Thalamic circuits for independent control of prefrontal signal and noise.

Interactions between the mediodorsal thalamus and the prefrontal cortex are critical for cognition. Studies in humans indicate that these interactions may resolve uncertainty in decision-making1, but the precise mechanisms are unknown. Here we identify two distinct mediodorsal projections to the prefrontal cortex that have complementary mechanistic roles in decision-making under uncertainty. Specifically, we found that a dopamine receptor (D2)-expressing projection amplifies prefrontal signals when task inputs are sparse and a kainate receptor (GRIK4) expressing-projection suppresses prefrontal noise when task inputs are dense but conflicting. Collectively, our data suggest that there are distinct brain mechanisms for handling uncertainty due to low signals versus uncertainty due to high noise, and provide a mechanistic entry point for correcting decision-making abnormalities in disorders that have a prominent prefrontal component2-6.

A Prelimbic Cortex-Thalamus Circuit Bidirectionally Regulates Innate and Stress-Induced Anxiety-Like Behavior.

Anxiety-related disorders respond to cognitive behavioral therapies, which involved the medial prefrontal cortex (mPFC). Previous studies have suggested that subregions of the mPFC have different and even opposite roles in regulating innate anxiety. However, the specific causal targets of their descending projections in modulating innate anxiety and stress-induced anxiety have yet to be fully elucidated. Here, we found that among the various downstream pathways of the prelimbic cortex (PL), a subregion of the mPFC, PL-mediodorsal thalamic nucleus (MD) projection, and PL-ventral tegmental area (VTA) projection exhibited antagonistic effects on anxiety-like behavior, while the PL-MD projection but not PL-VTA projection was necessary for the animal to guide anxiety-related behavior. In addition, MD-projecting PL neurons bidirectionally regulated remote but not recent fear memory retrieval. Notably, restraint stress induced high-anxiety state accompanied by strengthening the excitatory inputs onto MD-projecting PL neurons, and inhibiting PL-MD pathway rescued the stress-induced anxiety. Our findings reveal that the activity of PL-MD pathway may be an essential factor to maintain certain level of anxiety, and stress increased the excitability of this pathway, leading to inappropriate emotional expression, and suggests that targeting specific PL circuits may aid the development of therapies for the treatment of stress-related disorders.

Neural circuits underlying a psychotherapeutic regimen for fear disorders.

A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting effect of this treatment-described as eye movement desensitization and reprocessing-has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC-MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories.

Identifying the pathways required for coping behaviours associated with sustained pain.

Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example of these responses is the quick withdrawal of one's hand upon touching a hot object. When the first-line response fails to prevent tissue damage (for example, a finger is burnt), the resulting pain invokes a second-line coping response-such as licking the injured area to soothe suffering. However, the underlying neural circuits that drive these two strings of behaviour remain poorly understood. Here we show in mice that spinal neurons marked by coexpression of TAC1Cre and LBX1Flpo drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that-in humans-produce sustained pain, without affecting any of the reflexive defensive reactions that we tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei1-3. Consistently, spinal TAC1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, MRGPRD- and TRPV1-positive nociceptors are required to elicit reflexive and coping responses, respectively. Our study therefore reveals a fundamental subdivision within the cutaneous somatosensory system, and challenges the validity of using reflexive defensive responses to measure sustained pain.

Two contrasting mediodorsal thalamic circuits target the mouse medial prefrontal cortex.

