Ventromedial Thalamus Research Articles

Antinociceptive role of the thalamic dopamine D3 receptor in descending modulation of intramuscular formalin-induced muscle nociception in a rat model of Parkinson's disease

Pain in Parkinson's disease (PD) has been validated as one of the major non-motor dysfunctions affecting the quality of life and subsequent rehabilitation. In the present study, we investigated the role of the dopamine D3 receptor in the thalamic mediodorsal (MD) and ventromedial (VM) nuclei mediated descending control of nociception and intramuscular (i.m.) 2.5% formalin-induced persistent muscle nociception. Paw withdrawal reflexes were measured in naive rats and rats subjected to PD induced by unilateral microinjection of 6 μg 6-OHDA into the rat striatum. Formalin-induced muscle nociception in phase 1, inter-phase, and phase 2 was significantly greater in PD rats compared to naive and vehicle-treated rats (P < 0.001). PD rats exhibited bilaterally mechanical hyperalgesia and heat hypoalgesia in formalin-induced muscle nociception. Microinjection of SK609, a dopamine D3 receptor agonist, at various doses (2.5–7.5 nmol/0.5 μl) into the thalamic VM nucleus dose-dependently prolonged heat-evoked paw withdrawal latencies in both naive and PD rats. Administration of SK609 to either the MD or VM nuclei had no effect on noxious mechanically evoked paw withdrawal reflexes. Pre-treatment of the thalamic MD nucleus with SK609 significantly attenuated formalin-induced nociception, and reversed mechanical hyperalgesia, but not heat hypoalgesia. Pre-treatment of the thalamic VM nucleus with SK609 inhibited formalin-induced nociception in the late phase of phase 2 (30–75 min) and heat hypoalgesia, but not mechanical hyperalgesia (P < 0.05). It is suggested that the dopamine D3 receptors in the thalamus play an antinociceptive role in the descending modulation of nociception. Activation of D3 receptors within the thalamic MD and VM nuclei attenuates descending facilitation and enhances descending inhibition in rats during PD.

Involvement of 5-HT1A receptors of the thalamic descending pathway in the analgesic effect of intramuscular heating-needle stimulation in a rat model of lumbar disc herniation.

Intramuscular (IM) heating-needle therapy, a non-painful thermal therapy, has been found to exert an analgesic effect via the thalamic ventromedial (VM) nucleus, solely by reducing the triggering threshold for descending inhibition; this could be modulated by intracephalic 5-hydroxytryptamine-1A (5-HT1A) receptors, rather than via the regular analgesia pathway. In this study, the effect and the potential serotonergic mechanism of IM heating-needle stimulation at 43°C were explored in the case of the pathological state of lumbar disc herniation (LDH). A modified classic rat model of LDH, induced via autologous nucleus pulposus implantation, was utilized. IM inner heating-needles were applied at the attachment point of skeletal muscle on both sides of the L4 and L5 spinous processes. WAY-100635 and 8-OH-DAPT, 5-HT1A receptor antagonist and agonist, were separately injected into the bilateral thalamic mediodorsal (MD) and VM nucleus via an intrathalamic catheter. Nociception was assessed by bilateral paw withdrawal reflexes elicited by noxious mechanical and heat stimulation. IM heating-needle stimulation at a temperature of 43°C for 30 or 45 min significantly relieved both mechanical and heat hyperalgesia in the rat model of LDH (P < 0.05). Heat hyperalgesia was found to be significantly enhanced by administration of WAY-100635 into the thalamic VM nucleus, blocking the effect of heating-needle stimulation in a dose-dependent manner (P < 0.05), while no effects were detected after injection into the thalamic MD nucleus (P > 0.05). Injection of 8-OH-DAPT into the thalamic MD nucleus exerted no modulating effects on either mechanical or heat hyperalgesia (P > 0.05). IM heating-needle stimulation at 43°C for 30 min may activate 5-HT1A mechanisms, via the thalamic VM nucleus, to attenuate hyperalgesia in a rat model of LDH. This innocuous form of thermal stimulation is speculated to selectively activate the descending inhibition mediated by the thalamic VM nucleus, exerting an analgesic effect, without the involvement of descending facilitation of the thalamic MD nucleus.

