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The cerebellar involvement in cognitive functions such as attention, language, working memory, emotion, goal-directed behavior and spatial navigation is constantly growing. However, an exact connectivity map between the hippocampus and cerebellum in mice is still unknown. Here, we conducted a tracing study to identify the sequence of transsynaptic, cerebellar-hippocampal connections in the mouse brain using combinations of Recombinant adeno-associated virus (rAAV) and pseudotyped deletion-mutant rabies (RABV) viruses. Stereotaxic injection of a primarily anterograde rAAV-WGA (wheat germ agglutinin)-Cre tracer virus in the deep cerebellar nuclei (DCN) of a Cre-dependent tdTomato reporter mouse resulted in strong tdTomato labeling in hippocampal CA1 neurons, retrosplenial cortex (RSC), rhinal cortex (RC) as well as thalamic and cerebellar areas. Whereas hippocampal injections with the retrograde tracer virus rAAV-TTC (tetanus toxin C fragment)-eGFP, displayed eGFP positive cells in the rhinal cortex and subiculum. To determine the sequence of mono-transsynaptic connections between the cerebellum and hippocampus, we used the retrograde tracer RABVΔG-eGFP(EnvA). The tracing revealed a direct connection from the dentate gyrus (DG) in the hippocampus to the RSC, RC and subiculum (S), which are monosynaptically connected to thalamic laterodorsal and ventrolateral areas. These thalamic nuclei are directly connected to cerebellar fastigial (FN), interposed (IntP) and lateral (Lat) nuclei, discovering a new projection route from the fastigial to the laterodorsal thalamic nucleus in the mouse brain. Collectively, our findings suggest a new cerebellar-hippocampal connection the laterodorsal and ventrolateral thalamus to RSC, RC and S. These results strengthen the notion of the cerebellum's involvement in cognitive functions such as spatial navigation a polysynaptic circuitry.

•Modafinil shapes the thalamo-cortical functional connectivity in a specific manner.•The medial pulvinar increased connectivity with Sensorimotor/Attention Networks.•The anterior + inferior pulvinar enhanced connectivity with the Attention Network.•Ventral complex increased connectivity with the Default Mode/FrontoParietal Networks.•Connectivity changes overlap with the expression of 5-HT, mGluR5 receptors, and NET. Modafinil promotes wakefulness and enhances cognitive function through mechanisms and neural effects that are still partially unknown. Several studies have shown that the compound alters the functional cortical architecture. In contrast, its influence on subcortical regions and thalamocortical connections, which are crucial for modulating neocortical connectivity, remains unexplored. The acute modulation of thalamo-cortical connectivity was assessed in two groups of participants who received either a single 100 mg dose of modafinil (N = 25) or a placebo (N = 25). Magnetic Resonance Imaging (MRI) was used to parcel the thalamus into its constituent nuclei, which served as seeds for voxel-wise resting state functional connectivity analyses. Additionally, maps of nuclei-specific functional reorganization were compared to those of receptor/transporter expression to assess their spatial overlaps. Modafinil, but not placebo, altered the connectivity of three thalamic nuclei. Specifically, the medial pulvinar nuclei showed increased connectivity with cortical regions of the Sensorimotor and Salience/Ventral Attention (SVAN) Networks. These functional changes spatially overlapped with the distribution of the norepinephrine transporter (NET). Additionally, the anterior and inferior pulvinar complex exhibited enhanced connectivity with the insular and supramarginal regions of the SVAN and superior frontal area of the Default Mode Network (DMN). However, unlike the medial pulvinar, these effects were not spatially linked to the expression of any specific receptor or transporter. Finally, the ventro-lateral anterior complex exhibited increased connectivity with the posterior region of the DMN and the Fronto-Parietal Control Network, along with decreased connectivity to the premotor cortex. The topography of these functional modifications mainly overlaps with the distribution of glutamatergic and serotonergic receptors. In summary, our findings highlight modafinil's influence on thalamocortical circuits, emphasizing the role of higher-order pulvinar nuclei and ventro-lateral anterior complex.

