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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]

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.

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]

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.

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 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.)

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]

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]

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., Competing Interests: Declaration of interests P.R.C. is a cofounder of Tetricus Labs Inc., which did not fund this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

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]

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]

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.

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 mediodorsal (MD) and paraventricular (PV) thalamic nuclei play a significant role in limbic epilepsy, and previous reports have shown changes in GABA-A receptor (GABAAR) mediated synaptic function. In this study, we examined changes in the pharmacology of GABAergic drugs and the expression of the GABAAR subunits in the MD and PV neurons in epilepsy. We observed nucleus specific changes in the sensitivity of sIPSCs to zolpidem and phenobarbital in MD and PV neurons from epileptic animals. In contrast, the magnitude of change in electrically evoked response (eIPSC) to zolpidem and phenobarbital were uniformly diminished in both MD and PV neurons in epilepsy. Immunohistochemical studies revealed that in epilepsy, there was a reduction in GAD65 expression and NeuN positive neurons in the MD neurons. Also, there was a decrease in immunoreactivity of the α1 and β2/3 subunit of GABAARs, but not the γ2 of the GABAAR in both MD and PV in epilepsy. These findings demonstrate significant alterations in the pharmacology of GABA and GABAARs in a key region for seizure generation, which may have implications for the physiology and pharmacology of limbic epilepsy.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Urrutia Desmaison, Sala, Ayyaz, Nondhalee, Popa and Léna.)

The mediodorsal thalamic nucleus (MDT) is a higher order thalamic nucleus and its role in cognition is increasingly well established. Interestingly, components of the MDT also have a somewhat unique sensory function as they link primary olfactory cortex to orbitofrontal associative cortex. In fact, anatomical evidence firmly demonstrates that the MDT receives direct input from primary olfactory areas including the piriform cortex and has dense reciprocal connections with the orbitofrontal cortex. The functions of this olfactory pathway have been poorly explored but lesion, imaging, and electrophysiological studies suggest that these connections may be involved in olfactory processing including odor perception, discrimination, learning, and attention. However, many important questions regarding the MDT and olfaction remain unanswered. Our goal here is not only to briefly review the existing literature but also to highlight some of the remaining questions that need to be answered to better define the role(s) of the MDT in olfactory processing.

Background: Whereas acute nicotine administration alters brain function which may, in turn, contribute to enhanced attention and performance, chronic cigarette smoking is linked with regional brain atrophy and poorer cognition. However, results from structural magnetic resonance imaging (MRI) studies comparing smokers versus nonsmokers have been inconsistent and measures of gray matter possess limited ability to inform functional relations or behavioral implications. The purpose of this study was to address these interpretational challenges through meta-analytic techniques in the service of clarifying the impact of chronic smoking on gray matter integrity and more fully contextualizing such structural alterations. Methods: We first conducted a coordinate-based meta-analysis of structural MRI studies to identify consistent structural alterations associated with chronic smoking. Subsequently, we conducted two additional meta-analytic assessments to enhance insight into potential functional and behavioral relations. Specifically, we performed a multimodal meta-analytic assessment to test the structural--functional hypothesis that smoking-related structural alterations overlapped those same regions showing acute nicotinic drug-induced functional modulations. Finally, we employed database driven tools to identify pairs of structurally impacted regions that were also functionally related via meta-analytic connectivity modeling, and then delineated behavioral phenomena associated with such functional interactions via behavioral decoding. Results: Across studies, smoking was associated with convergent structural decreases in the left insula, right cerebellum, parahippocampus, multiple prefrontal cortex (PFC) regions, and the thalamus. Indicating a structural--functional relation, we observed that smoking-related gray matter decreases overlapped with the acute functional effects of nicotinic agonist administration in the left insula, ventromedial PFC, and mediodorsal thalamus. Suggesting structural-behavioral implications, we observed that the left insula's task-based, functional interactions with multiple other structurally impacted regions were linked with pain perception, the right cerebellum's interactions with other regions were associated with overt body movements, interactions between the parahippocampus and thalamus were linked with memory processes, and interactions between medial PFC regions were associated with face processing. Conclusions: Collectively, these findings emphasize brain regions (e.g., ventromedial PFC, insula, thalamus) critically linked with cigarette smoking, suggest neuroimaging paradigms warranting additional consideration among smokers (e.g., pain processing), and highlight regions in need of further elucidation in addiction (e.g., cerebellum). [ABSTRACT FROM AUTHOR]