Distinct hemodynamic and functional connectivity features of fatigue in clinically isolated syndrome and multiple sclerosis: accounting for the confounding effect of concurrent depression symptoms

PurposeThis study aims to identify common and distinct hemodynamic and functional connectivity (FC) features for self-rated fatigue and depression symptoms in patients with clinically isolated syndrome (CIS) and relapsing–remitting multiple sclerosis (RR-MS).MethodsTwenty-four CIS, 29 RR-MS patients, and 39 healthy volunteers were examined using resting-state fMRI (rs-fMRI) to obtain whole-brain maps of (i) hemodynamic response patterns (through time shift analysis), (ii) FC (via intrinsic connectivity contrast maps), and (iii) coupling between hemodynamic response patterns and FC. Each regional map was correlated with fatigue scores, controlling for depression, and with depression scores, controlling for fatigue.ResultsIn CIS patients, the severity of fatigue was associated with accelerated hemodynamic response in the insula, hyperconnectivity of the superior frontal gyrus, and evidence of reduced hemodynamics–FC coupling in the left amygdala. In contrast, depression severity was associated with accelerated hemodynamic response in the right limbic temporal pole, hypoconnectivity of the anterior cingulate gyrus, and increased hemodynamics–FC coupling in the left amygdala. In RR-MS patients, fatigue was associated with accelerated hemodynamic response in the insula and medial superior frontal cortex, increased functional role of the left amygdala, and hypoconnectivity of the dorsal orbitofrontal cortex, while depression symptom severity was linked to delayed hemodynamic response in the medial superior frontal gyrus; hypoconnectivity of the insula, ventromedial thalamus, dorsolateral prefrontal cortex, and posterior cingulate; and decreased hemodynamics–FC coupling of the medial orbitofrontal cortex.ConclusionThere are distinct FC and hemodynamic responses, as well as different magnitude and topography of hemodynamic connectivity coupling, associated with fatigue and depression in early and later stages of MS.

Dynamic reorganization of the cortico-basal ganglia-thalamo-cortical network during task learning.

SummaryAdaptive behavior is coordinated by neuronal networks that are distributed across multiple brain regions such as in the cortico-basal ganglia-thalamo-cortical (CBGTC) network. Here, we ask how cross-regional interactions within such mesoscale circuits reorganize when an animal learns a new task. We apply multi-fiber photometry to chronically record simultaneous activity in 12 or 48 brain regions of mice trained in a tactile discrimination task. With improving task performance, most regions shift their peak activity from the time of reward-related action to the reward-predicting stimulus. By estimating cross-regional interactions using transfer entropy, we reveal that functional networks encompassing basal ganglia, thalamus, neocortex, and hippocampus grow and stabilize upon learning, especially at stimulus presentation time. The internal globus pallidus, ventromedial thalamus, and several regions in the frontal cortex emerge as salient hub regions. Our results highlight the learning-related dynamic reorganization that brain networks undergo when task-appropriate mesoscale network dynamics are established for goal-oriented behavior.

P 2 Effects of deep brain stimulation (DBS) in the entopeduncular nucleus (EPN) in dystonic dtsz hamsters

