Rhythmic interactions between the mediodorsal thalamus and prefrontal cortex precede human visual perception

The thalamus is much more than a simple sensory relay. High-order thalamic nuclei, such as the mediodorsal thalamus, exert a profound influence over animal cognition. However, given the difficulty of directly recording from the thalamus in humans, next-to-nothing is known about thalamic and thalamocortical contributions to human cognition. To address this, we analysed simultaneously-recorded thalamic iEEG and whole-head MEG in six patients (four female, two male; plus MEG recordings from twelve healthy controls) as they completed a visual detection task. We observed that the phase of both ongoing mediodorsal thalamic and prefrontal low-frequency activity was predictive of perceptual performance. Critically however, mediodorsal thalamic activity mediated prefrontal contributions to perceptual performance. These results suggest that it is thalamocortical interactions, rather than cortical activity alone, that is predictive of upcoming perceptual performance and, more generally, highlights the importance of accounting for the thalamus when theorising about cortical contributions to human cognition

The mediodorsal thalamus as a higher order thalamic relay nucleus important for learning and decision-making

AbstractRecent evidence from monkey models of cognition shows that the magnocellular subdivision of the mediodorsal thalamus (MDmc) is more critical for learning new information than for retention of previously acquired information. Further, consistent evidence in animal models shows the mediodorsal thalamus (MD) contributes to adaptive decision-making. It is assumed that prefrontal cortex (PFC) and medial temporal lobes govern these cognitive processes so this evidence suggests that MD contributes a role in these cognitive processes too. Anatomically, the MD has extensive excitatory cortico-thalamo-cortical connections, especially with the PFC. MD also receives modulatory inputs from forebrain, midbrain and brainstem regions. It is suggested that the MD is a higher order thalamic relay of the PFC due to the dual cortico-thalamic inputs from layer V (‘driver’ inputs capable of transmitting a message) and layer VI (‘modulator’ inputs) of the PFC. Thus, the MD thalamic relay may support the transfer of information across the PFC via this indirect thalamic route. This review summarizes the current knowledge about the anatomy of MD as a higher order thalamic relay. It also reviews behavioral and electrophysiological studies in animals to consider how MD might support the transfer of information across the cortex during learning and decision-making. Current evidence suggests the MD is particularly important during rapid trial-by-trial associative learning and decision-making paradigms that involve multiple cognitive processes. Further studies need to consider the influence of the MD higher order relay to advance our knowledge about how the cortex processes higher order cognition

Cognitive Functions and Neurodevelopmental Disorders Involving the Prefrontal Cortex and Mediodorsal Thalamus

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

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

「何を買うんだっけ」と「どれにしよう」を処理する2つの脳回路を明らかに --霊長類の生体脳で神経経路を可視化・操作する技術で解明、高次脳機能の理解へ大きく前進--. 京都大学プレスリリース. 2021-06-24.The primate prefrontal cortex (PFC) is situated at the core of higher brain functions via neural circuits such as those linking the caudate nucleus and mediodorsal thalamus. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from dorsolateral part of the PFC (dlPFC) to the dorsal caudate (dCD) and lateral mediodorsal thalamus (MDl) individually in single monkeys. We found that silencing the bilateral dlPFC-MDl projections, but not the dlPFC-dCD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral dlPFC-dCD projection, but not the unilateral dlPFC-MDl projection, altered preference in a decision-making task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates

Long-range synchrony between medial prefrontal cortex, thalamus and hippocampus underlies working memory behavior in mice.

