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Background and Purpose: Neuropathic pain (NP) is a debilitating condition following spinal cord injury (SCI). The role of periaqueductal gray (PAG) in NP development following SCI remains underexplored. Using resting‐state functional MRI (rsfMRI), our study aimed to demonstrate the alterations in functional connectivity (FC) of PAG in NP following SCI. Methods: Ten SCI patients (SCI + NP, n = 7, and SCI − NP, n = 3), alongside 10 healthy controls (HCs), were enrolled. rsfMRI was conducted followed by seed‐to‐voxel analysis using PAG as the seed region and then group‐based analysis comprising three groups (SCI + NP, SCI − NP, and HC). Age and gender were considered as confounding variables. Results: Compared to HCs, SCI + NP demonstrated decreased FC between PAG and right insula, right frontal orbital cortex, right pallidum, dorsal raphe nucleus (DRN), red nuclei (RN), substantia nigra (SN), and ventral posterolateral (VPL) thalamic nuclei. Compared to SCI − NP, SCI + NP demonstrated increased FC between PAG and posterior cingulate cortex (PCC), hippocampus, cerebellar vermis lobules IV and V, and thalamic structures (posterior and lateral pulvinar, the mediodorsal nuclei, and the ventral lateral nuclei). Additionally, decreased FC between the PAG and VPL, geniculate bodies, intralaminar nuclei of thalamus, DRN, RN, SN, and prefrontal cortex was observed in this comparison. Conclusions: Altered FC between PAG and right anterior insula, VPL, DRN, RN, SN, cerebellar vermis lobules IV and V, frontal cortex, and PCC was associated with NP sequelae of SCI. Additionally, SCI was independently associated with decreased FC between PAG and right posterior insula, cerebellar lobules IV and V, and cerebellar vermis lobules III, IV, and V. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Imbalance is the most commonly reported side effect following focused ultrasound (FUS) thalamotomy for essential tremor (ET). It remains unknown which patients are more likely to develop imbalance following FUS treatment.To identify preoperative and treatment‐related sonication parameters that are predictive of imbalance following FUS treatment.We retrospectively collected demographic data, preoperative Fahn‐Tolosa‐Marin Clinical Rating Scale for Tremor (FTM) scores and FUS treatment parameters in patients undergoing FUS thalamotomy for treatment of ET. The presence of imbalance was evaluated at several discrete time‐points with up to 4 years of follow‐up. Multiple machine learning classifiers were built and evaluated, aiming to maximize accuracy while minimizing feature set.Of the 297 patients identified, the presence of imbalance peaked at 1 week following operation at 79%. This declined rapidly with 29% reporting imbalance at 3 months, and only 15% at 4 years. At 1 week, total preoperative FTM scores and Maximum Energy delivered in FUS could predict the presence of imbalance at 92.8% accuracy. At 3 months, the total preoperative FTM scores and maximum power delivered could predict the presence of imbalance with 90.6% accuracy. Post‐operative lesion size and extent into thalamic nuclei, internal capsule, and subthalamic regions were identified as likely key underlying drivers of these predictors.A machine learning model based on preoperative tremor scores and maximum energy/power delivered predicted the development of short‐term imbalance and long‐term imbalance following FUS thalamotomy. [ABSTRACT FROM AUTHOR]

Tinnitus has been identified as a potential contributor to anxiety. Thalamo-cortical pathway plays a crucial role in the transmission of auditory and emotional information, but its casual link to tinnitus-associated anxiety remains unclear. In this study, we explore the neural activities in the thalamus and cortex of the sodium salicylate (NaSal)-treated mice, which exhibit both hyperacusis and anxiety-like behaviors. We find an increase in gamma band oscillations (GBO) in both auditory cortex (AC) and prefrontal cortex (PFC), as well as phase-locking between cortical GBO and thalamic neural activity. These changes are attributable to a suppression of GABAergic neuron activity in thalamic reticular nucleus (TRN), and optogenetic activation of TRN reduces NaSal-induced hyperacusis and anxiety-like behaviors. The elevation of endocannabinoid (eCB)/ cannabinoid receptor 1 (CB1R) transmission in TRN contributes to the NaSal-induced abnormalities. Our results highlight the regulative role of TRN in the auditory and limbic thalamic-cortical pathways. Sodium salicylate enhances endocannabinoid signaling, reducing GABAergic activity in the thalamic reticular nucleus. This increases gamma oscillations in the auditory cortex and prefrontal cortex, causing hyperacusis and anxiety-like behaviors. [ABSTRACT FROM AUTHOR]

Head direction (HD) neurons, signalling facing direction, generate a signal that is primarily anchored to the outside world by visual inputs. We investigated the route for visual landmark information into the HD system in rats. There are two candidates: an evolutionarily older, larger subcortical retino‐tectal pathway and a more recently evolved, smaller cortical retino‐geniculo‐striate pathway. We disrupted the cortical pathway by lesioning the dorsal lateral geniculate thalamic nuclei bilaterally, and recorded HD cells in the postsubicular cortex as rats foraged in a visual‐cue‐controlled enclosure. In lesioned rats we found the expected number of postsubicular HD cells. Although directional tuning curves were broader across a trial, this was attributable to the increased instability of otherwise normal‐width tuning curves. Tuning curves were also poorly responsive to polarizing visual landmarks and did not distinguish cues based on their visual pattern. Thus, the retino‐geniculo‐striate pathway is not crucial for the generation of an underlying, tightly tuned directional signal but does provide the main route for vision‐based anchoring of the signal to the outside world, even when visual cues are high in contrast and low in detail. Key points: Head direction (HD) cells indicate the facing direction of the head, using visual landmarks to distinguish directions.In rats, we investigated whether this visual information is routed through the thalamus to the visual cortex or arrives via the superior colliculus, which is a phylogenetically older and (in rodents) larger pathway.We lesioned the thalamic dorsal lateral geniculate nucleus (dLGN) in rats and recorded the responsiveness of cortical HD cells to visual cues.We found that cortical HD cells had normal tuning curves, but these were slightly more unstable during a trial. Most notably, HD cells in dLGN‐lesioned animals showed little ability to distinguish highly distinct cues and none to distinguish more similar cues.These results suggest that directional processing of visual landmarks in mammals requires the geniculo‐cortical pathway, which raises questions about when and how visual directional landmark processing appeared during evolution. [ABSTRACT FROM AUTHOR]

Long-range axonal projections of diverse classes of neocortical excitatory neurons likely contribute to brain-wide interactions processing sensory, cognitive and motor signals. Here, we performed light-sheet imaging of fluorescently labeled axons from genetically defined neurons located in posterior primary somatosensory barrel cortex and supplemental somatosensory cortex. We used convolutional networks to segment axon-containing voxels and quantified their distribution within the Allen Mouse Brain Atlas Common Coordinate Framework. Axonal density was analyzed for different classes of glutamatergic neurons using transgenic mouse lines selectively expressing Cre recombinase in layer 2/3 intratelencephalic projection neurons (Rasgrf2-dCre), layer 4 intratelencephalic projection neurons (Scnn1a-Cre), layer 5 intratelencephalic projection neurons (Tlx3-Cre), layer 5 pyramidal tract projection neurons (Sim1-Cre), layer 5 projection neurons (Rbp4-Cre), and layer 6 corticothalamic neurons (Ntsr1-Cre). We found distinct axonal projections from the different neuronal classes to many downstream brain areas, which were largely similar for primary and supplementary somatosensory cortices. Functional connectivity maps obtained from optogenetic activation of sensory cortex and wide-field imaging revealed topographically organized evoked activity in frontal cortex with neurons located more laterally in somatosensory cortex signaling to more anteriorly located regions in motor cortex, consistent with the anatomical projections. The current methodology therefore appears to quantify brain-wide axonal innervation patterns supporting brain-wide signaling. [ABSTRACT FROM AUTHOR]