Introduction: DBS of the globus pallidus internus (GPi; entopeduncular nucleus, EPN, in rodents) has become important for the treatment of generalized dystonia. There is evidence that striatal dysfunctions cause a disturbed thalamocortical inhibition via altered neuronal activity in the GPi/EPN. However, the pathophysiology as well as the mechanisms of DBS are largely unknown, which hampers the detection of drug targets. In our project of the CRC “Electrically active implants” we aim to elucidate mechanisms of DBS in animal models of dystonia. We recently found that short-term (3 h) EPN-DBS with 130 Hz (50 µA, 60 µs) improves paroxysmal dystonia in the dt sz mutant hamster 1 and reduces spontaneous excitatory cortico-striatal activity in brain slices of this model 2 , indicating fast effects in synaptic plasticity. In the present study, we therefore examined whether short-term DBS leads to changes of c-Fos, an immunohistochemical marker of neuronal activity, in EPN-related network regions. Materials & Methods: For immunohistochemistry we used brains of stimulated dt s z hamsters, in which DBS had improved dystonia, as well as sham-stimulated and naïve animals and performed cell counting and fluorescence intensity measurements of c-Fos within the basal ganglia network. In addition, we performed double labeling of c-Fos with GAD67 and with parvalbumin (PV), respectively, in brain slices of the same animals. Results: After DBS vs. sham, c-Fos + around the electrode was increased. Unexpectedly, c-Fos + cells were decreased in deep cerebellar nuclei (DCN) after DBS, but no changes became evident within the whole EPN, habenula, ventromedial thalamus, cortex and striatum. Cell counting of c-Fos activated GAD67 + as well as activated PV + cells showed no differences between the groups in motor cortex and striatum. Conclusion: With regard to recent electrophysiological data, we expected c-Fos changes especially in cortical GABAergic neurons after DBS in dt sz hamsters. The lack of changes within the basal ganglia network could be related to the short duration of stimulation or the time interval between stimulation and c-Fos staining. Ongoing long-term EPN stimulations, now feasible by a new fully implantable stimulator 3 , probably lead to more pronounced effects within the network and will be useful to verify the DCN effects. Funded by the DFG within the Collaborative Research Centre 1270 ELAINE.

Ventromedial Thalamus-Projecting DCN Neurons Modulate Associative Sensorimotor Responses in Mice.

The deep cerebellar nuclei (DCN) integrate various inputs to the cerebellum and form the final cerebellar outputs critical for associative sensorimotor learning. However, the functional relevance of distinct neuronal subpopulations within the DCN remains poorly understood. Here, we examined a subpopulation of mouse DCN neurons whose axons specifically project to the ventromedial (Vm) thalamus (DCNVm neurons), and found that these neurons represent a specific subset of DCN units whose activity varies with trace eyeblink conditioning (tEBC), a classical associative sensorimotor learning task. Upon conditioning, the activity of DCNVm neurons signaled the performance of conditioned eyeblink responses (CRs). Optogenetic activation and inhibition of the DCNVm neurons in well-trained mice amplified and diminished the CRs, respectively. Chemogenetic manipulation of the DCNVm neurons had no effects on non-associative motor coordination. Furthermore, optogenetic activation of the DCNVm neurons caused rapid elevated firing activity in the cingulate cortex, a brain area critical for bridging the time gap between sensory stimuli and motor execution during tEBC. Together, our data highlights DCNVm neurons' function and delineates their kinematic parameters that modulate the strength of associative sensorimotor responses.

Thalamocortical Dysconnectivity In Lifelong Premature Ejaculation: A Functional MRI Study

ObjectivesTo detect seed-based functional connectivity (FC) between various cortical sub-regions and the thalamus in lifelong premature ejaculation (LPE) patients and explore whether specific thalamocortical networks are significantly altered in PE patients compared to healthy controls (HCs) MethodsFifty non-medicated LPE patients and 40 age-matched HCs underwent a resting-state functional MRI. FC was adopted to identify specific thalamocortical connectivity between the thalamus and 6 cortical regions of interest (i.e., the motor cortex/supplementary motor, the prefrontal cortex, the temporal lobe, the posterior parietal cortex, the somatosensory cortex and the occipital lobe). In LPE patients, regression analysis was subsequently conducted to assess relationships of thalamocortical connectivity with the Premature Ejaculation Diagnostic Tool (PEDT) score and the Intravaginal Ejaculatory Latency Time (IELT). ResultsLPE patients had significantly decreased FC between the motor cortex and bilateral ventral thalamus, between the prefrontal cortex and left dorsomedial thalamus, as well as between the temporal cortex and bilateral ventromedial thalamus. In LPE patients, PEDT score was significantly positively associated with the thalamus-posterior parietal cortex FC, and negatively associated with the thalamus-temporal cortex FC, while IELT was positively associated with the thalamus-temporal cortex and thalamus-motor cortex FC. ConclusionThese results enrich the imaging evidence for the understanding of the neurobiological mechanisms and/or consequences of LPE.

