7 weeks later, all rats were tested in anxiety-related and cognitive paradigms using the elevated plus maze and novel object recognition tests. Following behavioral testing (P70), rats were killed and the baseline expression of C-Fos protein and the number of GABAergic neurons were evaluated in the PFC and the BLA. The dendritic morphology and spine density in the PFC using Golgi-Cox staining was also evaluated. Adult rats with early postnatal bilateral MD damage exhibited disrupted recognition memory and increased anxiety-like behaviors. The lesion also caused a significant diminution of C-Fos immunolabeling and an increase of the number of GABAergic neurons in the PFC. In the BLA, the number of GABAergic neurons was significantly reduced, associated with an increase in C-Fos immunolabeling. Furthermore, in the PFC the lesion induced a significant reduction in dendritic branching and spine density. Our data are consistent with the hypothesis that the MD plays a role in the development of the PFC and, therefore, may be a good animal model to investigate cognitive symptoms associated with schizophrenia.