The mediodorsal thalamus (MDT) is a higher-order corticocortical thalamic nucleus involved in cognition and memory. However, anatomically, the MDT is also the primary site of olfactory representation in the thalamus, receiving strong inputs from olfactory cortex and having reciprocal connections with orbitofrontal cortex (OFC). Nonetheless, its role in olfaction remains unclear. Here, we recorded single units in the MDT, as well as local field potentials in the MDT, piriform cortex (PCX), and OFC in rats performing a two-alternative odor discrimination task. We show that subsets of MDT units display odorant selectivity during sampling, as well as encoding of spatio-motor aspects of the task. Furthermore, the olfactory trans-thalamic network rapidly switches functional connectivity between MDT and cortical areas depending on current task demands, with, for example, MDT-PCX coupling enhanced during odor sampling and MDT-OFC coupling enhanced during the decision/goal approach compared with baseline and presampling. These results demonstrate MDT representation of diverse sensorimotor components of an olfactory task. [ABSTRACT FROM AUTHOR]

The mediodorsal thalamic nucleus (MDT) is a higher order thalamic nucleus and its role in cognition is increasingly well established. Interestingly, components of the MDT also have a somewhat unique sensory function as they link primary olfactory cortex to orbitofrontal associative cortex. In fact, anatomical evidence firmly demonstrates that the MDT receives direct input from primary olfactory areas including the piriform cortex and has dense reciprocal connections with the orbitofrontal cortex. The functions of this olfactory pathway have been poorly explored but lesion, imaging, and electrophysiological studies suggest that these connections may be involved in olfactory processing including odor perception, discrimination, learning, and attention. However, many important questions regarding the MDT and olfaction remain unanswered. Our goal here is not only to briefly review the existing literature but also to highlight some of the remaining questions that need to be answered to better define the role(s) of the MDT in olfactory processing. [ABSTRACT FROM AUTHOR]

In unconscious status (e.g., deep sleep and anesthetic unconsciousness) where cognitive functions are not generated there is still a significant level of brain activity present. Indeed, the electrophysiology of the unconscious brain is characterized by well-defined thalamocortical rhythmicity. Here we address the ionic basis for such thalamocortical rhythms during unconsciousness. In particular, we address the role of CaV3.1 T-type Ca2+ channels, which are richly expressed in thalamic neurons. Toward this aim, we examined the electrophysiological and behavioral phenotypes of mice lacking CaV3.1 channels (CaV3.1 knockout) during unconsciousness induced by ketamine or ethanol administration. Our findings indicate that CaV3.1 KO mice displayed attenuated low-frequency oscillations in thalamocortical loops, especially in the 1- to 4-Hz delta band, compared with control mice (CaV3.1 WT). Intriguingly, we also found that CaV3.1 KO mice exhibited augmented highfrequency oscillations during unconsciousness. In a behavioral measure of unconsciousness dynamics, CaV3.1 KO mice took longer to fall into the unconscious state than controls. In addition, such unconscious events had a shorter duration than those of control mice. The thalamocortical interaction level between mediodorsal thalamus and frontal cortex in CaV3.1 KO mice was significantly lower, especially for delta band oscillations, compared with that of CaV3.1 WT mice, during unconsciousness. These results suggest that the CaV3.1 channel is required for the generation of a given set of thalamocortical rhythms during unconsciousness. Further, that thalamocortical resonant neuronal activity supported by this channel is important for the control of vigilance states. [ABSTRACT FROM AUTHOR]