An orbitofrontal cortex to midbrain projection modulates hypersensitivity after peripheral nerve injury.

Neuropathic pain is a debilitating condition that is often refractory to treatment. The network of neural substrates for pain transmission and control within the brain is complex and remains poorly understood. Through a combination of neuronal tracing, optogenetics, chemogenetics, electrophysiological recordings, and behavioral assessment, we demonstrate that activation of layer 5 pyramidal neurons in the ventrolateral orbitofrontal cortex (vlOFC) attenuates mechanical and thermal hypersensitivity and cold allodynia in mice with neuropathic pain induced by spared nerve injury (SNI). These vlOFC output neurons project to the posterior ventrolateral periaqueductal gray (vlPAG) region and receive inputs from the ventromedial thalamus (VM). Specific optogenetic and chemogenetic activation of the vlOFC-vlPAG and the VM-vlOFC circuits inhibits hypersensitivity associated with neuropathy. Thus, we reveal a modulatory role of the vlOFC and its projections to the vlPAG circuit in the processing of hypersensitive nociception.

Divergent Whole Brain Projections from the Ventral Midbrain in Macaques.

ABSTRACTTo understand the connectome of the axonal arborizations of dopaminergic midbrain neurons, we investigated the anterograde spread of highly sensitive viral tracers injected into the ventral tegmental area (VTA) and adjacent areas in 3 macaques. In 2 monkeys, injections were centered on the lateral VTA with some spread into the substantia nigra, while in one animal the injection targeted the medial VTA with partial spread into the ventro-medial thalamus. Double-labeling with antibodies against transduced fluorescent proteins (FPs) and tyrosine hydroxylase indicated that substantial portions of transduced midbrain neurons were dopaminergic. Interestingly, cortical terminals were found either homogeneously in molecular layer I, or more heterogeneously, sometimes forming patches, in the deeper laminae II–VI. In the animals with injections in lateral VTA, terminals were most dense in somatomotor cortex and the striatum. In contrast, when the medial VTA was transduced, dense terminals were found in dorsal prefrontal and temporal cortices, while projections to striatum were sparse. In all monkeys, orbitofrontal and occipito-parietal cortex received strong and weak innervation, respectively. Thus, the dopaminergic ventral midbrain sends heterogeneous projections throughout the brain. Furthermore, our results suggest the existence of subgroups in meso-dopaminergic neurons depending on their location in the primate ventral midbrain.

Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.

Effects of Heating-needle Stimulation in Restoration of Weakened Descending Inhibition of Nociception in a Rat Model of Parkinson’s Disease

Here we investigated variations of endogenous descending modulation of nociception and therapeutic effects of intramuscular (i.m.) heating-needle stimulation in early stage of Parkinson’s disease (PD) induced by unilateral microinjection of 3.5 μl of 2.5 μg/μl 6-hydroxydopamine into the rat striatum. Paw withdrawal reflexes to noxious mechanical and heat stimuli in PD rats with and without exposure to i.m. 5.8% saline induced muscle nociception were evaluated. Experimental PD had no influence on mechanical or heat sensitivity in the baseline condition, whereas descending facilitation was stronger and descending inhibition was weaker in PD rats than vehicle-treated or naive rats during muscle nociception (P < 0.05). Striatal administration of 5 μg of dopamine failed to reverse the PD-associated changes in descending facilitation or inhibition, whereas dopamine in the thalamic mediodorsal (MD) nucleus and ventromedial (VM) nucleus significantly decreased the increase in descending facilitation and reversed the attenuation in descending inhibition, respectively (P < 0.05). I.m. 43 °C of heating-needle stimulation had no effects on the enhanced descending facilitation in PD rats, but it markedly increased descending inhibition and reversed the increase in the number of apomorphine-induced body rotations (P < 0.05), which effects were dose-dependently attenuated by raclopride, a dopamine 2 receptor antagonist, in the thalamic VM nucleus (P < 0.05). The results indicate that the early-stage PD is associated with enhanced descending facilitation and weakened descending inhibition. From clinical perspective, 43 °C heat therapeutic regime promises to selectively enhance descending inhibition that is accompanied by improvement of motor dysfunction in PD.