Presently, there are no antipsychotic drugs capable of treating the cognitive dysfunctions of schizophrenia. In order to inform the development of better therapies, it is essential to understand the mechanism behind dysfunctional cognition, which requires an understanding of functional cognition. Spatial working memory, a measure of cognitive function, can be assessed in the mouse using a task of delayed alternation: the T-maze. In this thesis, I focus on spatial working memory behavior in the mouse and three brain regions that are implicated in this behavior: the medial prefrontal cortex (mPFC), the hippocampus (HPC) and the medial dorsal thalamus (MD). Lesion and electrophysiological studies in each structure have demonstrated their importance during working memory behavior. Disconnection studies also show that the coordination between the mPFC and either the HPC or MD is important for the behavior, but little is known about the mechanism by which they coordinate. The MD and the ventral region of the hippocampus (vHPC) have robust projections into the mPFC. They are therefore in a good position to influence mPFC activity. Previous reports show that the mPFC and the dorsal region of the hippocampus (dHPC) synchronize activity in the theta range (4-12 Hz) with working memory demand. However, the dHPC does not directly connect with the mPFC so it is unclear how this coordination occurs. We hypothesized that the vHPC may also be involved in spatial working memory behavior and that it may mediate the dHPC-mPFC theta synchrony observed. To test these hypotheses, we recorded neural activity simultaneously from the mPFC, dHPC and vHPC in mice performing the T-maze task. Local field potential oscillations (LFPs), thought to be a measure of synchronized synaptic activity, were obtained from each area. We observed an increase in theta synchrony between the mPFC and both the dHPC and vHPC. Removing the influence of vHPC both analytically and experimentally, we found a decrease in synchrony of the dHPC-mPFC.Aside from the disconnection studies, little is known about the MD-mPFC pathway in rodents. However, due to evidence from schizophrenia patients of altered correlation specifically between the MD and PFC, we hypothesized that an electrophysiological correlate of working memory exists in the MD-mPFC pathway as well and that a decrease in MD activity may lead to prefrontal dysfunction. To test these hypotheses, we recorded LFPs from the mPFC and both single unit activity and LFPs from the MD in mice performing the T-maze task. We observed an increase in phase locking of MD cells to mPFC LFPs in beta (13-30Hz) range during the choice phase of the task. We then utilized a pharmacogenetic technique to decrease firing rate in a small portion of MD cells, which resulted in a deficit in both task acquisition and performance. The increase in MD-mPFC beta phase locking we had observed was not present in MD-inactivated animals. Interestingly, beta coherence between the two structures across learning was highly correlated with choice accuracy on the task. This suggests that MD-PFC coordination is predictive of working memory performance.These findings illustrate how long-range synchrony of the mPFC with HPC in the theta frequency range and with the MD in the beta frequency range may be important markers for normal working memory behavior and if disrupted in humans, could contribute to the cognitive symptoms of schizophrenia

Affective and cognitive prefrontal cortex projections to the lateral habenula in humans

Anterior insula (AI) and dACC are known to process information about pain, loss, adversities, bad, harmful or suboptimal choices and consequences that threaten survival or well-being. Pain and loss activate also pregenual ACC (pgACC), linked to sad thoughts, hurt and regrets. The lateral habenula (LHb) is stimulated by predicted and received pain, discomfort, aversive outcome, loss. Its chronic stimulation makes us feel worse/low and gradually stops us choosing and moving for suboptimal, hurtful or punished choices, by direct and indirect (via RMTg) inhibition of DRN and VTA/SNc. Response selectivity of LHb neurons suggests their cortical input from affective and cognitive evaluative regions that make expectations about bad or suboptimal outcomes. Based on these facts I predicted direct corticohabenular projections from the dACC, pgACC and AI, as part of the adversity processing circuit that learns to avoid bad outcomes by suppressing dopamine and serotonin signal. Using DTI I found dACC, pgACC, AI, adjacent caudolateral and lateral OFC projections to LHb. I predicted no corticohabenular projections from the reward processing regions: medial OFC and vACC because both respond most strongly to good, high value stimuli and outcomes, inducing serotonin and dopamine release respectively. This lack of LHb projections was confirmed for vACC and likely for mOFC. The surprising findings were the corticohabenular projections from the cognitive prefrontal cortex regions, known for flexible reasoning, planning and combining whatever information are relevant for reaching current goals. I propose that prefrontohabenular projections provide a teaching signal for value-based choice behaviour, to learn to deselect, avoid or inhibit the potentially harmful, low valued or wrong choices, goals, strategies, predictions, models and ways of doing things, to prevent bad or suboptimal consequences.Comment: I renamed the medioventral part of the anterior thalamus via which the PFC to LHb fibre tracts from ventral anterior (AV) to medial anterior thalamic region. Apologies for that. My co-author decided to remove his nam

