Posterior Nucleus Research Articles

Reproducible protocol to obtain and measure first-order relay human thalamic white-matter tracts

The “primary” or “first-order relay” nuclei of the thalamus feed the cerebral cortex with information about ongoing activity in the environment or the subcortical motor systems. Because of the small size of these nuclei and the high specificity of their input and output pathways, new imaging protocols are required to investigate thalamocortical interactions in human perception, cognition and language. The goal of the present study was twofold: I) to develop a reconstruction protocol based on in vivo diffusion MRI to extract and measure the axonal fiber tracts that originate or terminate specifically in individual first-order relay nuclei; and, II) to test the reliability of this reconstruction protocol. In left and right hemispheres, we investigated the thalamocortical/corticothalamic axon bundles linking each of the first-order relay nuclei and their main cortical target areas, namely, the lateral geniculate nucleus (optic radiation), the medial geniculate nucleus (acoustic radiation), the ventral posterior nucleus (somatosensory radiation) and the ventral lateral nucleus (motor radiation). In addition, we examined the main subcortical input pathway to the ventral lateral posterior nucleus, which originates in the dentate nucleus of the cerebellum. Our protocol comprised three components: defining regions-of-interest; preprocessing diffusion data; and modeling white-matter tracts and tractometry. We then used computation and test-retest methods to check whether our protocol could reliably reconstruct these tracts of interest and their profiles. Our results demonstrated that the protocol had nearly perfect computational reproducibility and good-to-excellent test-retest reproducibility. This new protocol may be of interest for both basic human brain neuroscience and clinical studies and has been made publicly available to the scientific community.

Pattern of thalamic nuclei atrophy in early relapse-onset multiple sclerosis

BackgroundThalamic atrophy is prominent in multiple sclerosis; however, it is unclear which thalamic nuclei are most vulnerable, especially early in disease. IntroductionTo investigate which thalamic nuclei differ between patients in early stages of relapsing-remitting multiple sclerosis (RRMS) versus healthy controls and examine the relationship between thalamic nuclei volume and T2 lesion volume. MethodsWe derived 15 thalamic subfields from high-resolution 3T magnetic resonance images in 182 patients with early RRMS (diagnosed ≤5.0 years, median 2.0 years). Independent t-tests assessed differences between patients and 35 controls across thalamic subfield volumes. Pearson correlations assessed the relationships between thalamic volumes and T2 lesion volumes. ResultsPatients had lower anterior and posterior nuclei volume than controls, whereas medial and ventral nuclei volumes were preserved. Higher T2 lesion volumes were disproportionately related to lower posterior subfield volumes. ConclusionsWe found specific thalamic subfields were more vulnerable to early disease-related changes. We discuss potential mechanisms of differential thalamic subfield atrophy in early MS, including cortical demyelination, CSF toxicity, leptomeningeal inflammation, and iron deposition.

Sound induces analgesia through corticothalamic circuits.

Sound-including music and noise-can relieve pain in humans, but the underlying neural mechanisms remain unknown. We discovered that analgesic effects of sound depended on a low (5-decibel) signal-to-noise ratio (SNR) relative to ambient noise in mice. Viral tracing, microendoscopic calcium imaging, and multitetrode recordings in freely moving mice showed that low-SNR sounds inhibited glutamatergic inputs from the auditory cortex (ACxGlu) to the thalamic posterior (PO) and ventral posterior (VP) nuclei. Optogenetic or chemogenetic inhibition of the ACxGlu→PO and ACxGlu→VP circuits mimicked the low-SNR sound-induced analgesia in inflamed hindpaws and forepaws, respectively. Artificial activation of these two circuits abolished the sound-induced analgesia. Our study reveals the corticothalamic circuits underlying sound-promoted analgesia by deciphering the role of the auditory system in pain processing.

Morphological variations influencing the outcomes in posterior polar cataract.

