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Despite remarkable progress in understanding the fundamental bases of itching, its cortical mechanisms remain poorly understood. Herein, the causal contributions of defined anterior cingulate cortex (ACC) neuronal populations to acute itch modulation in mice are established. Using cell type‐specific manipulations, the opposing functions of ACC glutamatergic and GABAergic neurons in regulating acute itching are demonstrated. Photometry studies indicated that ACC glutamatergic neurons are activated during scratching induced by both histamine and chloroquine, whereas the activation pattern of GABAergic neurons is complicated by GABAergic subpopulations and acute itch modalities. By combining cell type‐ and projection‐specific techniques, a thalamocortical circuit is further identified from the mediodorsal thalamus driving the itch‐scratching cycle related to histaminergic and non‐histaminergic itching, which is contingent on the activation of postsynaptic parvalbumin‐expressing neurons in the ACC. These findings reveal a cellular and circuit signature of ACC neurons orchestrating behavioral responses to itching and may provide insights into therapies for itch‐related diseases. [ABSTRACT FROM AUTHOR]

Reinforcement learning (RL), particularly in primates, is often driven by symbolic outcomes. However, it is usually studied with primary reinforcers. To examine the neural mechanisms underlying learning from symbolic outcomes, we trained monkeys on a task in which they learned to choose options that led to gains of tokens and avoid choosing options that led to losses of tokens. We then recorded simultaneously from the orbitofrontal cortex (OFC), ventral striatum (VS), amygdala (AMY), and mediodorsal thalamus (MDt). We found that the OFC played a dominant role in coding token outcomes and token prediction errors. The other areas contributed complementary functions, with the VS coding appetitive outcomes and the AMY coding the salience of outcomes. The MDt coded actions and relayed information about tokens between the OFC and VS. Thus, the OFC leads the processing of symbolic RL in the ventral frontostriatal circuitry. [Display omitted] • OFC played a dominant role in coding primary and symbolic reinforcement signals • VS showed a strong bias for encoding appetitive choices and outcomes • AMY encoded outcome salience and encoded primary and symbolic reinforcers similarly • MDt relayed the flow of token update information between the OFC and VS Tang et al. show that OFC plays a more important role in learning from symbolic reinforcers than subcortical structures. OFC computes reinforcement signals and sends the information to the VS through MDt. AMY also participates in the process by encoding the salience of gains and losses of tokens. [ABSTRACT FROM AUTHOR]

Abstract Despite remarkable progress in understanding the fundamental bases of itching, its cortical mechanisms remain poorly understood. Herein, the causal contributions of defined anterior cingulate cortex (ACC) neuronal populations to acute itch modulation in mice are established. Using cell type‐specific manipulations, the opposing functions of ACC glutamatergic and GABAergic neurons in regulating acute itching are demonstrated. Photometry studies indicated that ACC glutamatergic neurons are activated during scratching induced by both histamine and chloroquine, whereas the activation pattern of GABAergic neurons is complicated by GABAergic subpopulations and acute itch modalities. By combining cell type‐ and projection‐specific techniques, a thalamocortical circuit is further identified from the mediodorsal thalamus driving the itch‐scratching cycle related to histaminergic and non‐histaminergic itching, which is contingent on the activation of postsynaptic parvalbumin‐expressing neurons in the ACC. These findings reveal a cellular and circuit signature of ACC neurons orchestrating behavioral responses to itching and may provide insights into therapies for itch‐related diseases.

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. [ABSTRACT FROM AUTHOR]

Impaired extinction of fear memory is one of the most common symptoms in post‐traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD‐ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle‐based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD‐related impaired extinction of fear memory and provide therapeutic insights into Kv3.2‐targeted RNA therapy for PTSD. [ABSTRACT FROM AUTHOR]

Sleep spindles are major oscillatory components of Non‐Rapid Eye Movement (NREM) sleep, reflecting hyperpolarization‐rebound sequences of thalamocortical neurons. Reports suggest a link between sleep spindles and several forms of high‐frequency oscillations which are considered as expressions of pathological off‐line neural plasticity in the central nervous system. Here we investigated the relationship between thalamic sleep spindles and ripples in the anterior and mediodorsal nuclei (ANT and MD) of epilepsy patients. Whole‐night LFP from the ANT and MD were co‐registered with scalp EEG/polysomnography by using externalized leads in 15 epilepsy patients undergoing a Deep Brain Stimulation protocol. Slow (~12 Hz) and fast (~14 Hz) sleep spindles were present in the human ANT and MD and roughly, 20% of them were associated with ripples. Ripple‐associated thalamic sleep spindles were characterized by longer duration and exceeded pure spindles in terms of spindle power as indicated by time‐frequency analysis. Furthermore, ripple amplitude was modulated by the phase of sleep spindles within both thalamic nuclei. No signs of pathological processes were correlated with measures of ripple and spindle association, furthermore, the density of ripple‐associated sleep spindles in the ANT showed a positive correlation with verbal comprehension. Our findings indicate the involvement of the human thalamus in coalescent spindle‐ripple oscillations of NREM sleep. Significance Statement: Thalamo‐cortical loops are associated with sensory processing, memory formation and executive functions, many of which are tightly related to sleep state‐dependent neural oscillations, such as sleep spindles. It was proposed that sleep‐related epileptic transformation of normal neurological networks interferes with sleep‐related synaptic homeostasis, neural plasticity and cognitive functioning. We had a unique opportunity to investigate the association between thalamic sleep spindles and ripples, and their associations with intellectual ability within two higher‐order thalamic nuclei in human subjects, the anterior thalamic and mediodorsal thalamic nuclei. Our findings indicate the involvement of the human thalamus in sleep‐spindle‐related activity. [ABSTRACT FROM AUTHOR]

Background: Working memory deficits in Alzheimer's disease (AD) are linked to impairments in the retrieval of stored memory information. However, research on the mechanism of impaired working memory retrieval in Alzheimer's disease is still lacking. Objective: The medial prefrontal cortex (mPFC) and mediodorsal thalamus (MD) are involved in memory retrieval. The purpose of this study is to investigate the functional interactions and information transmission between mPFC and MD in the AD model. Methods: We recorded local field potentials from mPFC and MD while the mice (APP/PS1 transgenic model and control) performed a T-maze spatial working memory task. The temporal dynamics of oscillatory activity and bidirectional information flow between mPFC and MD were assessed during the task phases. Results: We mainly found a significant decrease in theta flow from mPFC to MD in APP/PS1 mice during retrieval. Conclusions: Our results indicate an important role of the mPFC-MD input for retrieval and the disrupted information transfer from mPFC to MD may be the underlying mechanism of working memory deficits in APP/PS1 mice. [ABSTRACT FROM AUTHOR]

Abstract Impaired extinction of fear memory is one of the most common symptoms in post‐traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD‐ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle‐based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD‐related impaired extinction of fear memory and provide therapeutic insights into Kv3.2‐targeted RNA therapy for PTSD.