At the heart of the prefrontal network is the mediodorsal (MD) thalamus. Despite the importance of MD in a broad range of behaviors and neuropsychiatric disorders, little is known about the physiology of neurons in MD. We injected the retrograde tracer cholera toxin subunit B (CTB) into the medial prefrontal cortex (mPFC) of adult wild-type mice. We prepared acute brain slices and used current clamp electrophysiology to measure and compare the intrinsic properties of the neurons in MD that project to mPFC (MD→mPFC neurons). We show that MD→mPFC neurons are located predominantly in the medial (MD-M) and lateral (MD-L) subnuclei of MD. MD-L→mPFC neurons had shorter membrane time constants and lower membrane resistance than MD-M→mPFC neurons. Relatively increased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity in MD-L neurons accounted for the difference in membrane resistance. MD-L neurons had a higher rheobase that resulted in less readily generated action potentials compared with MD-M→mPFC neurons. In both cell types, HCN channels supported generation of burst spiking. Increased HCN channel activity in MD-L neurons results in larger after-hyperpolarization potentials compared with MD-M neurons. These data demonstrate that the two populations of MD→mPFC neurons have divergent physiologies and support a differential role in thalamocortical information processing and potentially behavior.NEW & NOTEWORTHY To realize the potential of circuit-based therapies for psychiatric disorders that localize to the prefrontal network, we need to understand the properties of the populations of neurons that make up this network. The mediodorsal (MD) thalamus has garnered attention for its roles in executive functioning and social/emotional behaviors mediated, at least in part, by its projections to the medial prefrontal cortex (mPFC). Here, we identify and compare the physiology of the projection neurons in the two MD subnuclei that provide ascending inputs to mPFC in mice. Differences in intrinsic excitability between the two populations of neurons suggest that neuromodulation strategies targeting the prefrontal thalamocortical network will have differential effects on these two streams of thalamic input to mPFC.

The role of the mediodorsal thalamus in chemosensory preference and consummatory behavior in rats.

Experience plays a pivotal role in determining our food preferences. Consuming food generates odor-taste associations that shape our perceptual judgements of chemosensory stimuli, such as their intensity, familiarity, and pleasantness. The process of making consummatory choices relies on a network of brain regions to integrate and process chemosensory information. The mediodorsal thalamus is a higher-order thalamic nucleus involved in many experience-dependent chemosensory behaviors, including olfactory attention, odor discrimination, and the hedonic perception of flavors. Recent research has shown that neurons in the mediodorsal thalamus represent the sensory and affective properties of experienced odors, tastes, and odor-taste mixtures. However, its role in guiding consummatory choices remains unclear. To investigate the influence of the mediodorsal thalamus in the consummatory choice for experienced odors, tastes, and odor-taste mixtures, we pharmacologically inactivated the mediodorsal thalamus during 2-bottle brief-access tasks. We found that inactivation altered the preference for specific odor-taste mixtures, significantly reduced consumption of the preferred taste and increased within-trial sampling of both chemosensory stimulus options. Our results show that the mediodorsal thalamus plays a crucial role in consummatory decisions related to chemosensory preference and attention.

Electrophysiological and morphological properties of prefrontal pyramidal neurons innervated by mediodorsal thalamus.

The high-order cognitive and executive functions are necessary for an individual to survive. The densely bidirectional innervations between the medial prefrontal cortex (mPFC) and the mediodorsal thalamus (MD) play a vital role in regulating high-order functions. Pyramidal neurons in mPFC have been classified into several subclasses according to their morphological and electrophysiological properties, but the properties of the input-specific pyramidal neurons in mPFC remain poorly understood. The present study aimed to profile the morphological and electrophysiological properties of mPFC pyramidal neurons innervated by MD. In the past, the studies for characterizing the morphological and electrophysiological properties of neurons mainly relied on the electrophysiological recording of a large number of neurons and their morphologic reconstructions. But, it is a low efficient method for characterizing the circuit-specific neurons. The present study combined the advantages of traditional morphological and electrophysiological methods with machine learning to address the shortcomings of the past method, to establish a classification model for the morphological and electrophysiological properties of mPFC pyramidal neurons, and to achieve more accurate and efficient identification of the properties from a small size sample of neurons. We labeled MD-innervated pyramidal neurons of mPFC using the trans-synaptic neural circuitry tracing method and obtained their morphological properties using whole-cell patch-clamp recording and morphologic reconstructions. The results showed that the classification model established in the present study could predict the electrophysiological properties of MD-innervated pyramidal neurons based on their morphology. MD-innervated pyramidal neurons exhibit larger basal dendritic length but lower apical dendrite complexity compared to non-MD-innervated neurons in the mPFC. The morphological characteristics of the two subtypes (ET-1 and ET-2) of mPFC pyramidal neurons innervated by MD are different, with the apical dendrites of ET-1 neurons being longer and more complex than those of ET-2 neurons. These results suggest that the electrophysiological properties of MD- innervated pyramidal neurons within mPFC correlate with their morphological properties, indicating that the different roles of these two subclasses in local circuits within PFC, as well as in PFC-cortical/subcortical brain region circuits.