Purpose:To study the intraoperative complications and postoperative clinical outcomes in different types of posterior polar cataract (PPC) following phacoemulsification, based on morphological classification.Methods: All consecutive patients with PPC who underwent phacoemulsification during the study period from 2016 to 2019 were included and sub-grouped based on the morphological characteristics according to Daljit Singh’s classification. Intraoperative complications such as posterior capsular rupture (PCR), vitreous loss, nucleus drop, and Postoperative best-corrected visual acuity (BCVA) at day 1 and day 30 were documented.Results: A total of 388 eyes of 380 patients were included. Eighty nine (22.9%) eyes belonged to type 1, 135 (34.8%) belonged to type 2, 8 (2.1%) belonged to type 3, and 156 (40.2%) belonged to type 4. Thirty-five (9.3%) eyes had intraoperative PCR, with vitreous loss in 21 (60%) eyes, and nucleus/cortex drop in 5 (1.3%) eyes. Six (75%) eyes of type 3, 14 (10.04%) eyes of type 2, 12 (17.7%) eyes of type 4, and 3 (3.4%) eyes of type 1 PPC had PCR. PCR occurred more during the emulsification of the nucleus (18 cases, 51.4%). A significant correlation was seen between intraoperative PCR and type of PPC with a higher incidence in type 3 (P < 0.001). BCVA was found to be significantly worse on day 1 among patients with PCR compared to those who did not and improved well by day 30.Conclusion: PPC morphology is significantly co-related with the occurrence of PCR, emphasizing the need for careful grading of posterior polar cataracts in predicting the risk of intraoperative complications.

The Superior Colliculus/Lateral Posterior Thalamic Nuclei in Mice Rapidly Transmit Fear Visual Information Through the Theta Frequency Band

Animals perceive threat information mainly from vision, and the subcortical visual pathway plays a critical role in the rapid processing of fear visual information. The superior colliculus (SC) and lateral posterior (LP) nuclei of the thalamus are key components of the subcortical visual pathway; however, how animals encode and transmit fear visual information is unclear. To evaluate the response characteristics of neurons in SC and LP thalamic nuclei under fear visual stimuli, extracellular action potentials (spikes) and local field potential (LFP) signals were recorded under looming and dimming visual stimuli. The results showed that both SC and LP thalamic nuclei were strongly responsive to looming visual stimuli but not sensitive to dimming visual stimuli. Under the looming visual stimulus, the theta (θ) frequency bands of both nuclei showed obvious oscillations, which markedly enhanced the synchronization between neurons. The functional network characteristics also indicated that the network connection density and information transmission efficiency were higher under fear visual stimuli. These findings suggest that both SC and LP thalamic nuclei can effectively identify threatening fear visual information and rapidly transmit it between nuclei through the θ frequency band. This discovery can provide a basis for subsequent coding and decoding studies in the subcortical visual pathways.

A versatile transcription factor: Multiple roles of orthopedia a (otpa) beyond its restricted localization in dopaminergic systems of developing and adult zebrafish (Danio rerio) brains.

Many transcription factors boost neural development and differentiation in specific directions and serve for identifying similar or homologous structures across species. The expression of Orthopedia (Otp) is critical for the development of certain cell groups along the vertebrate neuraxis, for example, the medial amygdala or hypothalamic neurosecretory neurons. Therefore, the primary focus of the present study is the distribution of Orthopedia a (Otpa) in the larval and adult zebrafish (Danio rerio) brain. Since Otpa is also critical for the development of zebrafish basal diencephalic dopaminergic cells, colocalization of Otpa with the catecholamine synthesizing enzyme tyrosine hydroxylase (TH) is studied. Cellular colocalization of Otpa and dopamine is only seen in magnocellular neurons of the periventricular posterior tubercular nucleus and in the posterior tuberal nucleus. Otpa-positive cells occur in many additional structures along the zebrafish neuraxis, from the secondary prosencephalon down to the hindbrain. Furthermore, Otpa expression is studied in shh-GFP and islet1-GFP transgenic zebrafish. Otpa-positive cells only express shh in dopaminergic magnocellular periventricular posterior tubercular cells, and only colocalize with islet1-GFP in the ventral zone and prerecesscaudal periventricular hypothalamic zone and the perilemniscal nucleus. The scarcity of cellular colocalization of Otpa in islet1-GFP cells indicates that the Shh-islet1 neurogenetic pathway is not active in most Otpa-expressing domains. Our analysis reveals detailed correspondences between mouse and zebrafish forebrain territories including the zebrafish intermediate nucleus of the ventral telencephalon and the mouse medial amygdala. The zebrafish preoptic Otpa-positive domain represents the neuropeptidergic supraopto-paraventricular region of all tetrapods. Otpa domains in the zebrafish basal plate hypothalamus suggest that the ventral periventricular hypothalamic zone corresponds to the otp-expressing basal hypothalamic tuberal field in the mouse. Furthermore, the mouse otp domain in the mammillary hypothalamus compares partly to our Otpa-positive domain in the prerecess caudal periventricular hypothalamic zone (Hc-a).