Central histamine (HA) signaling modulates diverse cortical and subcortical circuits throughout the brain, including the nucleus accumbens (NAc). The NAc, a key striatal subregion directing reward-related behavior, expresses diverse HA receptor subtypes that elicit cellular and synaptic plasticity. However, the neuromodulatory capacity of HA within interneuron microcircuits in the NAc remains unknown. We combined electrophysiology, pharmacology, voltammetry, and optogenetics in male transgenic reporter mice to determine how HA influences microcircuit motifs controlled by parvalbumin-expressing fast-spiking interneurons (PV-INs) and tonically active cholinergic interneurons (CINs) in the NAc shell. HA enhanced CIN output through an H 2 receptor (H 2 R)–dependent effector pathway requiring Ca2+-activated small-conductance K+ channels, with a small but discernible contribution from H 1 Rs and synaptic H 3 Rs. While PV-IN excitability was unaffected by HA, presynaptic H 3 Rs decreased feedforward drive onto PV-INs via AC-cAMP-PKA (adenylyl cyclase–cyclic adenosine monophosphate–protein kinase A) signaling. H 3 R-dependent plasticity was differentially expressed at mediodorsal thalamus and prefrontal cortex synapses onto PV-INs, with mediodorsal thalamus synapses undergoing HA-induced long-term depression. These effects triggered downstream shifts in PV-IN- and CIN-controlled microcircuits, including near-complete collapse of mediodorsal thalamus–evoked feedforward inhibition and increased mesoaccumbens dopamine release. HA targets H 1 R, H 2 R, and H 3 Rs in the NAc shell to engage synapse- and cell type–specific mechanisms that bidirectionally regulate PV-IN and CIN microcircuit activity. These findings extend the current conceptual framework of HA signaling and offer critical insight into the modulatory potential of HA in the brain. [ABSTRACT FROM AUTHOR]

Fear learning is mediated by a large network of brain structures and the understanding of their roles and interactions is constantly progressing. There is a multitude of anatomical and behavioral evidence on the interconnection of the cerebellar nuclei to other structures in the fear network. Regarding the cerebellar nuclei, we focus on the coupling of the cerebellar fastigial nucleus to the fear network and the relation of the cerebellar dentate nucleus to the ventral tegmental area. Many of the fear network structures that receive direct projections from the cerebellar nuclei are playing a role in fear expression or in fear learning and fear extinction learning. We propose that the cerebellum, via its projections to the limbic system, acts as a modulator of fear learning and extinction learning, using prediction-error signaling and regulation of fear related thalamo-cortical oscillations. [ABSTRACT FROM AUTHOR]

Fear learning is mediated by a large network of brain structures and the understanding of their roles and interactions is constantly progressing. There is a multitude of anatomical and behavioral evidence on the interconnection of the cerebellar nuclei to other structures in the fear network. Regarding the cerebellar nuclei, we focus on the coupling of the cerebellar fastigial nucleus to the fear network and the relation of the cerebellar dentate nucleus to the ventral tegmental area. Many of the fear network structures that receive direct projections from the cerebellar nuclei are playing a role in fear expression or in fear learning and fear extinction learning. We propose that the cerebellum, via its projections to the limbic system, acts as a modulator of fear learning and extinction learning, using prediction-error signaling and regulation of fear related thalamo-cortical oscillations.

The reciprocal interaction between pain and negative affect is acknowledged but pain‐related alterations in brain circuits involved in this interaction, such as the mediodorsal thalamus (MDThal), still require a better understanding. We sought to investigate the relationship between MDThal circuitry, negative affect and pain severity in chronic musculoskeletal pain. For these analyses, participants with chronic knee pain (CKP, n = 74) and without (n = 36) completed magnetic resonance imaging scans and questionnaires. Seed‐based MDThal functional connectivity (FC) was compared between groups. Within CKP group, we assessed the interdependence of MDThal FC with negative affect. Finally, post hoc moderation analysis explored whether burden of pain influences affect‐related MDThal FC. The CKP group showed altered MDThal FC to hippocampus, ventromedial prefrontal cortex and subgenual anterior cingulate. Furthermore, in CKP group, MDThal connectivity correlated significantly with negative affect in several brain regions, most notably the medial prefrontal cortex, and this association was stronger with increasing pain burden and absent in pain‐free controls. In conclusion, we demonstrate mediodorsal thalamo‐cortical dysconnectivity in chronic pain with areas linked to mood disorders and associations of MDThal FC with negative affect. Moreover, burden of pain seems to enhance affect sensitivity of MDThal FC. These findings suggest mediodorsal thalamic network changes as possible drivers of the detrimental interplay between chronic pain and negative affect. [ABSTRACT FROM AUTHOR]

The 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. [ABSTRACT FROM AUTHOR]

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.