Organization of primate amygdalar-thalamic pathways for emotions.

Studies on the thalamus have mostly focused on sensory relay nuclei, but the organization of pathways associated with emotions is not well understood. We addressed this issue by testing the hypothesis that the primate amygdala acts, in part, like a sensory structure for the affective import of stimuli and conveys this information to the mediodorsal thalamic nucleus, magnocellular part (MDmc). We found that primate sensory cortices innervate amygdalar sites that project to the MDmc, which projects to the orbitofrontal cortex. As in sensory thalamic systems, large amygdalar terminals innervated excitatory relay and inhibitory neurons in the MDmc that facilitate faithful transmission to the cortex. The amygdala, however, uniquely innervated a few MDmc neurons by surrounding and isolating large segments of their proximal dendrites, as revealed by three-dimensional high-resolution reconstruction. Physiologic studies have shown that large axon terminals are found in pathways issued from motor systems that innervate other brain centers to help distinguish self-initiated from other movements. By analogy, the amygdalar pathway to the MDmc may convey signals forwarded to the orbitofrontal cortex to monitor and update the status of the environment in processes deranged in schizophrenia, resulting in attribution of thoughts and actions to external sources.

The human mediodorsal thalamus: Organization, connectivity, and function.

The human mediodorsal thalamic nucleus (MD) is crucial for higher cognitive functions, while the fine anatomical organization of the MD and the function of each subregion remain elusive. In this study, using high-resolution data provided by the Human Connectome Project, an anatomical connectivity-based method was adopted to unveil the topographic organization of the MD. Four fine-grained subregions were identified in each hemisphere, including the medial (MDm), central (MDc), dorsal (MDd), and lateral (MDl), which recapitulated previous cytoarchitectonic boundaries from histological studies. The subsequent connectivity analysis of the subregions also demonstrated distinct anatomical and functional connectivity patterns, especially with the prefrontal cortex. To further evaluate the function of MD subregions, partial least squares analysis was performed to examine the relationship between different prefrontal-subregion connectivity and behavioral measures in 1012 subjects. The results showed subregion-specific involvement in a range of cognitive functions. Specifically, the MDm predominantly subserved emotional-cognition domains, while the MDl was involved in multiple cognitive functions especially cognitive flexibility and inhibition. The MDc and MDd were correlated with fluid intelligence, processing speed, and emotional cognition. In conclusion, our work provides new insights into the anatomical and functional organization of the MD and highlights the various roles of the prefrontal-thalamic circuitry in human cognition.

Organization of Corollary Discharge Neurons in Monkey Medial Dorsal Thalamus.

A corollary discharge (CD) is a copy of a neuronal command for movement sent to other brain regions to inform them of the impending movement. In monkeys, a circuit from superior colliculus (SC) through medial-dorsal nucleus of the thalamus (MD) to frontal eye field (FEF) carries such a CD for saccadic eye movements. This circuit provides the clearest example of such internal monitoring reaching cerebral cortex. In this report we first investigated the functional organization of the critical MD relay by systematically recording neurons within a grid of penetrations. In two male rhesus macaque monkeys (Macaca mulatta), we found that lateral MD neurons carrying CD signals discharged before saccades to ipsilateral as well as contralateral visual fields instead of just contralateral fields, often had activity over large movement fields, and had activity from both central and peripheral visual fields. Each of these characteristics has been found in FEF, but these findings indicate that these characteristics are already present in the thalamus. These characteristics show that the MD thalamic relay is not passive but instead assembles inputs from the SC before transmission to cortex. We next determined the exact location of the saccade-related CD neurons using the grid of penetrations. The neurons occupy an anterior-posterior band at the lateral edge of MD, and we established this band in stereotaxic coordinates to facilitate future study of CD neurons. These observations reveal both the organizational features of the internal CD signals within the thalamus, and the location of the thalamic relay for those signals.SIGNIFICANCE STATEMENT A corollary discharge (CD) circuit within the brain keeps an internal record of physical movements. In monkeys and humans, one such CD keeps track of rapid eye movements, and in monkeys, a circuit carrying this CD extends from midbrain to cerebral cortex through a relay in the thalamus. This circuit provides guidance for eye movements, contributes to stable visual perception, and when defective, might be related to difficulties that schizophrenic patients have in recognizing their own movements. This report facilitates the comparison of the circuit in monkeys and humans, particularly for comparison of the location of the thalamic relay in monkeys and in humans.