Effects of Intramuscular Heating-needle Stimulation in Controlling Adjuvant-induced Muscle Nociception in Rats: Differential Roles of Thalamic Purinergic P2X3 Receptors

Here we investigated effects of intramuscular (i.m.) heating-needle stimulation on persistent muscle nociception evoked by i.m. injection of different doses (50–200 µl) of complete Freund’s adjuvant (CFA) in rats. Paw withdrawal reflexes evoked by noxious mechanical and heat stimulation as well as hind limb swelling were determined prior to and two weeks after the CFA injection. The unilateral injection of CFA induced a dose-related and long-lasting (5–14 d), bilateral secondary mechanical hyperalgesia and heat hypoalgesia associated with long-term limb swelling. A period of 30–45 min 43 °C heating-needle stimulation significantly enhanced the i.m. CFA-induced bilateral heat hypoalgesia and alleviated hind limb swelling. In contrast, 30–45 min 46 °C heating-needle stimulation markedly enhanced both mechanical hyperalgesia and heat hypoalgesia, but failed to influence the CFA-induced hind limb swelling. Microinjection of P2X3 receptor antagonist A-317491 (0.5–4.5 nmol/0.5 µl) into the thalamic ventromedial (VM) nucleus dose-dependently inhibited the 43 °C and 46 °C heating-needle stimulation-induced heat hypoalgesia, whereas the 46 °C heating-needle stimulation-induced mechanical hyperalgesia was significantly prevented by microinjection of A-317491 into the thalamic mediodorsal (MD) nucleus. In contrast, the hind limb swelling was not affected by the microinjection of A-317491 into the thalamic VM or MD nucleus. The present study indicates that in the CFA-induced persistent muscle nociception condition, 43 °C heating-needle stimulation selectively increases descending inhibition, which effect is modulated by the thalamic VM nucleus. In addition to the antinociceptive role of P2X3 receptors in the thalamic VM nucleus, P2X3 receptors within the thalamic MD nucleus participate in the descending facilitation evoked by i.m. 46 °C heating-needle stimulation.

Deep brain stimulation in Tourette's syndrome: evidence to date.

Tourette’s syndrome (TS) is a neurodevelopmental disorder that comprises vocal and motor tics associated with a high frequency of psychiatric comorbidities, which has an important impact on quality of life. The onset is mainly in childhood and the symptoms can either fade away or require pharmacological therapies associated with cognitive-behavior therapies. In rare cases, patients experience severe and disabling symptoms refractory to conventional treatments. In these cases, deep brain stimulation (DBS) can be considered as an interesting and effective option for symptomatic control. DBS has been studied in numerous trials as a therapy for movement disorders, and currently positive data supports that DBS is partially effective in reducing the motor and non-motor symptoms of TS. The average response, mostly from case series and prospective cohorts and only a few controlled studies, is around 40% improvement on tic severity scales. The ventromedial thalamus has been the preferred target, but more recently the globus pallidus internus has also gained some notoriety. The mechanism by which DBS is effective on tics and other symptoms in TS is not yet understood. As refractory TS is not common, even reference centers have difficulties in performing large controlled trials. However, studies that reproduce the current results in larger and multicenter randomized controlled trials to improve our knowledge so as to support the best target and stimulation settings are still lacking. This article will discuss the selection of the candidates, DBS targets and mechanisms on TS, and clinical evidence to date reviewing current literature about the use of DBS in the treatment of TS.