Background: Post-operative delirium (POD), a common post-operative complication that aects up to 73. 5% of surgical patients, could prolong hospital stays, triple mortality rates, cause long-term cognitive decline and dementia, and boost medical expenses. However, the underlying mechanisms, especially the circuit mechanisms of POD remain largely unclear. Previous studies demonstrated that cannabis use might cause delirium-like behavior through the endocannabinoid system (eCBs), a widely distributed retrograde presynaptic neuromodulator system. We also found that the prelimbic (PrL) and intralimbic (IL) prefrontal cortex, a crucial hub for cognition and emotion, was involved in the eCBs-associated general anesthesia recovery. Objectives: The present study aimed to investigate the role of eCBs in POD development, and further clarify its neuronal specificity and circuit specificity attributed to POD. Methods: According to a previous study, 2 h of 1.4% isoflurane anesthesia and simple laparotomy were conducted to establish the POD model in C57/BL6 mice aged 8–12 weeks. A battery of behavioral tests, including the buried food, open field, and Y maze tests, were performed at 24 h before anesthesia and surgery (AS) and 6 and 9 h after AS. The behavioral results were calculated as a composite Z score for the POD assessment. To explore the dynamics of eCBs and their eect on POD regulation, an endocannabinoid (eCB) sensor was microinjected into the PrL, and the antagonists (AM281 and hemopressin) and agonist (nabilone) of type 1 cannabinoid receptor (CB1R), were administered systemically or locally (into PrL). Chemogenetics, combined Cre-loxP and Flp-FRT system, were employed in mutant mice for neuronal specificity and circuit specificity observation. Results: After AS, the composite Z score significantly increased at 6 and 9 but not at 24 h, whereas blockade of CB1R systemically and intra-PrL could specifically decrease the composite Z score at 6 and 9 h after AS. Results of fiber photometry further confirmed that the activity of eCB in the PrL was enhanced by AS, especially in the Y maze test at 6 h post-operatively. Moreove the activation of glutamatergic neurons in the PrL could reduce the composite Z score, which could be significantly reversed by exogenous cannabinoid (nabilone) at 6 and 9 h post-operatively. However, activation of GABAergic neurons only decreased composite Z score at 9 h post-operatively, with no response to nabilone application. Further study revealed the glutamatergic projection from mediodorsal thalamus (MD) to PrL glutamatergic neurons, but not hippocampus (HIP)-PrL circuit, was in charge of the eect of eCBs on POD. Conclusion: Our study firstly demonstrated the involvement of eCBs in the POD pathogenesis and further revealed that the eCBs may regulate POD through the specific MDglu-PrLglu circuit. These findings not only partly revealed the molecular and circuit mechanisms of POD, but also provided an applicable candidate for the clinical prevention and treatment of POD. [ABSTRACT FROM AUTHOR]

The mediodorsal thalamus is a multimodal region involved in a variety of cognitive behaviors, including olfactory attention, odor discrimination, and the hedonic perception of flavors. Although the mediodorsal thalamus forms connections with principal regions of the olfactory and gustatory networks, its role in processing olfactory and gustatory signals originating from the mouth remains unclear. Here, we recorded single-unit activity in the mediodorsal thalamus of behaving female rats during the intraoral delivery of individual odors, individual tastes, and odor-taste mixtures. Our results are the first to demonstrate that neurons in the mediodorsal thalamus dynamically encode chemosensory signals originating from the mouth. This chemoselective population is broadly tuned, exhibits excited and suppressed responses, and responds to odor-taste mixtures differently than an odor or taste alone. Furthermore, a subset of chemoselective neurons encodes the palatability-related features of tastes and may represent associations between previously experienced odor-taste pairs. Our results further demonstrate the multidimensionality of the mediodorsal thalamus and provide additional evidence of its involvement in processing chemosensory information important for ingestive behaviors. [ABSTRACT FROM AUTHOR]

Executive dysfunction is a prominent feature of schizophrenia and may drive core symptoms. Dorsolateral prefrontal cortex (dlPFC) deficits have been linked to schizophrenia executive dysfunction, but mechanistic details critical for treatment development remain unclear. Here, capitalizing on recent animal circuit studies, we develop a task predicted to engage human dlPFC and its interactions with the mediodorsal thalamus (MD). We find that individuals with schizophrenia exhibit selective performance deficits when attention is guided by conflicting cues. Task performance correlates with lateralized MD-dlPFC functional connectivity, identifying a neural readout that predicts susceptibility to conflict during working memory in a larger independent schizophrenia cohort. In healthy subjects performing a probabilistic reversal task, this MD-dlPFC network predicts switching behavior. Overall, our three independent experiments introduce putative biomarkers for executive function in schizophrenia and highlight animal circuit studies as inspiration for the development of clinically relevant readouts., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Predictive learning can engage a selective form of cognitive control that biases choice between actions based on information about future outcomes that the learning provides. This influence has been hypothesized to depend on a feedback circuit in the brain through which the basal ganglia modulate activity in the prefrontal cortex; however, direct evidence for this functional circuit has proven elusive. Here, using an animal model of cognitive control, we found that the influence of predictive learning on decision making is mediated by an inhibitory feedback circuit linking the medial ventral pallidum and the mediodorsal thalamus, the activation of which causes disinhibition of the orbitofrontal cortex via reduced activation of inhibitory parvalbumin interneurons during choice. Thus, we found that, for this function, the mediodorsal thalamus serves as a pallidal-cortical relay through which predictive learning controls action selection, which has important implications for understanding cognitive control and its vicissitudes in various psychiatric disorders and addiction. • Predictive learning affects choice via a ventral pallidum to MD-thalamus to OFC circuit • MD-thalamus activity inhibits the OFC via a projection onto OFC-PV neurons • The ventral pallidum releases choice by inhibiting this MD-thalamus to OFC-PV projection • Cognitive control involves a disinhibitory basal ganglia-cortical feedback circuit Cognitive control allows us and other animals to use predictive information to control choices between actions. Here, Leung et al. establish that this control process is mediated by a disinhibitory basal ganglia-cortical feedback circuit, via which the ventral pallidum inhibits the mediodorsal thalamus to disinhibit the orbitofrontal cortex and release choice. [ABSTRACT FROM AUTHOR]

The mediodorsal thalamus (MD) is a higher‐order nucleus located within the central thalamus in many mammalian species. Emerging evidence from MD lesions and tracer injections suggests that the MD is reciprocally connected to the prefrontal cortex (PFC) and plays an essential role in specific cognitive processes and tasks. MD subdivisions (medial, central, and lateral) are poorly segregated at the molecular level in rodents, leading to a lack of MD subdivision‐specific Cre driver mice. Moreover, this lack of molecular identifiers hinders MD subdivision‐ and cell‐type‐specific circuit formation and function analysis. Therefore, using publicly available databases, we explored molecules separately expressed in MD subdivisions. In addition to MD subdivision markers, we identified several genes expressed in a subdivision‐specific combination and classified them. Furthermore, after developing medial MD (MDm) or central MD (MDc) region‐specific Cre mouse lines, we identified diverse region‐ and layer‐specific PFC projection patterns. Comparison between classified MD marker genes in mice and common marmosets, a nonhuman primate model, revealed diverging gene expression patterns. These results highlight the species‐specific organization of cell types and their projections in the MD thalamus. [ABSTRACT FROM AUTHOR]