Mediodorsal Thalamus Contributes to the Timing of Instrumental Actions.

The perception of time is critical to adaptive behavior. While prefrontal cortex and basal ganglia have been implicated in interval timing in the seconds to minutes range, little is known about the role of the mediodorsal thalamus (MD), which is a key component of the limbic cortico-basal ganglia-thalamocortical loop. In this study, we tested the role of the MD in timing, using an operant temporal production task in male mice. In this task, that the expected timing of available rewards is indicated by lever pressing. Inactivation of the MD with muscimol produced rightward shifts in peak pressing on probe trials as well as increases in peak spread, thus significantly altering both temporal accuracy and precision. Optogenetic inhibition of glutamatergic projection neurons in the MD also resulted in similar changes in timing. The observed effects were found to be independent of significant changes in movement. Our findings suggest that the MD is a critical component of the neural circuit for interval timing, without playing a direct role in regulating ongoing performance.SIGNIFICANCE STATEMENT The mediodorsal nucleus (MD) of the thalamus is strongly connected with the prefrontal cortex and basal ganglia, areas which have been implicated in interval timing. Previous work has shown that the MD contributes to working memory and learning of action-outcome contingencies, but its role in behavioral timing is poorly understood. Using an operant temporal production task, we showed that inactivation of the MD significantly impaired timing behavior.

Thalamic-Medial Temporal Lobe Connectivity Underpins Familiarity Memory.

The neural basis of memory is highly distributed, but the thalamus is known to play a particularly critical role. However, exactly how the different thalamic nuclei contribute to different kinds of memory is unclear. Moreover, whether thalamic connectivity with the medial temporal lobe (MTL), arguably the most fundamental memory structure, is critical for memory remains unknown. We explore these questions using an fMRI recognition memory paradigm that taps familiarity and recollection (i.e., the two types of memory that support recognition) for objects, faces, and scenes. We show that the mediodorsal thalamus (MDt) plays a material-general role in familiarity, while the anterior thalamus plays a material-general role in recollection. Material-specific regions were found for scene familiarity (ventral posteromedial and pulvinar thalamic nuclei) and face familiarity (left ventrolateral thalamus). Critically, increased functional connectivity between the MDt and the parahippocampal (PHC) and perirhinal cortices (PRC) of the MTL underpinned increases in reported familiarity confidence. These findings suggest that familiarity signals are generated through the dynamic interaction of functionally connected MTL-thalamic structures.

Roles of the medial prefrontal cortex, mediodorsal thalamus, and their combined circuit for performance of the odor span task in rats: analysis of memory capacity and foraging behavior.

Working memory (WM), the capacity for short-term storage of small quantities of information for immediate use, is thought to depend on activity within the prefrontal cortex. Recent evidence indicates that the prefrontal neuronal activity supporting WM is driven by thalamocortical connections arising in mediodorsal thalamus (mdThal). However, the role of these connections has not been studied using olfactory stimuli leaving open the question of whether this circuit extends to all sensory modalities. Additionally, manipulations of the mdThal in olfactory memory tasks have yielded mixed results. In the present experiment, we investigated the role of connections between the rat medial prefrontal cortex (mPFC) and mdThal in the odor span task (OST) using a pharmacological contralateral disconnection technique. Inactivation of either the mPFC or mdThal alone both significantly impaired memory performance in the OST, replicating previous findings with the mPFC and confirming that the mdThal plays an essential role in intact OST performance. Contralateral disconnection of the two structures impaired OST performance in support of the idea that the OST relies on mPFC-mdThal connections, but ipsilateral control infusions also impaired performance, complicating this interpretation. We also performed a detailed analysis of rats' errors and foraging behavior and found a dissociation between mPFC and mdThal inactivation conditions. Inactivation of the mdThal and mPFC caused a significant reduction in the number of approaches rats made per odor, whereas only mdThal inactivation or mPFC-mdThal disconnection caused significant increases in choice latency. Our results confirm that the mdThal is necessary for performance of the OST and that it may critically interact with the mPFC to mediate OST performance. Additionally, we have provided evidence that the mPFC and mdThal play dissociable roles in mediating foraging behavior.