In mammals, action potentials fired by rapidly adapting mechanosensitive afferents are known to reliably time lock to the cycles of a vibration. How and where along the ascending neuraxis is the peripheral afferent temporal code transformed into a rate code are currently not clear. Here, we probed the encoding of vibrotactile stimuli with electrophysiological recordings along major stages of the ascending somatosensory pathway in mice. We discovered the main transformation step was identified at the level of the thalamus, and parvalbumin-positive interneurons in thalamic reticular nucleus participate in sharpening frequency selectivity and in disrupting the precise spike timing. When frequency-specific microstimulation was applied within the brainstem, it generated frequency selectivity reminiscent of real vibration responses in the somatosensory cortex and could provide informative and robust signals for learning in behaving mice. Taken together, these findings could guide biomimetic stimulus strategies to activate specific nuclei along the ascending somatosensory pathway for neural prostheses. [Display omitted] • Electrophysiological recording reveals a shift of neural coding for tactile vibration • Transformation from a temporal to a rate code involves thalamic inhibitory networks • Microstimulation in brainstem DCN can reproduce cortical selectivity for vibration • Microstimulation in DCN, but not in S1, can be used for vibrotactile discrimination Lee et al. show that the transformation of the vibrotactile temporal code found in the periphery into a rate code along the ascending somatosensory pathway involves thalamic processing, particularly through parvalbumin-positive interneurons in the reticular nucleus. Brainstem microstimulation mimics vibration responses in the somatosensory cortex, offering insights for neural prostheses. [ABSTRACT FROM AUTHOR]

• The anteroventral thalamic nucleus was assessed in individuals with Down syndrome. • There was increased beta-amyloid plaque expression in the AV in the Down syndrome group. • The proportion of CBP-immunopositive cells was reduced in the AV in Down syndrome. The anterior thalamic nuclei are important for cognition, and memory in particular. However, little is known about how the anterior thalamic nuclei are affected in many neurological disorders partly due to difficulties in selective segmentation in in vivo scans, due to their size and location. Post-mortem studies, therefore, remain a valuable source of information about the status of the anterior thalamic nuclei. We used post-mortem tissue to assess the status of the anteroventral thalamic nucleus in Down syndrome using samples from males and females ranging from 22-65 years in age and comparing to tissue from age matched controls. As expected, there was increased beta-amyloid plaque expression in the Down syndrome group. While there was a significant increase in neuronal density in the Down syndrome group, the values showed more variation consistent with a heterogeneous population. The surface area of the anteroventral thalamic nucleus was smaller in the Down syndrome group suggesting the increased neuronal density was due to greater neuronal packing but likely fewer overall neurons. There was a marked reduction in the proportion of neurons immunoreactive for the calcium-binding proteins calbindin, calretinin, and parvalbumin in individuals with Down syndrome. These findings highlight the vulnerability of calcium-binding proteins in the anteroventral nucleus in Down syndrome, which could both be driven by, and exacerbate, Alzheimer-related pathology in this region. [ABSTRACT FROM AUTHOR]

Summary: Sleep is a brain state characterised by a low vigilance level and diminished consciousness. Reaction to and processing of external stimuli is attenuated in sleep. During sleep, the reticular thalamic nucleus reduces the flow of sensory activity to the cerebral cortex through inhibition of the thalamus. This sensory gating process facilitates sleep. After reaching the afferent layers of primary cortex, the reduced sensory flow is adjusted, gained, and processed within various cortical layers before being transferred by the corticofugal system back to appropriate subdivisions of the thalamus as feedback. Thalamic subdivisions then dispatch this sensory information to related areas of the cerebral cortex, where it is (sub)consciously perceived. When necessary, a sleeping individual can be awakened by a wake‐up call, either by stimuli indicating danger, or by personally meaningful stimuli. It is safe for a sleeping individual that it can be aroused when necessary. Evidently, there are two processes by which the brain adjusts the response to sensory stimuli before entering (sub)consciousness. Firstly 'sensory gating', a process favourable to the maintenance of sleep by reducing the sensory input to the brain through the reticular thalamic nucleus and secondly 'sensory gaining', a process implying that the gained preserved sensory input is continuously analysed by the corticofugal system to detect dangerous and relevant environmental elements, indispensable for safeness and well‐being of the sleeper. [ABSTRACT FROM AUTHOR]

Background: The complexities of unilateral dystonia have led to exploring simultaneous (dual) globus pallidus internus (GPi) and motor ventral thalamus (Vim/Vop) deep brain stimulation (DBS), yet detailed assessments are lacking. Objectives: To assess the efficacy of GPi, Vim/Vop, and dual DBS in unilateral dystonia. Methods: Three patients with unilateral dystonia (two idiopathic, one acquired), implanted with two DBS electrodes targeting ipsilateral Vim/Vop and GPi, were included. Three stimulation modalities were assessed. First, one electrode was activated, then the other, and finally, both electrodes were activated simultaneously. Results: DBS yielded substantial symptomatic reductions in all three evaluated stimulation modalities. Patients exhibited varying responses regarding quality‐of‐life and depressive symptoms. Treatment satisfaction didn't align with clinical improvements, potentially affected by unrealistic expectations. Conclusions: This study contributes critical insights into GPi, Vim/Vop and simultaneous stimulation for unilateral dystonia. The safety of the procedure underscores the promise of this approach. [ABSTRACT FROM AUTHOR]

Efficient social interaction is essential for an adaptive life and consists of sequential processes of multisensory events with social counterparts. Social touch/contact is a unique component that promotes a sequence of social behaviours initiated by detection and approach to assess a social stimulus and subsequent touch/contact interaction to form prosocial relationships. We hypothesized that the thalamic sensory relay circuit from the posterior intralaminar nucleus of the thalamus (pIL) to the paraventricular nucleus of the hypothalamus (PVN) and the medial amygdala (MeA) plays a key role in the social contact‐mediated sequence of events. We found that neurons in the pIL along with the PVN and MeA were activated by social encounters and that pIL activity was more abundant in a direct physical encounter, whereas MeA activity was dominant in an indirect through grid encounter. Chemogenetic inhibition of pIL neurons selectively decreased the investigatory approach and sniffing of a same‐sex, but not an opposite‐sex, stimulus mouse in an indirect encounter situation and decreased the facial/snout contact ratio in a direct encounter setting. Furthermore, chemogenetic pIL inhibition had no impact on anxiety‐like behaviours or body coordinative motor behaviours, but it impaired whisker‐related and plantar touch tactile sense. We propose that the pIL circuit can relay social tactile sensations and mediate the sequence of nonsexual prosocial interactions through an investigatory approach to tactile contact and thus plays a significant role in establishing prosocial relationships in mouse models. [ABSTRACT FROM AUTHOR]

The ventral posterolateral nucleus (VPL), being categorized as the first‐order thalamic nucleus, is considered to be dedicated to uni‐modal somatosensory processing. Cross‐modal sensory interactions on thalamic reticular nucleus cells projecting to the VPL, on the other hand, suggest that VPL cells are subject to cross‐modal sensory influences. To test this possibility, the effects of auditory or visual stimulation on VPL cell activities were examined in anaesthetized rats, using juxta‐cellular recording and labelling techniques. Recordings were obtained from 70 VPL cells, including 65 cells responsive to cutaneous electrical stimulation of the hindpaw. Auditory or visual alone stimulation did not elicit cell activity except in three bi‐modal cells and one auditory cell. Cross‐modal alterations of somatosensory response by auditory and/or visual stimulation were recognized in 61 cells with regard to the response magnitude, latency (time and jitter) and/or burst spiking properties. Both early (onset) and late responses were either suppressed or facilitated, and de novo cell activity was also induced. Cross‐modal alterations took place depending on the temporal interval between the preceding counterpart and somatosensory stimulations, the intensity and frequency of sound. Alterations were observed mostly at short intervals (< 200 ms) and up to 800 ms intervals. Sounds of higher intensities and lower frequencies were more effective for modulation. The susceptibility to cross‐modal influences was related to cell location and/or morphology. These and previously reported similar findings in the auditory and visual thalamic nuclei suggest that cross‐modal sensory interactions pervasively take place in the first‐order sensory thalamic nuclei. [ABSTRACT FROM AUTHOR]