Both medial prefrontal cortex (mPFC) and serotonin play key roles in anxiety; however, specific mechanisms through which serotonin might act on the mPFC to modulate anxiety-related behavior remain unknown. Here, we use a combination of optogenetics and synaptic physiology to show that serotonin acts presynaptically via 5-HT1B receptors to selectively suppress inputs from the contralateral mPFC and ventral hippocampus (vHPC), while sparing those from mediodorsal thalamus. To elucidate how these actions could potentially regulate prefrontal circuit function, we infused a 5-HT1B agonist into the mPFC of freely behaving mice. Consistent with previous studies that have optogenetically inhibited vHPC-mPFC projections, activating prefrontal 5-HT1B receptors suppressed theta-frequency mPFC activity (4-12 Hz), and reduced avoidance of anxiogenic regions in the elevated plus maze. These findings suggest a potential mechanism, linking specific receptors, synapses, patterns of circuit activity, and behavior, through which serotonin may regulate prefrontal circuit function, including anxiety-related behaviors.

Prefrontal cortical GABAergic interneurons (INs) and their innervations are essential for the execution of complex behaviors such as working memory, social behavior, and fear expression. These behavior regulations are highly dependent on primary long-range afferents originating from the subcortical structures such as mediodorsal thalamus (MD), ventral hippocampus (vHPC), and basolateral amygdala (BLA). In turn, the regulatory effects of these inputs are mediated by activation of parvalbumin-expressing (PV) and/or somatostatin expressing (SST) INs within the prefrontal cortex (PFC). Here we review how each of these long-range afferents from the MD, vHPC, or BLA recruits a subset of the prefrontal interneuron population to exert precise control of specific PFC-dependent behaviors. Specifically, we first summarize the anatomical connections of different long-range inputs formed on prefrontal GABAergic INs, focusing on PV versus SST cells. Next, we elaborate on the role of prefrontal PV- and SST- INs in regulating MD afferents-mediated cognitive behaviors. We also examine how prefrontal PV- and SST- INs gate vHPC afferents in spatial working memory and fear expression. Finally, we discuss the possibility that prefrontal PV-INs mediate fear conditioning, predominantly driven by the BLA-mPFC pathway. This review will provide a broad view of how multiple long-range inputs converge on prefrontal interneurons to regulate complex behaviors and novel future directions to understand how PFC controls different behaviors.

Prefrontal cortical GABAergic interneurons (INs) and their innervations are essential for the execution of complex behaviors such as working memory, social behavior, and fear expression. These behavior regulations are highly dependent on primary long-range afferents originating from the subcortical structures such as mediodorsal thalamus (MD), ventral hippocampus (vHPC), and basolateral amygdala (BLA). In turn, the regulatory effects of these inputs are mediated by activation of parvalbumin-expressing (PV) and/or somatostatin expressing (SST) INs within the prefrontal cortex (PFC). Here we review how each of these long-range afferents from the MD, vHPC, or BLA recruits a subset of the prefrontal interneuron population to exert precise control of specific PFC-dependent behaviors. Specifically, we first summarize the anatomical connections of different long-range inputs formed on prefrontal GABAergic INs, focusing on PV versus SST cells. Next, we elaborate on the role of prefrontal PV- and SST- INs in regulating MD afferents-mediated cognitive behaviors. We also examine how prefrontal PV- and SST- INs gate vHPC afferents in spatial working memory and fear expression. Finally, we discuss the possibility that prefrontal PV-INs mediate fear conditioning, predominantly driven by the BLA-mPFC pathway. This review will provide a broad view of how multiple long-range inputs converge on prefrontal interneurons to regulate complex behaviors and novel future directions to understand how PFC controls different behaviors. [ABSTRACT FROM AUTHOR]

Beliefs—attitudes toward some state of the environment—guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia. [Display omitted] • Lesions to the mediodorsal thalamus (MD) in monkeys heighten belief volatility • Orbitofrontal cortex (OFC) lesions impair value learning • This is a double dissociation of belief learning between brain regions • Shared computational modeling across species implicates MD in paranoia Suthaharan et al. demonstrate a causal role of the primate mediodorsal thalamus (MD) in beliefs about environmental volatility. Applying a behavioral paradigm and a computational model, they establish that belief volatility increases in paranoid people and monkeys with lesions to the MD. This suggests a role for the MD in paranoia. [ABSTRACT FROM AUTHOR]

The brain continuously receives diverse information about the external environment and changes in the homeostatic state. The attribution of salience determines which stimuli capture attention and, therefore, plays an essential role in regulating emotions and guiding behaviors. Although the thalamus is included in the salience network, the neural mechanism of how the thalamus contributes to salience processing remains elusive. In this mini-review, we will focus on recent advances in understanding the specific roles of distinct thalamic nuclei in salience processing. We will summarize the functional connections between thalamus nuclei and other key nodes in the salience network. We will highlight the convergence of neural circuits involved in reward and pain processing, arousal, and attention control in thalamic structures. We will discuss how thalamic activities represent salience information in associative learning and how thalamic neurons modulate adaptive behaviors. Lastly, we will review recent studies which investigate the contribution of thalamic dysfunction to aberrant salience processing in neuropsychiatric disorders, such as drug addiction, posttraumatic stress disorder (PTSD), and schizophrenia. Based on emerging evidence from both human and rodent research, we propose that the thalamus, different from previous studies that as an information relay, has a broader role in coordinating the cognitive process and regulating emotions.