Occurrence of Hippocampal Ripples is Associated with Activity Suppression in the Mediodorsal Thalamic Nucleus.

Forming reliable memories requires coordinated activity within distributed brain networks. At present, neural mechanisms underlying systems-level consolidation of declarative memory beyond the hippocampal-prefrontal interactions remain largely unexplored. The mediodorsal thalamic nucleus (MD) is reciprocally connected with the medial prefrontal cortex (mPFC) and also receives inputs from parahippocampal regions. The MD may thus modulate functional connectivity between the hippocampus and the mPFC at different stages of information processing. Here, we characterized, in freely behaving Sprague Dawley male rats, the MD neural activity around hippocampal ripples, indicators of memory replay and hippocampal-cortical information transfer. Overall, the MD firing rate was transiently (0.76 ± 0.06 s) decreased around ripples, with the MD activity suppression preceding the ripple onset for 0.41 ± 0.04 s (range, 0.01-0.95 s). The degree of MD modulation correlated with ripple amplitude, differed across behavioral states, and also depended on the dynamics of hippocampal-cortical population activity. The MD suppression was the strongest and the most consistent during awake ripples. During non-rapid eye movement sleep, MD firing rate decreased around spindle-uncoupled ripples, but increased around spindle-coupled ripples. Our results suggest a competitive interaction between the thalamocortical and hippocampal-cortical networks supporting "on-line" and "off-line" information processing, respectively. We hypothesize that thalamic activity suppression during spindle-uncoupled ripples is favorable for memory replay, as it reduces interference from sensory relay. In turn, the thalamic input during hippocampal-cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer. Both predictions need to be tested in future experiments.SIGNIFICANCE STATEMENT Systems mechanisms of declarative memory consolidation beyond the hippocampal-prefrontal interactions remain largely unexplored. The connectivity of the mediodorsal thalamic nucleus (MD) with extrahippocampal regions and with medial prefrontal cortex underlies its role in execution of diverse cognitive functions. However, little is known about the MD involvement in "off-line" consolidation. We found that MD neural activity was transiently suppressed around hippocampal ripples, except for ripples co-occurring with sleep spindles, when the MD activity was elevated. The thalamic activity suppression at times of spindle-uncoupled ripples may be favorable for memory replay, as it reduces interference with sensory relay. In turn, the thalamic input during hippocampal-cortical communication, as indicated by spindle/ripple coupling, may contribute to selectivity and reliability of information transfer.

Medial Auditory Thalamus Is Necessary for Expression of Auditory Trace Eyelid Conditioning.

Transforming a brief sensory event into a persistent neural response represents a mechanism for linking temporally disparate stimuli together to support learning. The cerebellum requires this type of persistent input during trace conditioning to engage associative plasticity and acquire adaptively timed conditioned responses (CRs). An initial step toward identifying the sites and mechanisms generating and transmitting persistent signals to the cerebellum is to identify the input pathway. The medial auditory thalamic nuclei (MATN) are the necessary and sufficient source of auditory input to the cerebellum for delay conditioning in rodents and a possible input to forebrain sites generating persistent signals. Using pharmacological and computational approaches, we test (1) whether the necessity of MATN during auditory eyelid conditioning is conserved across species, (2) whether the MATN are necessary for the expression of trace eyelid CRs, and if so, (3)whether this relates to the generation of persistent signals. We find that contralateral inactivation of MATN with muscimol largely abolished trace and delay CRs in male rabbits. Residual CRs were decreased in amplitude, but CR timing was unaffected. Results from large-scale cerebellar simulations are consistent with previous experimental demonstrations that silencing only CS-duration inputs does not abolish trace CRs, and instead affects their timing. Together, these results suggest that the MATN are a necessary component of both the direct auditory stimulus pathway to the cerebellum and the pathway generating task-essential persistent signals.SIGNIFICANCE STATEMENT Persistent activity is required for working memory-dependent tasks, such as trace conditioning, and represents a mechanism by which sensory information can be used over time for learning and cognition. This neuronal response entails the transformation of a discrete sensory-evoked response into a signal that extends beyond the stimulus event. Understanding the generation and transmission of this stimulus transformation requires identifying the input sources necessary for task-essential persistent signals. We report that the medial auditory thalamic nuclei are required for the expression of auditory trace conditioning and suggest that these nuclei are a component of the pathway-generating persistent signals. Our study provides a foundation for testing circuit-level mechanisms underlying persistent activity in a cerebellar learning model with identified inputs and well defined behavioral outputs.