Neuroplasticity induction using transcranial magnetic stimulation

In this article, we have displayed the results of an analysis of modern scientific data on the induction of neuroplasticity using transcranial magnetic stimulation. We presented the multilevel neuroplastic effects of electromagnetic fields caused by transcranial magnetic stimulation (TMS). The authors of the article determined that transcranial magnetic stimulation uses variable magnetic fields to non-invasively stimulate neurons in the brain. The basis of this method is the modulation of neuroplasticity mechanisms with the subsequent reorganization of neural networks. Repeated TMS (rTMS), which is widely used in neurology, affects neurotransmitters and synaptic plasticity, glial cells and the prevention of neuronal death. The neurotrophic effects of rTMS on dendritic growth, as well as growth and neurotrophic factors, are described. An important aspect of the action of TMS is its effect on neuroprotective mechanisms. A neuroimaging study of patients with Parkinson's disease showed that rTMS increased the concentration of endogenous dopamine in the ipsilateral striatum. After rTMS exposure, the number of β-adrenergic receptors in the frontal and cingulate cortex decreases, but the number of NMDA receptors in the ventromedial thalamus, amygdala, and parietal cortex increases. These processes ultimately lead to the induction of prolonged potentiation. In response to rTMS, neuronal excitability changes due to a shift in ion balance around a population of stimulated neurons; this shift manifests itself as altered synaptic plasticity. Combinations of rTMS treatment and pharmacotherapy (e.g., small doses of memantine) may block the alleviating effect during prolonged potentiation. Studies using models of transient ischemic attack and prolonged ischemia have shown that rTMS protects neurons from death and alters the blood flow and metabolism in the brain. It has been demonstrated that TMS has a proven ability to modulate the internal activity of the brain in a frequency-dependent manner, generate contralateral responses, provide, along with the neuromodulating and neurostimulating effect, affect the brain as a global dynamic system.

Degeneration of cholinergic basal forebrain nuclei after focally evoked status epilepticus

Status epilepticus (SE) of limbic onset might cause degenerative phenomena in different brain structures, and may be associated with chronic cognitive and EEG effects. In the present study SE was evoked focally by microinfusing picomolar doses of cyclothiazide+bicuculline into the anterior extent of the piriform cortex (APC) in rats, the so-called area tempestas, an approach which allows to evaluate selectively the effects of seizure spreading through the natural anatomical circuitries up to secondary generalization. In the brain of rats submitted to SE we analyzed neuronal density, occurrence of degenerative phenomena (by Fluoro-Jade B-FJB- staining) and expression of heat shock protein-70 (HSP-70) in the piriform cortex, the hippocampus and ventromedial thalamus. We further analyzed in detail, the loss of cholinergic neurons, and the presence of FJB- and HSP-70 positive neurons in basal forebrain cholinergic areas, i.e. the medial septal nucleus (MSN, Ch1), the diagonal band of Broca (DBB, Ch2 and Ch3) and the Nucleus basalis of Meynert (NBM, Ch4). In fact, these nuclei are strictly connected with limbic structures, and play a key pivotal role in different cognitive functions and vigilance. Although recent studies begun to investigate these nuclei in experimental epilepsy and in persons with epilepsy, conflicting results were obtained so far. We showed that after severe and long-lasting, focally induced limbic SE there is a significant cell loss within all of the abovementioned cholinergic nuclei ipsi- and contra-laterally to the infusion site. In parallel, these nuclei show also FJB and heat shock protein-70 expression. Those effects vary depending on the single nucleus assessed and on the severity of the SE seizure score. We also showed the occurrence of cell loss and degenerative phenomena in limbic cortex, hippocampus and limbic thalamic areas. These novel findings show direct evidence of SE-induced neuronal damage which is solely due to seizure activity ruling out potential confounding effects produced by systemic pro-convulsant neurotoxins. A damage to basal forebrain cholinergic nuclei, which may underlie cognitive alterations, is documented for the first time in a model of SE triggered focally.

Anterolateral Motor Cortex Connects with a Medial Subdivision of Ventromedial Thalamus through Cell Type-Specific Circuits, Forming an Excitatory Thalamo-Cortico-Thalamic Loop via Layer 1 Apical Tuft Dendrites of Layer 5B Pyramidal Tract Type Neurons.