The brain continuously receives diverse information about the external environment and changes in the homeostatic state. The attribution of salience determines which stimuli capture attention and, therefore, plays an essential role in regulating emotions and guiding behaviors. Although the thalamus is included in the salience network, the neural mechanism of how the thalamus contributes to salience processing remains elusive. In this mini-review, we will focus on recent advances in understanding the specific roles of distinct thalamic nuclei in salience processing. We will summarize the functional connections between thalamus nuclei and other key nodes in the salience network. We will highlight the convergence of neural circuits involved in reward and pain processing, arousal, and attention control in thalamic structures. We will discuss how thalamic activities represent salience information in associative learning and how thalamic neurons modulate adaptive behaviors. Lastly, we will review recent studies which investigate the contribution of thalamic dysfunction to aberrant salience processing in neuropsychiatric disorders, such as drug addiction, posttraumatic stress disorder (PTSD), and schizophrenia. Based on emerging evidence from both human and rodent research, we propose that the thalamus, different from previous studies that as an information relay, has a broader role in coordinating the cognitive process and regulating emotions. [ABSTRACT FROM AUTHOR]

Altered prepulse inhibition (PPI) is an endophenotype associated with multiple brain disorders, including schizophrenia. Circuit mechanisms that regulate PPI have been suggested, but none has been demonstrated through direct manipulations. IRSp53 is an abundant excitatory postsynaptic scaffold implicated in schizophrenia, autism spectrum disorders, and attention-deficit/hyperactivity disorder. We found that mice lacking IRSp53 in cortical excitatory neurons display decreased PPI. IRSp53-mutant layer 6 cortical neurons in the anterior cingulate cortex (ACC) displayed decreased excitatory synaptic input but markedly increased neuronal excitability, which was associated with excessive excitatory synaptic input in downstream mediodorsal thalamic (MDT) neurons. Importantly, chemogenetic inhibition of mutant neurons projecting to MDT normalized the decreased PPI and increased excitatory synaptic input onto MDT neurons. In addition, chemogenetic activation of MDT-projecting layer 6 neurons in the ACC decreased PPI in wild-type mice. These results suggest that the hyperactive ACC-MDT pathway suppresses PPI in wild-type and IRSp53-mutant mice. [ABSTRACT FROM AUTHOR]

The thalamus engages in sensation, action, and cognition, but the structure underlying these functions is poorly understood. Thalamic innervation of associative cortex targets several interneuron types, modulating dynamics and influencing plasticity. Is this structure-function relationship distinct from that of sensory thalamocortical systems? Here, we systematically compared function and structure across a sensory and an associative thalamocortical loop in the mouse. Enhancing excitability of mediodorsal thalamus, an associative structure, resulted in prefrontal activity dominated by inhibition. Equivalent enhancement of medial geniculate excitability robustly drove auditory cortical excitation. Structurally, geniculate axons innervated excitatory cortical targets in a preferential manner and with larger synaptic terminals, providing a putative explanation for functional divergence. The two thalamic circuits also had distinct input patterns, with mediodorsal thalamus receiving innervation from a diverse set of cortical areas. Altogether, our findings contribute to the emerging view of functional diversity across thalamic microcircuits and its structural basis.

The frontal cortex and temporal lobes together regulate complex learning and memory capabilities. Here, we collected resting-state functional and diffusion-weighted MRI data before and after male rhesus macaque monkeys received extensive training to learn novel visuospatial discriminations (reward-guided learning). We found functional connectivity changes in orbitofrontal, ventromedial prefrontal, inferotemporal, entorhinal, retrosplenial, and anterior cingulate cortices, the subicular complex, and the dorsal, medial thalamus. These corticocortical and thalamocortical changes in functional connectivity were accompanied by related white matter structural alterations in the uncinate fasciculus, fornix, and ventral prefrontal tract: tracts that connect (sub)cortical networks and are implicated in learning and memory processes in monkeys and humans. After the well-trained monkeys received fornix transection, they were impaired in learning new visuospatial discriminations. In addition, the functional connectivity profile that was observed after the training was altered. These changes were accompanied by white matter changes in the ventral prefrontal tract, although the integrity of the uncinate fasciculus remained unchanged. Our experiments highlight the importance of different communication relayed among corticocortical and thalamocortical circuitry for the ability to learn new visuospatial associations (learning-to-learn) and to make reward-guided decisions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In schizophrenia, decreased hippocampal volume, reduced oligodendrocyte numbers in hippocampal cornu ammonis (CA) subregions and reduced neuron number in the dentate gyrus have been reported; reduced oligodendrocyte numbers were significantly related to cognitive deficits. The hippocampus is involved in cognitive functions and connected to the hypothalamus, anterior thalamus, and cingulate cortex, forming the Papez circuit, and to the mediodorsal thalamus. The relationship between the volume of these interconnected regions and oligodendrocyte and neuron numbers in schizophrenia is unknown. Therefore, we used stepwise logistic regression with subsequent multivariate stepwise linear regression and bivariate correlation to analyze oligodendrocyte and neuron numbers in the posterior hippocampal subregions CA1, CA2/3, CA4, dentate gyrus, and subiculum and volumes of the hippocampal CA region, cingulum, anterior and mediodorsal thalamus and hypothalamus in postmortem brains of 10 schizophrenia patients and 11 age- and gender-matched healthy controls. Stepwise logistic regression identified the following predictors for diagnosis, in order of inclusion: (1) oligodendrocyte number in CA4, (2) hypothalamus volume, (3) oligodendrocyte number in CA2/3, and (4) mediodorsal thalamus volume. Subsequent stepwise linear regression analyses identified the following predictors: (1) for oligodendrocyte number in CA4: (a) oligodendrocyte number in CA2/3, (b) diagnostic group, (c) hypothalamus volume, and (d) neurons in posterior subiculum; (2) for hypothalamus volume: (a) mediodorsal thalamus volume; (3) for oligodendrocyte number in CA2/3: oligodendrocyte number (a) in posterior CA4 and (b) in posterior subiculum; (4) for mediodorsal thalamus volume: volumes of (a) anterior thalamus and (b) hippocampal CA. In conclusion, we found a positive relationship between hippocampal oligodendrocyte number and the volume of the hypothalamus, a brain region connected to the hippocampus, which is important for cognition. [ABSTRACT FROM AUTHOR]

The medial prefrontal cortex (mPFC) integrates inputs from multiple subcortical regions including the mediodorsal nucleus of the thalamus (MD) and the ventral hippocampus (vHPC). How the mPFC differentially processes these inputs is not known. One possibility is that these two inputs target discreet populations of mPFC cells. Alternatively, individual prefrontal cells could receive convergent inputs but distinguish between both inputs based on synaptic differences, such as communication frequency. To address this, we utilized a dual wavelength optogenetic approach to stimulate MD and vHPC inputs onto single, genetically defined mPFC neuronal subtypes. Specifically, we compared the convergence and synaptic dynamics of both inputs onto mPFC pyramidal cells, and parvalbumin (PV)- and vasoactive intestinal peptide (VIP)-expressing interneurons. We found that all individual pyramidal neurons in layer 2/3 of the mPFC receive convergent input from both MD and vHPC. In contrast, PV neurons receive input biased from the MD, while VIP cells receive input biased from the vHPC. Independent of the target, MD inputs transferred information more reliably at higher frequencies (20 Hz) than vHPC inputs. Thus, MD and vHPC projections converge functionally onto mPFC pyramidal cells, but both inputs are distinguished by frequency-dependent synaptic dynamics and preferential engagement of discreet interneuron populations. [ABSTRACT FROM AUTHOR]