The cerebral cortex is organized into specialized sensory areas, whose initial territory is determined by intracortical molecular determinants. Yet, sensory cortical area size appears to be fine tuned during development to respond to functional adaptations. Here we demonstrate the existence of a prenatal sub-cortical mechanism that regulates the cortical areas size in mice. This mechanism is mediated by spontaneous thalamic calcium waves that propagate among sensory-modality thalamic nuclei up to the cortex and that provide a means of communication among sensory systems. Wave pattern alterations in one nucleus lead to changes in the pattern of the remaining ones, triggering changes in thalamic gene expression and cortical area size. Thus, silencing calcium waves in the auditory thalamus induces Rorβ upregulation in a neighbouring somatosensory nucleus preluding the enlargement of the barrel-field. These findings reveal that embryonic thalamic calcium waves coordinate cortical sensory area patterning and plasticity prior to sensory information processing. How sensory maps are formed in the brain is only partially understood. Here the authors describe spontaneous calcium waves that propagate across different sensory nuclei in the embryonic thalamus; disrupting the wave pattern triggers thalamic gene expression changes and eventually alters the size of cortical areas.

In the basal ganglia (BG), anatomically segregated and topographically organized feedforward circuits are thought to modulate multiple behaviors in parallel. Although topographically arranged BG circuits have been described, the extent to which these relationships are maintained across the BG output nuclei and in downstream targets is unclear. Here, using focal trans-synaptic anterograde tracing, we show that the motor-action-related topographical organization of the striatum is preserved in all BG output nuclei. The topography is also maintained downstream of the BG and in multiple parallel closed loops that provide striatal input. Furthermore, focal activation of two distinct striatal regions induces either licking or turning, consistent with their respective anatomical targets of projection outside of the BG. Our results confirm the parallel model of BG function and suggest that the integration and competition of information relating to different behavior occur largely outside of the BG.This study demonstrates that basal ganglia functional topography is maintained across and downstream of its output nuclei, and in closed loops. Focal stimulation of distinct striatal subregions induces distinct action, supporting a model of parallel behavioral control.

The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition 1 – 5 . TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders 6 – 9 . However, little is known about the organizational principles that underlie its divergent functions. Here we performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that cellular heterogeneity in the TRN is characterized by a transcriptomic gradient of two negatively correlated gene-expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core or shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections with the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN–thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. In sum, our study provides a comprehensive atlas of TRN neurons at single-cell resolution and links molecularly defined subnetworks to the functional organization of thalamocortical circuits. A study integrating single-cell RNA-sequencing and electrophysiology data shows that in mouse, the cellular repertoire of the thalamic reticular nucleus is characterized by a transcriptomic gradient defined at its extremes by mutually exclusive expression of Spp1 and Ecel1 , providing insights into the organizational principles underlying the divergent functions of this brain region.

Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics. Thalamocortical dysrhythmia is a key pathology of chronic pain. Here, the authors propose an analytical pipeline to study dynamic fMRI brain networks and demonstrate that chronic low back pain pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.

The human thalamus is a brain structure that comprises numerous, highly specific nuclei. Since these nuclei are known to have different functions and to be connected to different areas of the cerebral cortex, it is of great interest for the neuroimaging community to study their volume, shape and connectivity in vivo with MRI. In this study, we present a probabilistic atlas of the thalamic nuclei built using ex vivo brain MRI scans and histological data, as well as the application of the atlas to in vivo MRI segmentation. The atlas was built using manual delineation of 26 thalamic nuclei on the serial histology of 12 whole thalami from six autopsy samples, combined with manual segmentations of the whole thalamus and surrounding structures (caudate, putamen, hippocampus, etc.) made on in vivo brain MR data from 39 subjects. The 3D structure of the histological data and corresponding manual segmentations was recovered using the ex vivo MRI as reference frame, and stacks of blockface photographs acquired during the sectioning as intermediate target. The atlas, which was encoded as an adaptive tetrahedral mesh, shows a good agreement with previous histological studies of the thalamus in terms of volumes of representative nuclei. When applied to segmentation of in vivo scans using Bayesian inference, the atlas shows excellent test-retest reliability, robustness to changes in input MRI contrast, and ability to detect differential thalamic effects in subjects with Alzheimer's disease. The probabilistic atlas and companion segmentation tool are publicly available as part of the neuroimaging package FreeSurfer. [Display omitted] •A probabilistic atlas of the human thalamus (26 nuclei) derived from histology.•3D histology reconstruction assisted by ex vivo MRI and blockface photographs.•Companion Bayesian method segments the nuclei from in vivo scans of any MRI contrast.•Method has excellent test-retest reliability and detects differential effects in AD.•The method is publicly available as part of FreeSurfer.