The thalamus is organized into nuclei that have distinct input and output connectivities with the cortex. Whereas first-order (FO) nuclei - also called core nuclei - relay input from sensory organs on the body surface and project to primary cortical sensory areas, higherorder (HO) nuclei - matrix nuclei - instead receive their driver input from the cortex and project to secondary and associative areas within cortico-thalamo-cortical loops. Input-dependent processes have been shown to play a crucial role in the emergence of FO thalamic neuron identity from a ground-state HO neuron identity, yet how this identity emerges during development remains unknown. Here, using single-cell RNA sequencing of the developing mouse embryonic thalamus, we show that, although they are born together, HO neurons start differentiating earlier than FO neurons. Within the FO visual thalamus, postnatal peripheral input is crucial for the maturation of excitatory, but not inhibitory, neurons. Our findings reveal different differentiation tempos and input sensitivities of HO and FO neurons, and highlight neuron type-specific molecular differentiation programs in the developing thalamus. [ABSTRACT FROM AUTHOR]

Understanding the molecular mechanisms underlying the generation of absence seizures is crucial for developing effective, patient-specific treatments for childhood absence epilepsy (CAE). Currently, one-third of patients remain refractive to the antiseizure medications (ASMs), previously called antiepileptic drugs (AEDs), available to treat CAE. Additionally, these ASMs often produce serious side effects and can even exacerbate symptoms in some patients. Determining the precise cellular and molecular mechanisms directly responsible for causing this type of epilepsy has proven challenging as they appear to be complex and multifactorial in patients with different genetic backgrounds. Aberrant neuronal activity in CAE may be caused by several mechanisms that are not fully understood. Thus, dissecting the causal factors that could be targeted in the development of precision medicines without side effects remains a high priority and the ultimate goal in this field of epilepsy research. The aim of this review is to highlight our current understanding of potential causative mechanisms for absence seizure generation, based on the latest research using cutting-edge technologies. This information will be important for identifying potential targets for future therapeutic intervention. [ABSTRACT FROM AUTHOR]

Thalamic brain areas play an important role in adaptive behaviors. Nevertheless, the population dynamics of thalamic relays during learning across sensory modalities remain unknown. Using a cross-modal sensory reward-associative learning paradigm combined with deep brain two-photon calcium imaging of large populations of auditory thalamus (medial geniculate body, MGB) neurons in male mice, we identified that MGB neurons are biased towards reward predictors independent of modality. Additionally, functional classes of MGB neurons aligned with distinct task periods and behavioral outcomes, both dependent and independent of sensory modality. During non-sensory delay periods, MGB ensembles developed coherent neuronal representation as well as distinct co-activity network states reflecting predicted task outcome. These results demonstrate flexible cross-modal ensemble coding in auditory thalamus during adaptive learning and highlight its importance in brain-wide cross-modal computations during complex behavior. The computational role of individual sensory thalamic nuclei in flexible encoding during adaptive behaviors is not fully understood. Here authors, using longitudinal deep brain two-photon calcium imaging, show that changes in mouse auditory thalamus single cell and neuronal population dynamics are predictive of task outcome in cross-modal associative learning. [ABSTRACT FROM AUTHOR]

Research into the role of thalamocortical circuits in anesthesia-induced unconsciousness is difficult due to anatomical and functional complexity. Prior neuroimaging studies have examined either the thalamus as a whole or focused on specific subregions, overlooking the distinct neuronal subtypes like core and matrix cells. We conducted a study of heathy volunteers and functional magnetic resonance imaging during conscious baseline, deep sedation, and recovery. We advanced the functional gradient mapping technique to delineate the functional geometry of thalamocortical circuits, within a framework of the unimodal-transmodal functional axis of the cortex. Here we show a significant shift in this geometry during deep sedation, marked by a transmodal-deficient geometry. This alteration is closely linked to the spatial variations in the matrix cell composition within the thalamus. This research bridges cellular and systems-level understanding, highlighting the crucial role of thalamic core–matrix functional architecture in understanding the neural mechanisms of states of consciousness. Anesthesia alters thalamocortical circuits, causing a shift from unimodal-transmodal functional geometry to a transmodal-deficient pattern. This change is associated with disrupted matrix cell connectivity, suggesting a mechanism for unconsciousness. [ABSTRACT FROM AUTHOR]

A substantial body of evidence implicates dysfunction in N -methyl- d -aspartate receptors (NMDARs) in the pathophysiology of schizophrenia. This article illustrates how NMDAR dysfunction may give rise to many of the neurobiological phenomena frequently associated with schizophrenia with a particular focus on how NMDAR dysfunction affects the thalamic reticular nucleus (nRT) and pedunculopontine tegmental nucleus (PPTg). Furthermore, this article presents a model for schizophrenia illustrating how dysfunction in the nRT may interrupt prefrontal regulation of midbrain dopaminergic neurons, and how dysfunction in the PPTg may drive increased, irregular burst firing. [ABSTRACT FROM AUTHOR]

The reticular thalamic nucleus (RTN) is a thin shell that covers the dorsal thalamus and controls the overall information flow from the thalamus to the cerebral cortex through GABAergic projections that contact thalamo-cortical neurons (TC). RTN neurons receive glutamatergic afferents fibers from neurons of the sixth layer of the cerebral cortex and from TC collaterals. The firing mode of RTN neurons facilitates the generation of sleep–wake cycles; a tonic mode or desynchronized mode occurs during wake and REM sleep and a burst-firing mode or synchronized mode is associated with deep sleep. Despite the presence of cannabinoid receptors CB1 (CB1Rs) and mRNA that encodes these receptors in RTN neurons, there are few works that have analyzed the participation of endocannabinoid-mediated transmission on the electrical activity of RTN. Here, we locally blocked or activated CB1Rs in ketamine anesthetized rats to analyze the spontaneous extracellular spiking activity of RTN neurons. Our results show the presence of a tonic endocannabinoid input, since local infusion of AM 251, an antagonist/inverse agonist, modifies RTN neurons electrical activity; furthermore, local activation of CB1Rs by anandamide or WIN 55212-2 produces heterogeneous effects in the basal spontaneous spiking activity, where the main effect is an increase in the spiking rate accompanied by a decrease in bursting activity in a dose-dependent manner; this effect is inhibited by AM 251. In addition, previous activation of GABA-A receptors suppresses the effects of CB1Rs on reticular neurons. Our results show that local activation of CB1Rs primarily diminishes the burst firing mode of RTn neurons. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate whether the dorsal claustrum receives afferent input from the intralaminar thalamic nuclei – centromedian nucleus, central lateral nucleus and paracentral nucleus. The intralaminar thalamic nuclei of eight cats were electrolytically lesioned. We obtained samples from the dorsal claustrum for electron microscopic analysis from the second to the seventh post-procedural day. Two types of degenerated synaptic boutons were observed: electron-dense which formed the majority of boutons, and electron-lucent comprising the remaining samples. Between the second and seventh post-procedural day, we observed a steady increase in the number of electron-dense boutons which were diffusely distributed throughout the dorsal claustrum. Electron-dense degenerated boutons formed asymmetrical contacts with dendritic spines as well as with small and medium-sized dendrites. In contrast, electron-lucent degenerated boutons were observed in earlier post-procedural periods and formed symmetrical axodendritic contacts. [ABSTRACT FROM AUTHOR]