• Intraperitoneal injection of scopolamine impaired memory consolidation. • Intra-MD microinjection of NMDA or D-AP5 had no effect on memory consolidation alone. • Intra-MD microinjection of NMDA reversed the amnesic effect of scopolamine. • Intra-MD microinjection of D-AP5 potentiated the amnesic effect of scopolamine. • Blockade of the NMDA receptors inhibited the effect of NMDA on scopolamine response. The current study was designed to examine the role of glutamate NMDA receptors of the mediodorsal thalamus (MD) in scopolamine-induced memory impairment. Adult male rats were bilaterally cannulated into the MD. According to the results, intraperitoneal (i.p.) administration of scopolamine (1.5 mg/kg) immediately after the training phase (post-training) impaired memory consolidation. Bilateral microinjection of the glutamate NMDA receptors agonist, N-Methyl-D-aspartic acid (NMDA; 0.05 µg/rat), into the MD significantly improved scopolamine-induced memory consolidation impairment. Co-administration of D-AP5, a glutamate NMDA receptor antagonist (0.001–0.005 µg/rat, intra-MD) potentiated the response of an ineffective dose of scopolamine (0.5 mg/kg, i.p.) to impair memory consolidation, mimicking the response of a higher dose of scopolamine. Noteworthy, post-training intra-MD microinjections of the same doses of NMDA or D-AP5 alone had no effect on memory consolidation. Moreover, the blockade of the glutamate NMDA receptors by 0.003 ng/rat of D-AP5 prevented the improving effect of NMDA on scopolamine-induced amnesia. Thus, it can be concluded that the MD glutamatergic system may be involved in scopolamine-induced memory impairment via the NMDA receptor signaling pathway. [ABSTRACT FROM AUTHOR]

The ability to flexibly use knowledge is one cardinal feature of goal-directed behaviors. We recently showed that thalamocortical and corticothalamic pathways connecting the medial prefrontal cortex and the mediodorsal thalamus (MD) contribute to adaptive decision-making (Alcaraz et al., 2018). In this study, we examined the impact of disconnecting the MD from its other main cortical target, the orbitofrontal cortex (OFC) in a task assessing outcome devaluation after initial instrumental training and after reversal of action-outcome contingencies. Crossed MD and OFC lesions did not impair instrumental performance. Using the same approach, we found however that disconnecting the OFC from its other main thalamic afferent, the submedius nucleus, produced a specific impairment in adaptive responding following action-outcome reversal. Altogether, this suggests that multiple thalamocortical circuits may act synergistically to achieve behaviorally relevant functions.

Identifying the neurocognitive mechanisms that lead individuals remembering to execute an intention at the right moment (prospective memory, PM) and how such mechanisms are influenced by the features of that intention is a fundamental theoretical challenge. In particular, the functional contribution of subcortical regions to PM is still unknown. This study was aimed at investigating the role of the medial subdivision of the mediodorsal thalamic nucleus (mMDT) in PM, with particular focus on the processes that are mediated by the projections from/to this structure. We analysed the performance of a patient (OG) with a right‐sided lesion involving the mMDT in a series of PM tasks that varied for focality (i.e., overlapping of processes for the PM and ongoing tasks) and emotional valence of the stimuli, comparing the patient's performance with that of a control group. We found that the mMDT damage led to deficits in PM that were modulated by focality and emotional valence. OG indeed showed: a greater cost in the ongoing performance when a non‐focal PM task was added; a slowing down in retrieving the intentions, in particular when these were associated with focal PM cues; an abnormal performance in the task with positive PM cues. Our findings provide evidence of a contribution of mMDT to PM and suggest a modulation of prefrontal‐dependent strategic monitoring and a possible interaction with the limbic structures in the integration of emotion and PM processes. They also give support to the still controversial idea that connections with the perirhinal cortex mediate familiarity‐based recognition. [ABSTRACT FROM AUTHOR]

The objective of the study were to investigate patterns of multiunit cluster firing in the piriform cortex (PC) and mediodorsal thalamus (MDT) in a rat model of genetic generalized epilepsy (GGE) with absence seizures and to assess whether these regions contribute to the initiation or spread of generalized epileptiform discharges. Multiunit clusters and their corresponding local field potentials (LFPs) were recorded from microelectrode arrays implanted in the PC and MDT in urethane anesthetized Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and nonepileptic control (NEC) rats. Peristimulus time histograms (PSTHs) and cross-correlograms were used to observe transient changes in both the rate of firing and synchrony over time. The phase locking of multiunit clusters to LFP signals (spike-LFP phase locking) was calculated for frequency bands associated with olfactory communication between the two brain regions. There were significant increases in both rate of firing and synchronous activity at the onset of generalized epileptiform discharges in both PC and MDT. Prior to and following these increases in synchronous activity, there were periods of suppression. Significant increases in spike-LFP phase locking were observed within the PC prior to the onset of epileptiform discharges across all spectral bands. There were also significant increases in spike-LFP phase locking within the theta band of the MDT prior to onset. Between the two brain regions, there was a significant decrease in spike-LFP phase locking − 0.5 s prior to onset in the theta band which coincided with a significant elevation in spike-LFP phase locking in the gamma band. Both the PC and MDT are engaged in the absence epilepsy network. Early spike-LFP phase locking between these two brain regions suggests potential involvement in the initiation of seizure activity. • There is recent evidence of possible involvement of mesial temporal structures in absence epilepsy including the piriform cortex • We recorded multi-unit clusters from the piriform cortex and mediodorsal thalamus in an absence epilepsy rat model • Pre-seizure onset changes in spike-LFP phase locking between the piriform cortex and mediodorsal thalamus • We conclude the piriform cortex and mediodorsal thalamus may contribute to the initiation of epileptiform discharges in absence epilepsy [ABSTRACT FROM AUTHOR]