Roles of Prefrontal Cortex and Mediodorsal Thalamus in Task Engagement and Behavioral Flexibility.

Behavioral tasks involving auditory cues activate inhibitory neurons within auditory cortex, leading to a reduction in the amplitude of auditory evoked response potentials (ERPs). One hypothesis is that this process, termed "task engagement," may enable context-dependent behaviors. Here we set out to determine (1) whether the medial prefrontal cortex (mPFC) plays a role in task engagement and (2) how task engagement relates to the context-dependent processing of auditory cues in male and female mice performing a decision-making task that can be guided by either auditory or visual cues. We found that, in addition to auditory ERP suppression, task engagement is associated with increased mPFC activity and an increase in theta band (4-7 Hz) synchronization between the mPFC and auditory cortex. Optogenetically inhibiting the mPFC eliminates the task engagement-induced auditory ERP suppression, while also preventing mice from switching between auditory and visual cue-based rules. However, mPFC inhibition, which eliminates task engagement-induced auditory ERP suppression, did not prevent mice from making decisions based on auditory cues. Furthermore, a more specific manipulation, selective disruption of mPFC outputs to the mediodorsal (MD) thalamus, is sufficient to prevent switching between auditory and visual rules but does not affect auditory ERPs. Based on these findings, we conclude that (1) the mPFC contributes to both task engagement and behavioral flexibility; (2) mPFC-MD projections are important for behavioral flexibility but not task engagement; and (3) task engagement, evidenced by the suppression of cortical responses to sensory input, is not required for sensory cue-guided decision making.SIGNIFICANCE STATEMENT When rodents perform choice-selection tasks based on sensory cues, neural responses to these cues are modulated compared with task-free conditions. Here we demonstrate that this phenomenon depends on the prefrontal cortex and thus represents a form of "top-down" regulation. However, we also show that this phenomenon is not critical for task performance, as rodents can make decisions based on specific sensory cues even when the task-dependent modulation of responses to those cues is abolished. Furthermore, disrupting one specific set of prefrontal outputs impairs rule switching but not the task-dependent modulation of sensory responses. These results show that the prefrontal cortex comprises multiple circuits that mediate dissociable functions related to behavioral flexibility and sensory processing.

Topographic organization of connections between prefrontal cortex and mediodorsal thalamus: Evidence for a general principle of indirect thalamic pathways between directly connected cortical areas.

Our ability to act flexibly, according to goals and context, is known as cognitive control. Hierarchical levels of control, reflecting different levels of abstraction, are represented across prefrontal cortex (PFC). Although the mediodorsal thalamic nucleus (MD) is extensively interconnected with PFC, the role of MD in cognitive control is unclear. Tract tracer studies in macaques, involving subsets of PFC areas, have converged on coarse MD-PFC connectivity principles; but proposed finer-grained topographic schemes, which constrain interactions between MD and PFC, disagree in many respects. To investigate a unifying topographic scheme, we performed probabilistic tractography on diffusion MRI data from eight macaque monkeys, and estimated the probable paths connecting MD with each of all 19 architectonic areas of PFC. We found a connectional topography where the orderly progression from ventromedial to anterior to posterolateral PFC was represented from anteromedial to posterolateral MD. The projection zones of posterolateral PFC areas in MD showed substantial overlap, and those of ventral and anteromedial PFC areas in MD overlapped. The exception was cingulate area 24: its projection zone overlapped with projections zones of all other PFC areas. Overall, our data suggest that nearby, functionally related, directly connected PFC areas have partially overlapping projection zones in MD, consistent with a role for MD in coordinating communication across PFC. Indeed, the organizing principle for PFC projection zones in MD appears to reflect the flow of information across the hierarchical, multi-level PFC architecture. In addition, cingulate area 24 may have privileged access to influence thalamocortical interactions involving all other PFC areas.

Macaque parvocellular mediodorsal thalamus: dissociable contributions to learning and adaptive decision-making.

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.