• We examined volumetric and functional connectivity changes in the thalamus in Alzheimer's disease. • Medial group nuclei are significantly affected in Alzheimer's disease. • The thalamo-frontal and thalamo-occipital connections are affected in Alzheimer's disease. Memory processes known to be impaired in Alzheimer's disease (AD) are maintained by a large-scale neurocognitive network with subcortical components, including the thalamus. Therefore, we aimed to examine the volumetric and functional changes of the thalamic nuclei at different scales across AD stages. MRI data of patients diagnosed with 20 AD dementia (ADD), 30 amnestic mild cognitive impairment (MCI), and 30 subjective cognitive impairment (SCI) were used. Volumetric and functional connectivity analyzes were performed by dividing the thalamus into anterior, medial, posterior, lateral and intralaminar nucleus groups and their specific subnuclei. In the course of AD, the volume of the medial group nuclei, especially the mediodorsal medial magnocellular (MDm) nucleus, decreases. Medial group nuclei and MDm functional connectivity with frontal areas were decreased both in ADD and MCI compared to SCI group, while both of them increased their functional connectivity with visual areas in the ADD group compared to the MCI group. Our study suggests that the medial group of the thalamus, and specifically the MDm, may be affected in AD. Specific thalamic nuclei may be a critical anatomical region for investigating structural and functional changes in AD. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Abnormal thalamic nuclei volumes and their link to cognitive impairments have been observed in schizophrenia. However, whether and how this finding extends to the schizophrenia spectrum is unknown. We hypothesized a distinct pattern of aberrant thalamic nuclei volume across the spectrum and examined its potential associations with cognitive symptoms. Study Design We performed a FreeSurfer-based volumetry of T1-weighted brain MRIs from 137 healthy controls, 66 at-risk mental state (ARMS) subjects, 89 first-episode psychosis (FEP) individuals, and 126 patients with schizophrenia to estimate thalamic nuclei volumes of six nuclei groups (anterior, lateral, ventral, intralaminar, medial, and pulvinar). We used linear regression models, controlling for sex, age, and estimated total intracranial volume, both to compare thalamic nuclei volumes across groups and to investigate their associations with positive, negative, and cognitive symptoms. Study Results We observed significant volume alterations in medial and lateral thalamic nuclei. Medial nuclei displayed consistently reduced volumes across the spectrum compared to controls, while lower lateral nuclei volumes were only observed in schizophrenia. Whereas positive and negative symptoms were not associated with reduced nuclei volumes across all groups, higher cognitive scores were linked to lower volumes of medial nuclei in ARMS. In FEP, cognition was not linked to nuclei volumes. In schizophrenia, lower cognitive performance was associated with lower medial volumes. Conclusions Results demonstrate distinct thalamic nuclei volume reductions across the schizophrenia spectrum, with lower medial nuclei volumes linked to cognitive deficits in ARMS and schizophrenia. Data suggest a distinctive trajectory of thalamic nuclei abnormalities along the course of schizophrenia. [ABSTRACT FROM AUTHOR]

The thalamus plays a central coordinating role in the brain. Thalamic neurons are organized into spatially distinct nuclei, but the molecular architecture of thalamic development is poorly understood, especially in humans. To begin to delineate the molecular trajectories of cell fate specification and organization in the developing human thalamus, we used single-cell and multiplexed spatial transcriptomics. We show that molecularly defined thalamic neurons differentiate in the second trimester of human development and that these neurons organize into spatially and molecularly distinct nuclei. We identified major subtypes of glutamatergic neuron subtypes that are differentially enriched in anatomically distinct nuclei and six subtypes of γ-aminobutyric acid-mediated (GABAergic) neurons that are shared and distinct across thalamic nuclei.

The cerebellum and its thalamic projections to the primary motor cortex (M1) are well known to play an essential role in executing daily actions. Anatomic investigations in animals and postmortem humans have established the reciprocal connections between these regions; however, how these pathways can shape cortical activity in behavioral contexts and help promote recovery in neuropathological conditions remains not well understood. The present review aims to provide a comprehensive description of these pathways in animals and humans and discuss how novel noninvasive brain stimulation (NIBS) methods can be used to gain a deeper understanding of the cerebellar-M1 connections. In the first section, we focus on recent animal literature that details how information sent from the cerebellum and thalamus is integrated into an broad network of cortical motor neurons. We then discuss how NIBS approaches in humans can be used to reliably assess the connectivity between the cerebellum and M1. Moreover, we provide the latest perspectives on using advanced NIBS approaches to investigate and modulate multiple cerebellar-cortical networks involved in movement behavior and plasticity. Finally, we discuss how these emerging methods have been used in translation research to produce long-lasting modifications of cerebellar-thalamic-M1 to restore cortical activity and motor function in neurologic patients. [ABSTRACT FROM AUTHOR]

Anhedonia stands as a life-threatening transdiagnostic feature of many mental illnesses, most notably major depression and involves neural circuits for processing reward information. The paraventricular nucleus of the thalamus (PVT) is associated with reward-seeking behavior, however, links between the PVT circuit and anhedonia have not been investigated in humans. In a sample of adults with and without psychiatric symptoms (n = 75, 18–41 years, 55 female), we generated an anhedonia factor score for each participant using a latent factor analysis, utilizing data from depression and anxiety assessments. Functional connectivity between the PVT and the nucleus accumbens (NAc) was calculated from high-resolution (1.5 mm) resting state fMRI. Anhedonia factor scores showed a positive relationship with functional connectivity between the PVT and the NAc, principally in males and in those with psychiatric symptoms. In males, connectivity between other midline thalamic nuclei and the NAc did not show these relationships, suggesting that this link may be specific to PVT. This cohort was originally recruited to study depression and not anhedonia per se. The distribution of male and female participants in our cohort was not equal. Partial acquisition in high-resolution fMRI scans restricted regions of interest outside of the thalamus and reward networks. We report evidence that anhedonia is associated with enhanced functional connectivity between the PVT and the NAc, regions that are relevant to reward processing. These results offer clues as to the potential prevention and prevention and treatment of anhedonia. • Anhedonia has been associated with alterations in reward processing neural circuits. • The paraventricular nucleus of the thalamus (PVT) projects to reward and threat regions. • Altering PVT is associated with anhedonia in animal models. • In humans, anhedonia symptoms are associated with increased functional connectivity between PVT and nucleus accumbens, particularly in males. • This provides evidence that the human PVT circuit is involved in anhedonia. [ABSTRACT FROM AUTHOR]

The cerebral cortex contains multiple, distinct areas that individually perform specific computations. A particular strength of the cortex is the communication of signals between cortical areas that allows the outputs of these compartmentalized computations to influence and build on each other, thereby dramatically increasing the processing power of the cortex and its role in sensation, action, and cognition. Determining how the cortex communicates signals between individual areas is, therefore, critical for understanding cortical function. Historically, corticocortical communication was thought to occur exclusively by direct anatomical connections between areas that often sequentially linked cortical areas in a hierarchical fashion. More recently, anatomical, physiological, and behavioral evidence is accumulating indicating a role for the higher-order thalamus in corticocortical communication. Specifically, the transthalamic pathway involves projections from one area of the cortex to neurons in the higher-order thalamus that, in turn, project to another area of the cortex. Here, we consider the evidence for and implications of having two routes for corticocortical communication with an emphasis on unique processing available in the transthalamic pathway and the consequences of disorders and diseases that affect transthalamic communication. [ABSTRACT FROM AUTHOR]

Synchronization of spikes carried by the visual streams is strategic for the proper binding of cortical assemblies, hence for the perception of visual objects as coherent units. Perception of a complex visual scene involves multiple trains of gamma oscillations, coexisting at each stage in visual and associative cortex. Here, we analyze how this synchrony is managed, so that the perception of each visual object can emerge despite this complex interweaving of cortical activations. After a brief review of structural and temporal facts, we analyze the interactions which make the oscillations coherent for the visual elements related to the same object. We continue with the propagation of these gamma oscillations within the sensory chain. The dominant role of the pulvinar and associated reticular thalamic nucleus as cortical coordinator is the common thread running through this step-by-step description. Synchronization mechanisms are analyzed in the context of visual perception, although the present considerations are not limited to this sense. A simple experiment is described, with the aim of assessing the validity of the elements developed here. A first set of results is provided, together with a proposed method to go further in this investigation. [ABSTRACT FROM AUTHOR]