Cortico-thalamocortical interactions for learning, memory and decision-making

This is the final version. Available on open access from Wiley via the DOI in this recordThe thalamus and cortex are interconnected both functionally and anatomically and share a common developmental trajectory. Interactions between the mediodorsal thalamus (MD) and different parts of the prefrontal cortex are essential in cognitive processes, such as learning and adaptive decision-making. Cortico-thalamocortical interactions involving other dorsal thalamic nuclei, including the anterior thalamus and pulvinar, also influence these cognitive processes. Our work, and that of others, indicates a crucial influence of these interdependent cortico-thalamocortical neural networks that contributes actively to the processing of information within the cortex. Each of these thalamic nuclei also receives potent subcortical inputs that are likely to provide additional influences on their regulation of cortical activity. Here, we highlight our current neuroscientific research aimed at establishing when cortico-MD thalamocortical neural network communication is vital within the context of a rapid learning and memory discrimination task. We are collecting evidence of MD-prefrontal cortex neural network communication in awake, behaving male rhesus macaques. Given the prevailing evidence, further studies are needed to identify both broad and specific mechanisms that govern how the MD, anterior thalamus and pulvinar cortico-thalamocortical interactions support learning, memory and decision-making. Current evidence shows that the MD (and the anterior thalamus) are crucial for frontotemporal communication, and the pulvinar is crucial for frontoparietal communication. Such work is crucial to advance our understanding of the neuroanatomical and physiological bases of these brain functions in humans. In turn, this might offer avenues to develop effective treatment strategies to improve the cognitive deficits often observed in many debilitating neurological disorders and diseases and in neurodegeneration.Wellcome Trus

An examination of the effects of thalamic lesions on learning and memory in the rat

The study examined the effects of lesions of the thalamic nucleus medialis dorsalis (MD) made by neurotoxin in three cohorts ofrats to help understand the contribution of this nucleus to learning and memory. The lesions typically provided comprehensive damage to . MD, while the use of an excitotoxin helped to minimise damage to fibres of passage or adjacent fibre tracts. This excluded one confounding influence that may have been present in some previous studies. Some MD lesions also affected the anterior thalamic nuclei, and this additional damage led to spatial memory impairments, helping to confirm the value of results from rats with lesions confined to MD. Whilst the groups with MD lesions were largely unimpaired on non-spatial tests of visual recognition and discrimination, they were impaired on a configural discrimination task. The MD lesions did not impair spatial nonmatching to sample in aT-maze, nor the acquisition or performance over delay conditions of the standard radial maze task. There were impairments, however, when the radial maze was rotated during the delay, requiring a strategy shift. Similar impairment was found when a matching, rather than non-matching, strategy was required on the T-maze task and also when only some arms were rewarded on the radial arm maze task for reference memory measurement. No impairment was seen when the T-maze matching task was reversed to the non-matching variant, emphasising the lesion rats' preference for preexisting rules. In addition, some evidence was found that MD lesions brought about increased activity, but had no effect on conditioned place preference. The study concludes that MD damage in rats does not directly cause memory deficits. The influence that MD damage has on memory is, however, similar to that associated with damage to prefrontal cortex causing deficits in rule-switching ability, a higher order frontal lobe function

The Cognitive Thalamus as a gateway to mental representations

Historically, the thalamus has been viewed as little more than a relay, simply transferring information to key players of the cast, the cortex and hippocampus, without providing any unique functional contribution. In recent years, evidence from multiple laboratories researching different thalamic nuclei has contradicted this idea of the thalamus as a passive structure. Dated models of thalamic functions are being pushed aside, revealing a greater and far more complex contribution of the thalamus for cognition. In this Viewpoint, we show how recent data support novel views of thalamic functions that emphasize integrative roles in cognition, ranging from learning and memory to flexible adaption. We propose that these apparently separate cognitive functions may, in fact, be supported by a more general role in shaping mental representations. Several features of thalamocortical circuits are consistent with this suggested role and we highlight how divergent and convergent thalamocortical and corticothalamic pathways may complement each other to support these functions. Furthermore, the role of the thalamus for subcortical integration is highlighted as a key mechanism for maintaining and updating representations. Finally, we discuss future areas of research and stress the importance of incorporating new experimental findings into existing knowledge to continue developing thalamic models. The presence of thalamic pathology in a number of neurological conditions reinforces the need to better understand the role of this region in cognition