The objective of the study was to quantify effective connectivity from the piriform cortex to mediodorsal thalamus, in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Local field potentials (LFPs) were recorded using microelectrode arrays implanted in the mediodorsal thalamus and piriform cortex, in three urethane anesthetized GAERS and three control rats. Screw electrodes were placed in the primary motor cortex to identify epileptiform discharges. We used transfer entropy to measure effective connectivity from piriform cortex to mediodorsal thalamus prior to and during generalized epileptiform discharges. We observed increased theta band effective connectivity from piriform cortex to mediodorsal thalamus, prior to and during epileptiform discharges in GAERS compared with controls. Increased effective connectivity was also observed in beta and gamma bands from the piriform cortex to mediodorsal thalamus, but only during epileptiform discharges. This preliminary study suggests that increased effective theta connectivity from the piriform cortex to the mediodorsal thalamus may be a feature of the 'epileptic network' associated with genetic absence epilepsy. Our findings indicate an underlying predisposition of this direct pathway to propagate epileptiform discharges in genetic absence epilepsy. • Transfer entropy measured effective connectivity from piriform cortex to mediodorsal thalamus in an absence epilepsy model • Effective theta connectivity increased along this pathway prior to and during epileptiform discharges • This pathway may be predisposed to the propagation of epileptiform discharges [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • PFC connections topographically organized along anteromedial-posterolateral MD axis. • Ventromedial to posterolateral PFC mapped across this axis in MD. • Nearby, functionally-related PFC areas have overlapping projection zones in MD. • Projection zone overlap allows MD to integrate information from multiple PFC areas. • MD can contribute to cognitive control by influencing cortico-cortical communication. [ABSTRACT FROM AUTHOR]

A growing body of evidence shows that olfactory information is processed within a thalamic nucleus in both rodents and humans. The mediodorsal thalamic nucleus (MDT) receives projections from olfactory cortical areas including the piriform cortex (PCX) and is interconnected with the orbitofrontal cortex (OFC). Using electrophysiology in freely moving rats, we recently demonstrated the representation of olfactory information in the MDT and the dynamics of functional connectivity between the PCX, MDT and OFC. Notably, PCX-MDT coupling is specifically increased during odor sampling of an odor discrimination task. However, whether this increase of coupling is functionally relevant is unknown. To decipher the importance of PCX-MDT coupling during the sampling period, we used optogenetics to specifically inactivate the PCX inputs to MDT during an odor discrimination task and its reversal in rats. We demonstrate that inactivating the PCX inputs to MDT does not affect the performance accuracy of an odor discrimination task and its reversal, however, it does impact the rats' sampling duration. Indeed, rats in which PCX inputs to MDT were inactivated during the sampling period display longer sampling duration during the odor reversal learning compared to controls—an effect not observed when inactivating OFC inputs to MDT. We demonstrate a causal link between the PCX inputs to MDT and the odor sampling performance, highlighting the importance of this specific cortico-thalamic pathway in olfaction. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The mediodorsal thalamus is a higher order thalamic nucleus critical for many cognitive behaviors. Defined by its reciprocal connections with the prefrontal cortex, the mediodorsal thalamus receives strong projections from chemosensory cortical areas for taste and smell, gustatory cortex and piriform cortex. Recent studies indicate the mediodorsal thalamus is involved in experience-dependent chemosensory processes, including olfactory attention and discrimination and the hedonic perception of odor-taste mixtures. How novel and familiar chemosensory stimuli are represented within this structure remains unclear. Here, we compared the expression of c-Fos in the mediodorsal thalami of rats familiar with an odor, a taste, or an odor-taste mixture with those that sampled the stimuli for the first time. We found that familiar tastes or odor-taste mixtures induced significantly greater c-Fos expression in the mediodorsal thalamus than novel tastes or odor-taste mixtures, whereas novel odors induced greater c-Fos expression than familiar odors. These experience-dependent and modality-specific differences in c-Fos expression may relate to the behavioral relevance of the chemosensory stimulus, including odor neophobia. In a two-bottle brief-access preference task, rats preferred water to isoamyl acetate-odorized water over multiple days. However, after experience with isoamyl acetate mixed with sucrose (odor-taste mixture), the preference for water was eliminated. These findings demonstrate that experience with chemosensory stimuli modulates responses in the mediodorsal thalamus, suggesting this structure plays an integral role in communicating behaviorally relevant chemosensory information to higher order areas to guide food-related behaviors. [ABSTRACT FROM AUTHOR]

The Mediodorsal (MD) thalamus that represents a fundamental subcortical relay has been underrepresented in the studies focusing on the molecular changes in the brains of subjects with alcohol use disorder (AUD). In the current study, MD thalamic regions from AUD subjects and controls were analyzed with Affymetrix Clariom S human microarray. Long-term alcohol use induced a significant (FDR ≤ 0.05) upregulation of 2802 transcripts and downregulation of 1893 genes in the MD thalamus of AUD subjects. A significant upregulation of GRIN1 (glutamate receptor NMDA type 1) and FTO (alpha-ketoglutarate dependent dioxygenase) was confirmed in western blot analysis. Immunohistochemical staining revealed similar heterogenous distribution of GRIN1 in the thalamic nuclei of both AUD and control subjects. The most prevalent functional categories of upregulated genes were related to glutamatergic and GABAergic neurotransmission, cellular metabolism, and neurodevelopment. The prevalent gene cluster among down-regulated genes was immune system mediators. Forty-two differentially expressed genes, including FTO, ADH1B, DRD2, CADM2, TCF4, GCKR, DPP6, MAPT and CHRH1, have been shown to have strong associations (FDR p < 10−8) with AUD or/and alcohol use phenotypes in recent GWA studies. Despite a small number of subjects, we were able to detect robust molecular changes in the mediodorsal thalamus caused by alcohol emphasizing the importance of deeper brain structures such as diencephalon, in the development of AUD-related dysregulation of neurocircuitry.