The rat lateral posterior thalamic nucleus (LP) is composed of the rostromedial (LPrm), lateral (LPl), and caudomedial parts, with LPrm and LPl being areas involved in information processing within the visual cortex. Nevertheless, the specific differences in the subcortical projections to the LPrm and LPl remain elusive. In this study, we aimed to reveal the subcortical regions that project axon fibers to the LPl and LPrm using a retrograde neural tracer, Fluorogold (FG). After FG injection into the LPrm or LPl, the area was visualized immunohistochemically. Retrogradely labeled neurons from the LPrm were distributed in the retina and the region from the diencephalon to the medulla oblongata. Diencephalic labeling was found in the reticular thalamic nucleus (Rt), zona incerta (ZI), ventral lateral geniculate nucleus (LGv), intergeniculate leaflet (IGL), and hypothalamus. In the midbrain, prominent labeling was found in the periaqueductal gray (PAG) and deep layers of the superior colliculus. Additionally, retrograde labeling was observed in the cerebellar and trigeminal nuclei. When injected into the LPl, several cell bodies were labeled in the visual-related regions, including the retina, LGv, IGL, and olivary pretectal nucleus (OPT), as well as in the Rt and anterior pretectal nucleus (APT). Less labeling was found in the cerebellum and medulla oblongata. When the number of retrogradely labeled neurons from the LPrm or LPl was compared as a percentage of total subcortical labeling, a larger percentage of subcortical inputs to the LPl included projections from the APT, OPT, and Rt, whereas a large proportion of subcortical inputs to the LPrm originated from the ZI, reticular formation, and PAG. These results suggest that LPrm not only has visual but also multiple sensory-and motor-related functions, whereas the LPl takes part in a more visual-specific role. This study enhances our understanding of subcortical neural circuits in the thalamus and may contribute to our exploration of the mechanisms and disorders related to sensory perception and sensory-motor integration. [ABSTRACT FROM AUTHOR]

A 55‐year‐old Japanese woman with a history of hypertension and right putaminal hemorrhage developed simultaneous hemorrhages in the left thalamus and putamen and died 24 h later. There were no vascular anomalies in the brain. Synaptophysin immunostaining combined with eosin azure 50 (EA50) staining clearly identified the hematoma and the surrounding brain structures. In the right cerebral hemisphere, a cystic lesion as a sequela of the usual type of hypertensive putaminal hematoma was evident. In the left cerebral hemisphere, two fresh hematomas were evident. One was a thalamic hematoma, which had destroyed the dorsal and medial structures of the thalamus, and the other was an unusual putaminal hematoma, which had destroyed the entire putamen and crossed the internal capsule and caudate nucleus. α‐Smooth muscle actin immunostaining combined with EA50 and Victoria bleu staining demonstrated three ruptured arteries associated with fibrin aggregates in the anterior thalamic nucleus and anterior putamen. Some circular structures composed of fibrin, suggesting the presence of ruptured arteries in the neighborhood, were evident in the thalamus and putamen. In the putamen, ruptured arteries and circular structures were present in the lateral to medial areas. Fibrin aggregates in the anterior thalamic nucleus were more numerous than those in the putamen. On the basis of these findings, we concluded that: (i) the artery with numerous fibrin aggregates in the anterior thalamic nucleus had ruptured first, followed by the arteries distributed in other parts of the thalamus and putamen; (ii) the unusual putaminal hematoma was attributable to rupture of the arteries around the center of the putamen, which are not responsible for the usual type of hypertensive putaminal hematoma; and (iii) it is suggested that even if hypertensive hemorrhage occurs simultaneously in the ipsilateral putamen and thalamus, the usual type of hypertensive mixed‐type hematoma does not form. [ABSTRACT FROM AUTHOR]

The human septum verum represents a small but clinically important region of the brain. Based on the results of animal experiments, the stimulation of its medial part was recently proposed with various indications like epilepsy or cognitive impairment after traumatic brain injury. The aim of our study was to present the anatomical relationships of the human septum verum using fiber dissection and histological analysis to support its research and provide essential information for future deep brain stimulation therapies. 16 human cadaveric brains were dissected according to Klingler's method. To validate our macroscopical findings, 12 samples obtained from the dissected brains and 2 additional specimens from unfrozen brains were prepared for histological examinations. We identified the following white matter connections of the septum verum: (1) the precommissural fibers of the fornix; (2) the inferior fascicle of the septum pellucidum; (3) the cingulum; (4) the medial olfactory stria; (5) the ventral amygdalofugal pathway; (6) the stria medullaris of the thalamus and (7) the stria terminalis. Moreover, we could distinguish a less-known fiber bundle connecting the postcommissural column of the fornix to the stria medullaris of the thalamus and the anterior thalamic nuclei. In this study we present valuable anatomical information about this region to promote safe and effective deep brain stimulation therapies in the future. [ABSTRACT FROM AUTHOR]

Psychedelics like LSD (Lysergic acid diethylamide) and psilocybin are known to modulate perceptual modalities due to the activation of mostly serotonin receptors in specific cortical (e.g., visual cortex) and subcortical (e.g., thalamus) regions of the brain. In the visual domain, these psychedelic modulations often result in peculiar disturbances of viewed objects and light and sometimes even in hallucinations of non-existent environments, objects, and creatures. Although the underlying processes are poorly understood, research conducted over the past twenty years on the subjective experience of psychedelics details theories that attempt to explain these perceptual alterations due to a disruption of communication between cortical and subcortical regions. However, rare medical conditions in the visual system like Charles Bonnet syndrome that cause perceptual distortions may shed new light on the additional importance of the retinofugal pathway in psychedelic subjective experiences. Interneurons in the retina called amacrine cells could be the first site of visual psychedelic modulation and aid in disrupting the hierarchical structure of how humans perceive visual information. This paper presents an understanding of how the retinofugal pathway communicates and modulates visual information in psychedelic and clinical conditions. Therefore, we elucidate a new theory of psychedelic modulation in the retinofugal pathway. [ABSTRACT FROM AUTHOR]

Current concepts of corticothalamic organization in the mammalian brain are mainly based on sensory systems, with less focus on circuits for higher-order cognitive functions. In sensory systems, first-order thalamic relays are driven by subcortical inputs and modulated by cortical feedback, while higher-order relays receive strong excitatory cortical inputs. The applicability of these principles beyond sensory systems is uncertain. We investigated mouse prefronto-thalamic projections to the midline thalamus, revealing distinct top-down control. Unlike sensory systems, this pathway relies on indirect modulation via the thalamic reticular nucleus (TRN). Specifically, the prelimbic area, which influences emotional and motivated behaviors, impacts instrumental avoidance responses through direct and indirect projections to the paraventricular thalamus. Both pathways promote defensive states, but the indirect pathway via the TRN is essential for organizing avoidance decisions through disinhibition. Our findings highlight intra-thalamic circuit dynamics that integrate cortical cognitive signals and their role in shaping complex behaviors. How prefronto-thalamic circuits shape emotional and motivated behaviors are not fully understood. Here authors report a top-down modulation in mouse prefronto-thalamic projections. The prelimbic area influences avoidance via direct and indirect pathways, revealing distinctive intrathalamic dynamics essential for complex behavior integration. [ABSTRACT FROM AUTHOR]

Neurons in the caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt) that express the glucagon gene (Gcg) give rise to glucagon-like peptide 1 (GLP1)-immunopositive axons in the spinal cord and many subcortical brain regions. Central GLP1 receptor signaling contributes to motivated behavior and stress responses in rats and mice, in which hindbrain GLP1 neurons are activated to express c-Fos in a metabolic state-dependent manner. The present study examined whether GLP1 inputs to distinct brain regions arise from distinct subsets of Gcg-expressing neurons, and mapped the distribution of axon collaterals arising from projection-defined GLP1 neural populations. Using our Gcg-Cre knock-in rat model, Cre-dependent adeno-associated virus (AAV) tracing was conducted in adult male and female rats to compare axonal projections of IRt versus cNTS GLP1 neurons. Overlapping projections were observed in all brain regions that receive GLP1 input, with the caveat that cNTS injections produced Cre-dependent labeling of some IRt neurons, and vice versa. In additional experiments, specific diencephalic or limbic forebrain nuclei were microinjected with Cre-dependent retrograde AAVs (AAVrg) that expressed reporters to fully label the axon collaterals of transduced GLP1 neurons. AAVrg injected into each forebrain site labeled Gcg-expressing neurons in both the cNTS and IRt. The collective axon collaterals of labeled neurons entered the spinal cord and every brain region previously reported to contain GLP1-positive axons. These results indicate that the axons of GLP1 neural populations that innervate the thalamic paraventricular nucleus, paraventricular nucleus of the hypothalamus, and/or bed nucleus of the stria terminalis collectively innervate all central regions that receive GLP1 axonal input. [ABSTRACT FROM AUTHOR]

Metabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively), as well as the cortical layers involved in CT signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (adeno-associated virus-CRE mediated) and cell-type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knock-out (PVgrm8 knock-out) mice exhibited (1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and (2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field test (OFT). Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRNgrm8 knockdown) in repeated OFT. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function. [ABSTRACT FROM AUTHOR]

Consciousness, a cornerstone of human cognition, is believed to arise from complex neural interactions. Traditional views have focused on localized fronto-parietal networks or broader inter-regional dynamics. In our study, we leverage advanced fMRI techniques, including the novel Functionnectome framework, to unravel the intricate relationship between brain circuits and functional activity shaping visual consciousness. Our findings underscore the importance of the superior longitudinal fasciculus within the fronto-parietal fibers, linking conscious perception with spatial neglect. Additionally, our data reveal the critical contribution of the temporo-parietal fibers and the splenium of the corpus callosum in connecting visual information with conscious representation and their verbalization. Central to these networks is the thalamus, posited as a conductor in synchronizing these interactive processes. Contrasting traditional fMRI analyses with the Functionnectome approach, our results emphasize the important explanatory power of interactive mechanisms over localized activations for visual consciousness. This research paves the way for a comprehensive understanding of consciousness, highlighting the complex network of neural connections that lead to awareness. Advanced fMRI, including the Functionnectome framework, reveals that visual consciousness arises from complex neural interactions, involving the superior longitudinal fasciculus, temporo-parietal fibers, the corpus callosum, and thalamic radiations [ABSTRACT FROM AUTHOR]

• Region-specific cerebral metabolic alterations existed in PD patients with different cognitive status. • tCr amounts varied during PD progression and is not suitable as an internal control metabolite in PCC and left thalamus regions. • The combination of thalamic and PCC metabolites showed a 75.6% accuracy in distinguishing PDMCI patients from PDN patients. N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) are brain metabolites involved in some key neuronal functions within the brain, such as cognitive function. The aim of this study was to investigate whether Parkinson's disease (PD) with different cognitive status induces regional brain metabolite differences. 38 diagnosed PD patients, including 18 PD patients with normal cognitive (PDN), 20 PD subjects with cognitive impairment (PDMCI) and 25 healthy controls (HC) participated in this study. All subjects underwent a single-voxel proton MR spectroscopy (1H-MRS) on a 3T scanner. 1H-MRS were obtained from bilateral PCC, left thalamus and PFC regions in all subjects, respectively. Region-specific cerebral metabolic alterations existed in PD patients with different cognitive status. PDMCI patients showed a significant reduction of NAA, Cho and tCr in the PCC and left thalamus, compared to healthy controls; whereas lower levels of NAA and Cho in thalamus were found in PDN patients. Moreover, Cho and tCr levels were positively correlated with MMSE scores. Both NAA and tCr in PCC levels were positively correlated with MMSE and MoCA scores. The combination of thalamic and PCC metabolites showed a 75.6% accuracy in distinguishing PDMCI patients from PDN patients. This study provides preliminary evidence that thalamic, PCC and PFC neurometabolic alterations occur in PD patients with cognition decline. Findings of this study indicate that NAA and tCr abnormalities in PCC and thalamus might be used as a biomarker to track cognitive decline in Parkinson's disease in clinical settings. [ABSTRACT FROM AUTHOR]

Perception is largely supported by cortical processing that involves communication among multiple areas, typically starting with primary sensory cortex and then involving higher order cortices. This communication is served in part by transthalamic (cortico-thalamo-cortical) pathways, which ubiquitously parallel direct corticocortical pathways, but their role in sensory processing has largely remained unexplored. Here, we suggest that transthalamic processing propagates task-relevant information required for correct sensory decisions. Using optogenetics, we specifically inhibited the pathway at its synapse in higher order somatosensory thalamus of mice performing a texture-based discrimination task. We concurrently monitored the cellular effects of inhibition in primary or secondary cortex using two-photon calcium imaging. Inhibition severely impaired performance despite intact direct corticocortical projections, thus challenging the purely corticocentric map of perception. Interestingly, the inhibition did not reduce overall cell responsiveness to texture stimulation in somatosensory cortex, but rather disrupted the texture selectivity of cells, a discriminability that develops over task learning. This discriminability was more disrupted in the secondary than primary somatosensory cortex, emphasizing the feedforward influence of the transthalamic route. Transthalamic pathways may therefore act to deliver performance-relevant information to higher order cortex and are underappreciated hierarchical pathways in perceptual decision-making. Perceptual signaling is understood to involve direct cortical projections. Here, the authors show that cortical signaling via higher order thalamus is necessary for somatosensory discrimination and stimulus selectivity in higher order cortical cells. [ABSTRACT FROM AUTHOR]

Introduction: Pharmacoresistant epilepsy is a multicomponent disease that can be successfully treated surgically if the surgical tactics are properly defined. We present the first case of stimulation of anterior thalamic nuclei in pharmacoresistant epilepsy in Kazakhstan. This will be a new opportunity for Kazakhstanis diagnosed with epilepsy to achieve stable epilepsy remission. Materials: The patient was born in 2000. The first episode of tonic clonic seizures with loss of consciousness occurred in 2014. Repeatedly underwent therapeutic and diagnostic measures in the neurological department. The frequency of seizures increased in dynamics. The results of instrumental examination revealed the following morphological changes: Morphological changes: Focal cortical dysplasia (FCD) in the left cingulate gyrus, hypometabolism in the left thalamus and forehead, signs of hippocampal sclerosis on both sides. Electroencephalogram (EEG) shows activity in frontal areas on both sides, more on the right. Based on clinical and instrumental data according to the 2017 ILAE classification, the diagnosis was Structural focal frontal lobe epilepsy with bilateral tonic-clonic seizures. FCD of the left cingulate gyrus. Resistance to antiepileptic therapy. Methods: The patient was hospitalized in the department of neurosurgery. In light of the evidence indicating structural changes in the brain substance and ambiguous EEG findings, the indications for deep brain stimulation (DBS) of the anterior nucleus (ANT) were made. Electrode implantation was performed under general anesthesia, and preoperative computer tomography (CT) scans were performed using the CRWR stereotactic system in combination with magnetic resonance imaging (MRI) scans using Brainlab Neuronavigation with 3D Atlas to identify the anterior thalamic nuclei. Conclusion: The observed structural changes in the brain substance and the ambiguous EEG results call into question the efficacy of surgical procedures aimed at removing existing foci or destroying them. Based on the above, as well as the experience of foreign colleagues, the choice of neurosurgeons was DBS ANT. Although the selection of ideal candidates for thalamic stimulation is still controversial, in the described case we were able to achieve control of seizure activity. The patient was seizure free for 2 months after surgery. The patient was discharged on postoperative day 7. [ABSTRACT FROM AUTHOR]

The dominant models of learning and memory, such as Hebbian plasticity, propose that experiences are transformed into memories through input-specific synaptic plasticity at the time of learning. However, synaptic plasticity is neither strictly input-specific nor restricted to the time of its induction. The impact of such forms of non-Hebbian plasticity on memory has been difficult to test, and hence poorly understood. Here, we demonstrate that synaptic manipulations can deviate from the Hebbian model of learning, yet produce a lasting memory. First, we established a weak associative conditioning protocol in mice, where optogenetic stimulation of sensory thalamic input to the amygdala was paired with a footshock, but no detectable memory was formed. However, when the same input was potentiated minutes before or after, or even 24 hr later, the associative experience was converted into a lasting memory. Importantly, potentiating an independent input to the amygdala minutes but not 24 hr after the pairing produced a lasting memory. Thus, our findings suggest that the process of transformation of a transient experience into a memory is neither restricted to the time of the experience nor to the synapses triggered by it; instead, it can be influenced by past and future events. [ABSTRACT FROM AUTHOR]