Determining the Neural Substrate for Encoding a Memory of Human Pain and the Influence of Anxiety.

To convert a painful stimulus into a briefly maintainable construct when the painful stimulus is no longer accessible is essential to guide human behavior and avoid dangerous situations. Because of the aversive nature of pain, this encoding process might be influenced by emotional aspects and could thus vary across individuals, but we have yet to understand both the basic underlying neural mechanisms as well as potential interindividual differences. Using fMRI in combination with a delayed-discrimination task in healthy volunteers of both sexes, we discovered that brain regions involved in this working memory encoding process were dissociable according to whether the to-be-remembered stimulus was painful or not, with the medial thalamus and the rostral anterior cingulate cortex encoding painful and the primary somatosensory cortex encoding nonpainful stimuli. Encoding of painful stimuli furthermore significantly enhanced functional connectivity between the thalamus and medial prefrontal cortex (mPFC). With regards to emotional aspects influencing encoding processes, we observed that more anxious participants showed significant performance advantages when encoding painful stimuli. Importantly, only during the encoding of pain, the interindividual differences in anxiety were associated with the strength of coupling between medial thalamus and mPFC, which was furthermore related to activity in the amygdala. These results indicate not only that there is a distinct signature for the encoding of a painful experience in humans, but also that this encoding process involves a strong affective component.SIGNIFICANCE STATEMENT To convert the sensation of pain into a briefly maintainable construct is essential to guide human behavior and avoid dangerous situations. Although this working memory encoding process is implicitly contained in the majority of studies, the underlying neural mechanisms remain unclear. Using fMRI in a delayed-discrimination task, we found that the encoding of pain engaged the activation of the medial thalamus and the functional connectivity between the thalamus and medial prefrontal cortex. These fMRI data were directly and indirectly related to participants' self-reported trait and state anxiety. Our findings indicate that the mechanisms responsible for the encoding of noxious stimuli differ from those for the encoding of innocuous stimuli, and that these mechanisms are shaped by an individual's anxiety levels.

Causal Evidence from Humans for the Role of Mediodorsal Nucleus of the Thalamus in Working Memory.

The mediodorsal nucleus of the thalamus (MD), with its extensive connections to the lateral pFC, has been implicated in human working memory and executive functions. However, this understanding is based solely on indirect evidence from human lesion and imaging studies and animal studies. Direct, causal evidence from humans is missing. To obtain direct evidence for MD's role in humans, we studied patients treated with deep brain stimulation (DBS) for refractory epilepsy. This treatment is thought to prevent the generalization of a seizure by disrupting the functioning of the patient's anterior nuclei of the thalamus (ANT) with high-frequency electric stimulation. This structure is located superior and anterior to MD, and when the DBS lead is implanted in ANT, tip contacts of the lead typically penetrate through ANT into the adjoining MD. To study the role of MD in human executive functions and working memory, we periodically disrupted and recovered MD's function with high-frequency electric stimulation using DBS contacts reaching MD while participants performed a cognitive task engaging several aspects of executive functions. We hypothesized that the efficacy of executive functions, specifically working memory, is impaired when the functioning of MD is perturbed by high-frequency stimulation. Eight participants treated with ANT-DBS for refractory epilepsy performed a computer-based test of executive functions while DBS was repeatedly switched ON and OFF at MD and at the control location (ANT). In comparison to stimulation of the control location, when MD was stimulated, participants committed 2.26 times more errors in general (total errors; OR = 2.26, 95% CI [1.69, 3.01]) and 2.86 times more working memory-related errors specifically (incorrect button presses; OR = 2.88, CI [1.95, 4.24]). Similarly, participants committed 1.81 more errors in general ( OR = 1.81, CI [1.45, 2.24]) and 2.08 times more working memory-related errors ( OR = 2.08, CI [1.57, 2.75]) in comparison to no stimulation condition. "Total errors" is a composite score consisting of basic error types and was mostly driven by working memory-related errors. The facts that MD and a control location, ANT, are only few millimeters away from each other and that their stimulation produces very different results highlight the location-specific effect of DBS rather than regionally unspecific general effect. In conclusion, disrupting and recovering MD's function with high-frequency electric stimulation modulated participants' online working memory performance providing causal, in vivo evidence from humans for the role of MD in human working memory.