Survival depends on a balance between seeking rewards and avoiding potential threats, but the neural circuits that regulate this motivational conflict remain largely unknown. Using an approach-food vs. avoid-predator threat conflict test in rats, we identified a subpopulation of neurons in the anterior portion of the paraventricular thalamic nucleus (aPVT) which express corticotrophin-releasing factor (CRF) and are preferentially recruited during conflict. Inactivation of aPVT CRF neurons during conflict biases animal’s response toward food, whereas activation of these cells recapitulates the food-seeking suppression observed during conflict. aPVT CRF neurons project densely to the nucleus accumbens (NAc), and activity in this pathway reduces food seeking and increases avoidance. In addition, we identified the ventromedial hypothalamus (VMH) as a critical input to aPVT CRF neurons, and demonstrated that VMH-aPVT neurons mediate defensive behaviors exclusively during conflict. Together, our findings describe a hypothalamic-thalamostriatal circuit that suppresses reward-seeking behavior under the competing demands of avoiding threats. Animals constantly balance seeking food with avoiding predators. Here, the authors report that CRF positive neurons in the paraventricular thalamus projecting to the nucleus accumbens in rats are an indispensable component of a feedback circuit that can interrupt appetitive behaviour in favor of a defensive response in the presence of a competing threat stimulus.

The “non-specific” ventromedial thalamic nucleus (VM) has long been considered a candidate for mediating cortical arousal due to its diffuse, superficial projections, but direct evidence was lacking. Here, we show in mice that the activity of VM calbindin1-positive matrix cells is high in wake and REM sleep and low in NREM sleep, and increases before cortical activity at the sleep-to-wake transition. Optogenetic stimulation of VM cells rapidly awoke all mice from NREM sleep and consistently caused EEG activation during slow wave anesthesia, while arousal did not occur from REM sleep. Conversely, chemogenetic inhibition of VM decreased wake duration. Optogenetic activation of the “specific” ventral posteromedial nucleus (VPM) did not cause arousal from either NREM or REM sleep. Thus, matrix cells in VM produce arousal and broad cortical activation during NREM sleep and slow wave anesthesia in a way that accounts for the effects classically attributed to “non-specific” thalamic nuclei. The ventromedial thalamus (VM) is thought to control cortical arousal through its diffuse projections to cortex. Here the authors record and manipulate the activity of calbindin1-positive matrix cells in VM and show that they bidirectionally regulate the sleep-wake transition.

Subcortical neuronal activity is highly relevant for mediating communication in large-scale brain networks. While electroencephalographic (EEG) recordings provide appropriate temporal resolution and coverage to study whole brain dynamics, the feasibility to detect subcortical signals is a matter of debate. Here, we investigate if scalp EEG can detect and correctly localize signals recorded with intracranial electrodes placed in the centromedial thalamus, and in the nucleus accumbens. Externalization of deep brain stimulation (DBS) electrodes, placed in these regions, provides the unique opportunity to record subcortical activity simultaneously with high-density (256 channel) scalp EEG. In three patients during rest with eyes closed, we found significant correlation between alpha envelopes derived from intracranial and EEG source reconstructed signals. Highest correlation was found for source signals in close proximity to the actual recording sites, given by the DBS electrode locations. Therefore, we present direct evidence that scalp EEG indeed can sense subcortical signals. Electroencephalography (EEG) allows the measurement of electrical signals associated with brain activity, but it is unclear if EEG can accurately measure subcortical activity. Here, the authors show that source dynamics, reconstructed from scalp EEG, correlate with activity recorded from human thalamus and nucleus accumbens.