Many species living in groups can perform prosocial behaviors via voluntarily helping others with or without benefits for themselves. To provide a better understanding of the neural basis of such prosocial behaviors, we adapted a preference lever-switching task in which mice can prevent harm to others by switching from using a lever that causes shocks to a conspecific one that does not. We found the harm avoidance behavior was mediated by self-experience and visual and social contact but not by gender or familiarity. By combining single-unit recordings and analysis of neural trajectory decoding, we demonstrated the dynamics of anterior cingulate cortex (ACC) neural activity changes synchronously with the harm avoidance performance of mice. In addition, ACC neurons projected to the mediodorsal thalamus (MDL) to modulate the harm avoidance behavior. Optogenetic activation of the ACC-MDL circuit during non-preferred lever pressing (nPLP) and inhibition of this circuit during preferred lever pressing (PLP) both resulted in the loss of harm avoidance ability. This study revealed the ACC-MDL circuit modulates prosocial behavior to avoid harm to conspecifics and may shed light on the treatment of neuropsychiatric disorders with dysfunction of prosocial behavior. [Display omitted] • Mice exhibit helping behavior to a conspecific experiencing harm • The helping behavior is dependent on self-experience and social contact • Anterior cingulate cortex neurons change dynamically during this behavior • An ACC-mediodorsal thalamus neural circuit modulates the prosocial behavior Song and Wang et al. demonstrate that mice help conspecifics to avoid harm, a behavior that relies on the neural activities of the anterior cingulate cortex (ACC). Optogenetic modulation of mediodorsal thalamus-projecting ACC neurons at specific time points abolishes the behavior. [ABSTRACT FROM AUTHOR]

The thalamus has been implicated in many cognitive processes, including long-term memory. More specifically, the anterior (AT) and mediodorsal (MD) thalamic nuclei have been associated with long-term memory. Despite extensive mapping of the anatomical connections between these nuclei and other brain regions, little is known regarding their functional connectivity during long-term memory. The current study sought to determine which brain regions are functionally connected to AT and MD during spatial long-term memory and whether sex differences exist in the patterns of connectivity. During encoding, abstract shapes were presented to the left and right of fixation. During retrieval, shapes were presented at fixation, and participants made an “old-left” or “old-right” judgment. Activations functionally connected to AT and MD existed in regions with known anatomical connections to each nucleus as well as in a broader network of long-term memory regions. Sex differences were identified in a subset of these regions. A targeted region-of-interest analysis identified anti-correlated activity between MD and the hippocampus that was specific to females, which is consistent with findings in rodents. The current results suggest that AT and MD play key roles during spatial long-term memory and suggest that these functions may be sex specific.

The mediodorsal nucleus (MD) represents just one piece of a complex relay structure situated within the brain, called the thalamus. MD is characterized by its robust interconnections with other brain areas, especially with limbic-related structures. Given the close anatomo-functional relationship between the MD and the limbic system, this particular thalamic nucleus can directly influence various affective behaviors and participate in cognition. In this work, we review data collected from multiple anatomical studies conducted in rodent, human, and non-human primates, highlighting the complexity of this structure and of the neural networks in which it takes part. We provide proof that the MD is involved in the unification of several anatomical structures, being able to process the information and influence the activity in numerous cortical and subcortical neural circuits. Moreover, we uncover intrinsic and extrinsic mechanisms that offer MD the possibility to execute and control specific high functions of the nervous system. The collected data indicate the great importance of the MD in the limbic system and offer relevant insight into the organization of thalamic circuits that support MD functions.

The function of the human mediodorsal thalamic nucleus (MD) has so far eluded a clear definition in terms of specific cognitive processes and tasks. Although it was at first proposed to play a role in long-term memory, a set of recent studies in animals and humans has revealed a more complex, and broader, role in several cognitive functions. The MD seems to play a multifaceted role in higher cognitive functions together with the prefrontal cortex and other cortical and subcortical brain areas. Specifically, we propose that the MD is involved in the regulation of cortical networks especially when the maintenance and temporal extension of persistent activity patterns in the frontal lobe areas are required. Highlights The mediodorsal thalamic nucleus is involved in the cognitive deficits observed in several neurological and psychiatric disorders. The long-standing belief in a role of the mediodorsal thalamic nucleus mainly in long-term memory is now being reconsidered. Recent studies emphasize its function in many cognitive tasks related to the prefrontal cortex. The mediodorsal thalamic nucleus is required for the rapid and accurate performance of cognitive tasks and temporally extends the efficiency of cortical networks involving the prefrontal cortex. We propose that the common ground of multiple lines of evidence from human studies points to a role of the mediodorsal thalamic nucleus in regulating prefrontal activity patterns. These hypotheses can be tested by developing specific neuropsychological tasks, parceling the thalamus with high-resolution MRI, and using intracranial recordings in humans. [ABSTRACT FROM AUTHOR]

Abstract: Technology allowing genetically targeted cells to be modulated by light has revolutionized neuroscience in the past decade, and given rise to the field of optogenetic stimulation. For this, non‐native, light activated proteins (e.g., channelrhodopsin) are expressed in a specific cell phenotype (e.g., glutamatergic neurons) in a subset of central nervous system nuclei, and short pulses of light of a narrow wavelength (e.g., blue, 473 nm) are used to modulate cell activity. Cell activity can be increased or decreased depending on which light activated protein is used. We review how the greater precision provided by optogenetics has transformed the study of neural circuits, in terms of cognition and behavior, with a focus on learning and memory. We also explain how optogenetic modulation is facilitating a better understanding of the mechanistic underpinnings of some neurological and psychiatric conditions. Based on this research, we suggest that optogenetics may provide tools to improve memory in neurological conditions, particularly diencephalic amnesia and Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract: The prefrontal cortex (PFC) is usually defined as the frontal cortical area receiving a mediodorsal thalamic (MD) innervation. Certain areas in the medial wall of the rat frontal area receive a MD innervation. A second frontal area that is the target of MD projections is located dorsal to the rhinal sulcus and often referred to as the orbitofrontal cortex (OFC). Both the medial PFC and OFC are comprised of a large number of cytoarchitectonic regions. We assessed the afferent innervation of the different areas of the OFC, with a focus on projections arising from the mediodorsal thalamic nucleus, the basolateral nucleus of the amygdala, and the midbrain dopamine neurons. Although there are specific inputs to various OFC areas, a simplified organizational scheme could be defined, with the medial areas of the OFC receiving thalamic inputs, the lateral areas of the OFC being the recipient of amygdala afferents, and a central zone that was the target of midbrain dopamine neurons. Anterograde tracer data were consistent with this organization of afferents, and revealed that the OFC inputs from these three subcortical sites were largely spatially segregated. This spatial segregation suggests that the central portion of the OFC (pregenual agranular insular cortex) is the only OFC region that is a prefrontal cortical area, analogous to the prelimbic cortex in the medial prefrontal cortex. These findings highlight the heterogeneity of the OFC, and suggest possible functional attributes of the three different OFC areas. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]