The anterolateral motor cortex (ALM) and ventral medial (VM) thalamus are functionally linked to support persistent activity during motor planning. We analyzed the underlying synaptic interconnections using optogenetics and electrophysiology in mice (female/male). In cortex, thalamocortical (TC) axons from VM thalamus excited VM-projecting pyramidal tract (PT) neurons in layer 5B of ALM. These axons also strongly excited layer 2/3 neurons (which strongly excite PT neurons, as previously shown) but not VM-projecting corticothalamic (CT) neurons in layer 6. The strongest connections in the VM → PT circuit were localized to apical tuft dendrites of PT neurons, in layer 1. These tuft inputs were selectively augmented after blocking hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. In thalamus, axons from ALM PT neurons excited ALM-projecting VM neurons, located medially in VM. These axons provided weak input to neurons in mediodorsal nucleus, and little or no input either to neurons in the GABAergic reticular thalamic nucleus or to neurons in VM projecting to primary motor cortex (M1). Conversely, M1 PT axons excited M1- but not ALM-projecting VM neurons. Our findings indicate, first, a set of cell type-specific connections forming an excitatory thalamo-cortico-thalamic loop for ALM ↔ VM communication and a circuit-level substrate for supporting reverberant activity in this system. Second, a key feature of this loop is the prominent involvement of layer 1 synapses onto apical dendrites, a subcellular compartment with distinct signaling properties, including HCN-mediated gain control. Third, the segregation of the ALM ↔ VM loop from M1-related circuits of VM adds cellular-level support for the concept of parallel pathway organization in the motor system.SIGNIFICANCE STATEMENT Anterolateral motor cortex (ALM), a higher-order motor area in the mouse, and ventromedial (VM) thalamus are anatomically and functionally linked, but their synaptic interconnections at the cellular level are unknown. Our results show that ALM pyramidal tract neurons monosynaptically excite ALM-projecting thalamocortical neurons in a medial subdivision of VM thalamus, and vice versa. The thalamo-cortico-thalamic loop formed by these recurrent connections constitutes a circuit-level substrate for supporting reverberant activity in this system.

A New Analysis of Resting State Connectivity and Graph Theory Reveals Distinctive Short-Term Modulations due to Whisker Stimulation in Rats.

Resting state (RS) connectivity has been increasingly studied in healthy and diseased brains in humans and animals. This paper presents a new method to analyze RS data from fMRI that combines multiple seed correlation analysis with graph-theory (MSRA). We characterize and evaluate this new method in relation to two other graph-theoretical methods and ICA. The graph-theoretical methods calculate cross-correlations of regional average time-courses, one using seed regions of the same size (SRCC) and the other using whole brain structure regions (RCCA). We evaluated the reproducibility, power, and capacity of these methods to characterize short-term RS modulation to unilateral physiological whisker stimulation in rats. Graph-theoretical networks found with the MSRA approach were highly reproducible, and their communities showed large overlaps with ICA components. Additionally, MSRA was the only one of all tested methods that had the power to detect significant RS modulations induced by whisker stimulation that are controlled by family-wise error rate (FWE). Compared to the reduced resting state network connectivity during task performance, these modulations implied decreased connectivity strength in the bilateral sensorimotor and entorhinal cortex. Additionally, the contralateral ventromedial thalamus (part of the barrel field related lemniscal pathway) and the hypothalamus showed reduced connectivity. Enhanced connectivity was observed in the amygdala, especially the contralateral basolateral amygdala (involved in emotional learning processes). In conclusion, MSRA is a powerful analytical approach that can reliably detect tiny modulations of RS connectivity. It shows a great promise as a method for studying RS dynamics in healthy and pathological conditions.