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

Heterologous sensitization of adenylyl cyclase (AC) results in elevated cAMP signaling transduction that contributes to drug dependence. Inhibiting cullin3-RING ligases by blocking the neddylation of cullin3 abolishes heterologous sensitization, however, the modulating mechanism remains uncharted. Here, we report an essential role of the potassium channel tetramerization domain (KCTD) protein 2, 5, and 17, especially the dominant isoform KCTD5 in regulating heterologous sensitization of AC1 and morphine dependence via working with cullin3 and the cullin-associated and neddylation-dissociated 1 (CAND1) protein. In cellular models, we observed enhanced association of KCTD5 with Gβ and cullin3, along with elevated dissociation of Gβ from AC1 as well as of CAND1 from cullin3 in heterologous sensitization of AC1. Given binding of CAND1 inhibits the neddylation of cullin3, we further elucidated that the enhanced interaction of KCTD5 with both Gβ and cullin3 promoted the dissociation of CAND1 from cullin3, attenuated the inhibitory effect of CAND1 on cullin3 neddylation, ultimately resulted in heterologous sensitization of AC1. The paraventricular thalamic nucleus (PVT) plays an important role in mediating morphine dependence. Through pharmacological and biochemical approaches, we then demonstrated that KCTD5/cullin3 regulates morphine dependence via modulating heterologous sensitization of AC, likely AC1 in PVT in mice. In summary, the present study revealed the underlying mechanism of heterologous sensitization of AC1 mediated by cullin3 and discovered the role of KCTD proteins in regulating morphine dependence in mice. Heterologous sensitization of adenylyl cyclase (AC) contributes to drug dependence. This study shows that KCTD proteins 2, 5 and 17 regulate AC heterologous sensitization by enabling Cullin3 neddylation, and identifies a crucial role of this pathway in the paraventricular thalamic nucleus in regulating morphine dependence. [ABSTRACT FROM AUTHOR]

Rodents continuously move their heads and whiskers in a coordinated manner while perceiving objects through whisker-touch. Studies in head-fixed rodents showed that the ventroposterior medial (VPM) and posterior medial (POm) thalamic nuclei code for whisker kinematics, with POm involvement reduced in awake animals. To examine VPM and POm involvement in coding head and whisker kinematics in awake, head-free conditions, we recorded thalamic neuronal activity and tracked head and whisker movements in male mice exploring an open arena. Using optogenetic tagging, we found that in freely moving mice, both nuclei equally coded whisker kinematics and robustly coded head kinematics. The fraction of neurons coding head kinematics increased after whisker trimming, ruling out whisker-mediated coding. Optogenetic activation of thalamic neurons evoked overt kinematic changes and increased the fraction of neurons leading changes in head kinematics. Our data suggest that VPM and POm integrate head and whisker information and can influence head kinematics during tactile perception. Whether the posterior medial (POm) thalamic nucleus processes whisking kinematics was not clear from studies in head-fixed rodents. By studying freely moving mice, here authors demonstrate that the POm does encode whisker kinematics. Additionally, they show that both POm and the ventroposterior medial (VPM) thalamic nuclei process and can influence head kinematics. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a central disorder characterized by chronic pain, fatigue, insomnia, depression, and other minor symptoms. Knowledge about pathogenesis is lacking, diagnosis difficult, clinical approach puzzling, and patient management disappointing. We conducted a theoretical study based on literature data and computational analysis, aimed at developing a comprehensive model of FM pathogenesis and addressing suitable therapeutic targets. We started from the evidence that FM must involve a dysregulation of central pain processing, is female prevalent, suggesting a role for the hypothalamus-pituitary-gonadal (HPG) axis, and is stress-related, suggesting a role for the HP-adrenocortical (HPA) axis. Central pathogenesis was supposed to involve a pain processing loop system including the thalamic ventroposterolateral nucleus (VPL), the primary somatosensory cortex (SSC), and the thalamic reticular nucleus (TRN). For decreasing GABAergic and/or increasing glutamatergic transmission, the loop system crosses a bifurcation point, switching from monostable to bistable, and converging on a high-firing-rate steady state supposed to be the pathogenic condition. Thereafter, we showed that GABAergic transmission is positively correlated with gonadal-hormone-derived neurosteroids, notably allopregnanolone, whereas glutamatergic transmission is positively correlated with stress-induced glucocorticoids, notably cortisol. Finally, we built a dynamic model describing a multistable, double-inhibitory loop between HPG and HPA axes. This system has a high-HPA/low-HPG steady state, allegedly reached in females under combined premenstrual/postpartum brain allopregnanolone withdrawal and stress condition, driving the thalamocortical loop to the high-firing-rate steady state, and explaining the connection between endocrine and neural mechanisms in FM pathogenesis. Our model accounts for FM female prevalence and stress correlation, suggesting the use of neurosteroid drugs as a possible solution to currently unsolved problems in the clinical treatment of the disease. [ABSTRACT FROM AUTHOR]

Objective: Although the clinical efficacy of deep brain stimulation targeting the anterior nucleus (AN) and centromedian nucleus (CM) of the thalamus has been actively investigated for the treatment of medication‐resistant epilepsy, few studies have investigated dynamic ictal changes in corticothalamic connectivity in human electroencephalographic (EEG) recording. This study aims to establish the complex spatiotemporal dynamics of the ictal corticothalamic network associated with various seizure foci. Methods: We analyzed 10 patients (aged 2.7–28.1 years) with medication‐resistant focal epilepsy who underwent stereotactic EEG evaluation with thalamic sampling. We examined both undirected and directed connectivity, incorporating coherence and spectral Granger causality analysis (GCA) between the diverse seizure foci and thalamic nuclei (AN and CM) at ictal onset. Results: In our analysis of 36 seizures, coherence between seizure onset and thalamic nuclei increased across all frequencies, especially in slower bands (delta, theta, alpha). GCA showed increased information flow from seizure onset to the thalamus across all frequency bands, but outflows from the thalamus were mainly in slower frequencies, particularly delta. In the subgroup analysis based on various seizure foci, the delta coherence showed a more pronounced increase at CM than at AN during frontal lobe seizures. Conversely, in limbic seizures, the delta coherence increase was greater at AN compared to CM. Significance: It appears that the delta frequency plays a pivotal role in modulating the corticothalamic network during seizures. Our results underscore the significance of comprehending the spatiotemporal dynamics of the corticothalamic network at ictal onset, and this knowledge could guide personalized responsive neuromodulation treatment strategies. [ABSTRACT FROM AUTHOR]

During magnetic-resonance-guided focused ultrasound ablation of the ventral intermediate thalamic nucleus (VIM) for essential tremor (ET) and Parkinson's disease (PD), targeting is generally performed using a standard atlas-based stereotactic approach. The purpose of our work is to evaluate the anatomic variations in the venous vasculature of the thalamus in patients treated with MRgFUS, as a possible landmark for targeting. We retrospectively evaluated the relationship between the obtained thalamotomy lesion and the ipsilateral superior thalamic vein (STV). A total of 36 patients (25 ET and 11 PD) who underwent MRgFUS treatment were evaluated, and the STV was studied with susceptibility weighted imaging (SWI) sequences. Based on the axial SWI images, the distance between the STV and the center of the lesion at the presumed site of the VIM was measured in follow-up MRI images one month after treatment. Statistical analysis shows that there is a correlation between the STV and the presumed site of the VIM. The STV visible in SWI could be used as an additional, real-time, and patient-specific anatomical landmark for VIM identification during MR examination and just before and during FUS treatment. [ABSTRACT FROM AUTHOR]