Reciprocal Circuits Linking the Prefrontal Cortex with Dorsal and Ventral Thalamic Nuclei

Reciprocal interactions between the prefrontal cortex (PFC) and thalamus play a critical role in cognition, but the underlying circuits remain poorly understood. Here we use optogenetics to dissect the specificity and dynamics of cortico-thalamo-cortical networks in the mouse brain. We find that cortico-thalamic (CT) neurons in prelimbic PFC project to both mediodorsal (MD) and ventromedial (VM) thalamus, where layer 5 and 6 inputs activate thalamo-cortical (TC) neurons with distinct temporal profiles. We show that TC neurons in MD and VM in turn make distinct connections in PFC, with MD preferentially and strongly activating layer 2/3 cortico-cortical (CC) neurons. Finally, we assess local connections from superficial CC to deep CT neurons, which link thalamo-cortical and cortico-thalamic networks within the PFC. Together our findings indicate that PFC strongly drives neurons in the thalamus, whereas MD and VM indirectly influence reciprocally connected neurons in the PFC, providing a mechanistic understanding of these circuits.

Repeated corticosterone injections in adult mice alter stress hormonal receptor expression in the cerebellum and motor coordination without affecting spatial learning

Receptors for glucocorticoid (GR) and corticotropin-releasing hormone (CRH) are largely found in brain sensorimotor structures, particularly in cerebellum, underlining a potential role of stress hormones in the regulation of motor function. Since CRH is involved in neuroplasticity, known for its trophic effect on synapses, we investigated how manipulations in corticosterone serum levels can modulate the CRH system in the cerebellum and affect motor coordination. Corticosterone at doses of either 15 or 30mg/kg was injected in mice and the status of hormonal expression evaluated in cerebellum, hippocampus, and hypothalamus in undisturbed housing conditions or after different behavioral tests. Under both conditions, metabolic activity in numerous brain regions involved in motor functions and emotion was measured by means of cytochrome oxidase (COX) activity labeling. After six consecutive days of corticosterone administration, CRH-R1 transcription was downregulated in hypothalamic and cerebellar regions and hypometabolic changes were observed in mice treated with the higher dose for several limbic and sensorimotor circuitries, notably basal ganglia, deep cerebellar nuclei, and red nucleus. Corticosterone did not modify motor activity, anxiety, and spatial orientation, but decreased latencies before falling from the rotorod and prevented mice from reaching targets in the coat-hanger test. In addition, COX activities were similar to control mice except in ventromedial thalamus and dorsal neostriatum, possibly indicating that physical activity protected brain energy metabolism against the stress hormone. The present findings showed that the CRH/CRH-R1 system might play a role in mediating the effects of stress on cerebellar function, affecting especially motor learning tasks.

"Real-time" imaging of cortical and subcortical sites of cardiovascular control: concurrent recordings of sympathetic nerve activity and fMRI in awake subjects.

We review our approach to functionally identifying cortical and subcortical areas involved in the generation of spontaneous fluctuations in sympathetic outflow to muscle or skin. We record muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA), via a tungsten microelectrode inserted percutaneously into the common peroneal nerve, at the same time as performing functional magnetic resonance imaging (fMRI) of the brain. By taking advantage of the neurovascular coupling delay associated with BOLD (blood oxygen level dependent) fMRI, and the delay associated with conduction of a burst of sympathetic impulses to the peripheral recording site, we can identify structures in which BOLD signal intensity covaries with MSNA or SSNA. Using this approach, we found MSNA-coupled increases in BOLD signal intensity in the mid-insula and dorsomedial hypothalamus on the left side, and in dorsolateral prefrontal cortex, posterior cingulate cortex, precuneus, ventromedial hypothalamus and rostral ventrolateral medulla on both sides. Conversely, spontaneous bursts of SSNA were positively correlated with BOLD signal intensity in the ventromedial thalamus and posterior insula on the left side, and in the anterior insula, orbitofrontal cortex and frontal cortex on the right side, and in the mid-cingulate cortex and precuneus on both sides. Inverse relationships were observed between MSNA and BOLD signal intensity in the right ventral insula, nucleus tractus solitarius and caudal ventrolateral medulla, and between SSNA and signal intensity in the left orbitofrontal cortex. These results emphasize the contributions of cortical regions of the brain to sympathetic outflow in awake human subjects, and the extensive interactions between cortical and subcortical regions in the ongoing regulation of sympathetic nerve activity to muscle and skin in awake human subjects.