Enkephalins are endogenous opioid pentapeptides that play a role in neurotransmission and pain modulation in vertebrates. However, the distribution pattern of enkephalinergic neurons in the brains of reptiles has been understudied. This study reports the organization of the methionine-enkephalin (M-ENK) and leucine-enkephalin (L-ENK) neuronal systems in the central nervous system of the gecko Hemidactylus frenatus using an immunofluorescence labeling method. Although M-ENK and L-ENK-immunoreactive (ir) fibers extended throughout the pallial and subpallial subdivisions, including the olfactory bulbs, M-ENK and L-ENK-ir cells were found only in the dorsal septal nucleus. Enkephalinergic perikarya and fibers were highly concentrated in the periventricular and lateral preoptic areas, as well as in the anterior and lateral subdivisions of the hypothalamus, while enkephalinergic innervation was observed in the hypothalamic periventricular nucleus, infundibular recess nucleus and median eminence. The dense accumulation of enkephalinergic content was noticed in the pars distalis of the hypophysis. In the thalamus, the nucleus rotundus and the dorsolateral, medial, and medial posterior thalamic nuclei contained M-ENK and L-ENK-ir fibers, whereas clusters of M-ENK and L-ENK-ir neurons were observed in the pretectum, mesencephalon, and rhombencephalon. The enkephalinergic fibers were also seen in the area X around the central canal, as well as the dorsal and ventral horns. The widespread distribution of enkephalin-containing neurons within the central nervous system implies that enkephalins regulate a variety of functions in the gecko, including sensory, behavioral, hypophysiotropic, and neuroendocrine functions. [ABSTRACT FROM AUTHOR]

Objective: To analyze the local field potentials (LFPs) in patients with focal drugresistant epilepsy (DRE) from the anterior nucleus of the thalamus (ANT) during inter-ictal state and seizure state. Method: ANT stereotactic EEG (SEEG) recordings were studied in four patients with focal temporal lobe epilepsy. SEEG data was classified as inter-ictal and ictal state and sub-categorized into electrographic (ESz), focal aware seizure (FAS), focal with impaired awareness (FIA), or focal to bilateral tonic-clonic seizure (FBTC). LFP was analyzed at 4 Hz, 8 Hz, 16 Hz, 32 Hz, high gamma (100 Hz), and ripples (200 Hz) using spectrogram analysis and a statistical comparison of normalized power spectral density (PSD) averaged during seizures versus preictal baseline segments. Result: The LFP recordings were analyzed for 162 seizures (127 ESz, 23 FAS, 6 FIA, and 6 FBTC). Based on time-frequency data (spectrogram), a broad band of activity, occurring between 2 and 6 Hz and centered at 4 Hz, and thin-band activity occurring specifically at 8 Hz on the frequency spectrogram were observed during the inter-ictal state. Statistically significant changes in LFP-PSD were seen for FAS, FIA, and FBTC. We observed a significant gain in LFP at the lower frequency band during FAS at 4 Hz, FIA, and FBTC at 4, 8, and 16 Hz while also observing increases at higher frequencies during FBTC at 100 and 200 Hz and a decrease during FAS seizures at 32 Hz. In contrast, no significant change in LFP power was seen for electrographic seizures. Interpretation: Our observations from a limited dataset indicate that all clinical seizure types, but not electrographic seizures, caused a change in ANT-LFP based on the magnitude of the associated power spectral density (PSD). Future work will be needed to validate the use of ANT-LFP at these frequencies as accurate measurements of seizure occurrence and severity. This work represents a first step toward understanding ANT thalamic LFP patterns during focal seizures and developing adaptive DBS strategies. [ABSTRACT FROM AUTHOR]

We report the case of a 53-year-old man who was diagnosed with Holmes tremor and underwent deep brain stimulation of the ventro-intermediate thalamic nucleus and posterior subthalamic area. We assessed the patients' tremor with the Fahn-Tolosa-Marin Tremor Rating Scale at 1, 3, 6, 12 and 24 months after deep brain stimulation. Deep brain stimulation relieved the patient's tremor during the 24-month follow-up period. [ABSTRACT FROM AUTHOR]

While light can affect emotional and cognitive processes of the medial prefrontal cortex (mPFC), no light-encoding was hitherto identified in this region. Here, extracellular recordings in awake mice revealed that over half of studied mPFC neurons showed photosensitivity, that was diminished by inhibition of intrinsically photosensitive retinal ganglion cells (ipRGCs), or of the upstream thalamic perihabenular nucleus (PHb). In 15% of mPFC photosensitive neurons, firing rate changed monotonically along light-intensity steps and gradients. These light-intensity-encoding neurons comprised four types, two enhancing and two suppressing their firing rate with increased light intensity. Similar types were identified in the PHb, where they exhibited shorter latency and increased sensitivity. Light suppressed prelimbic activity but boosted infralimbic activity, mirroring the regions' contrasting roles in fear-conditioning, drug-seeking, and anxiety. We posit that prefrontal photosensitivity represents a substrate of light-susceptible, mPFC-mediated functions, which could be ultimately studied as a therapeutical target in psychiatric and addiction disorders. The medial prefrontal cortex (mPFC) orchestrates multifaceted light-sensitive cognitive and emotional processes. Here, Zangen et al. show mPFC neuronal encoding of environmental light intensity, and propose a pathway that may drive this encoding. [ABSTRACT FROM AUTHOR]

A key to motor control is the motor thalamus, where several inputs converge. One excitatory input originates from layer 5 of primary motor cortex (M1L5), while another arises from the deep cerebellar nuclei (Cb). M1L5 terminals distribute throughout the motor thalamus and overlap with GABAergic inputs from the basal ganglia output nuclei, the internal segment of the globus pallidus (GPi), and substantia nigra pars reticulata (SNr). In contrast, it is thought that Cb and basal ganglia inputs are segregated. Therefore, we hypothesized that one potential function of the GABAergic inputs from basal ganglia is to selectively inhibit, or gate, excitatory signals from M1L5 in the motor thalamus. Here, we tested this possibility and determined the circuit organization of mouse (both sexes) motor thalamus using an optogenetic strategy in acute slices. First, we demonstrated the presence of a feedforward transthalamic pathway from M1L5 through motor thalamus. Importantly, we discovered that GABAergic inputs from the GPi and SNr converge onto single motor thalamic cells with excitatory synapses from M1L5. Separately, we also demonstrate that, perhaps unexpectedly, GABAergic GPi and SNr inputs converge with those from the Cb. We interpret these results to indicate that a role of the basal ganglia is to gate the thalamic transmission of M1L5 and Cb information to cortex. [ABSTRACT FROM AUTHOR]

Defining the brain mechanisms underlying initial emotional evaluation is a key but unexplored clue to understanding affective processing. Event-related potentials (ERPs), especially suited for investigating this issue, were recorded in two experiments (n = 36 and n = 35). We presented emotionally negative (spiders) and neutral (wheels) silhouettes homogenized regarding their visual parameters. In Experiment 1, stimuli appeared at fixation or in the periphery (200 trials per condition and location), the former eliciting a N40 (39 milliseconds) and a P80 (or C1: 80 milliseconds) component, and the latter only a P80. In Experiment 2, stimuli were presented only at fixation (500 trials per condition). Again, an N40 (45 milliseconds) was observed, followed by a P100 (or P1: 105 milliseconds). Analyses revealed significantly greater N40-C1P1 peak-to-peak amplitudes for spiders in both experiments, and ANCOVAs showed that these effects were not explained by C1P1 alone, but that processes underlying N40 significantly contributed. Source analyses pointed to V1 as an N40 focus (more clearly in Experiment 2). Sources for C1P1 included V1 (P80) and V2/LOC (P80 and P100). These results and their timing point to low-order structures (such as visual thalamic nuclei or superior colliculi) or the visual cortex itself, as candidates for initial evaluation structures. [ABSTRACT FROM AUTHOR]

Heart rate (HR) can be voluntarily regulated when individuals receive real-time feedback. In a rat model of HR biofeedback, the neocortex and medial forebrain bundle were stimulated as feedback and reward, respectively. The rats reduced their HR within 30 minutes, achieving a reduction of approximately 50% after 5 days of 3-hour feedback. The reduced HR persisted for at least 10 days after training while the rats exhibited anxiolytic behavior and an elevation in blood erythrocyte count. This bradycardia was prevented by inactivating anterior cingulate cortical (ACC) neurons projecting to the ventromedial thalamic nucleus (VMT). Theta-rhythm stimulation of the ACC-to-VMT pathway replicated the bradycardia. VMT neurons projected to the dorsomedial hypothalamus (DMH) and DMH neurons projected to the nucleus ambiguus, which innervates parasympathetic neurons in the heart. [ABSTRACT FROM AUTHOR]