Visual imaging as a predictor of neurodegeneration in experimental autoimmune demyelination and multiple sclerosis

Thalamic volume is associated with clinical disability in multiple sclerosis (MS) and is vulnerable to secondary neurodegeneration due to its extensive connectivity throughout the central nervous system (CNS). Using a model of autoimmune demyelination that exhibits CNS-infiltrating immune cells in both spinal cord white matter and optic nerve, we sought to evaluate neurodegenerative changes due to lesions affecting the spino- and retino-thalamic pathways. We found comparable axonal loss in spinal cord white matter and optic nerve during the acute phase of disease consistent with synaptic loss, but not neuronal cell body loss in the thalamic nuclei that receive input from these discrete pathways. Loss of spinal cord neurons or retinal ganglion cells retrograde to their respective axons was not observed until the chronic phase of disease, where optical coherence tomography (OCT) documented reduced inner retinal thickness. In patients with relapsing–remitting MS without a history of optic neuritis, OCT measures of inner retinal volume correlated with retino-thalamic (lateral geniculate nucleus) and spino-thalamic (ventral posterior nucleus) volume as well as neuroperformance measures. These data suggest retinal imaging may serve as an important noninvasive predictor of neurodegeneration in MS.

Identifying the neural basis for rosacea using positron emission tomography-computed tomography cerebral functional imaging analysis: A cross-sectional study.

The neural basis of rosacea is not well understood. This study aimed to determine whether cerebral glucose metabolism (CGM) changes on 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET)/computed tomography (CT) scans can detect functional network changes in specific brain areas in patients with rosacea. Eight adults with rosacea and 10 age/sex-matched healthy adults (controls) were enrolled in the study. 18 F-FDG PET/CT brain images for all eight patients and whole-body images for two of the patients were analyzed qualitatively and semi-quantitatively. Differences between the study groups were examined using Fischer's exact test and a Student's t-test. A voxel-based analysis using statistical parametric mapping was performed to compare the brain metabolism of the patients with that of the controls. Compared with the controls, the patients with rosacea showed extensive changes in the CGM signals in the cerebral cortex and limbic system, with less CGM shown in the right superior parietal lobule, right postcentral gyrus, right parahippocampal gyrus, left superior frontal gyrus, and lateral posterior thalamic nucleus and more CGM in the right precentral gyrus, left inferior frontal gyrus, and cerebellar tonsil. No dysmetabolic lesions were found in the whole-body 18 F-FDG PET/CT images. Specific neural functional changes occur in patients with rosacea that may explain its pathogenesis.

Medical and Surgical Treatment for Medication-Induced Tremor: Case Report and Systematic Review.

ABSTRACTObjectiveTo present a case of refractory medication‐induced tremor successfully treated with deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (Vim) and to propose a medical and surgical treatment algorithm based on a systematical review of the literature.MethodsPatient data were retrospectively collected. A systematic search was performed in PubMed, Embase, and Cochrane Library. Subjective and objective data were pooled for analysis by classifying them into 5 predefined categories(no, minimal, moderate, good, and excellent effects).ResultsThe patient presented with lithium‐induced bilateral progressive hand tremor lasting 25 years. After DBS, he reported excellent tremor suppression until the last follow‐up (36 months after Vim‐DBS). For the review, 34 of 140 studies were included and evaluated (178 unique subjects, 31 different treatments). A good‐to‐excellent tremor suppression (50%–100%) in at least 50% of subjects was achieved using propranolol (12 studies, 50% of 56 subjects), tetrabenazine (5 studies, 51% of 13 subjects), and metoprolol (4 studies, 75% of 8 subjects). The effect of benztropine and diphenhydramine was none or only minimal to moderate (up to 50% improvement; both: 3 studies, 50% of 4 patients). One article reported minimal‐to‐moderate effectiveness after DBS of the ventral oral posterior nucleus of the thalamus. Methods were highly heterogeneous. All studies scored grade III or IV quality of evidence, which was insufficient for recommendations (level U).ConclusionTreatment decision making should be performed on a case‐by‐case basis considering the low level of evidence, and we propose a practically oriented treatment algorithm. Propranolol, tetrabenazine, and metoprolol might be effective. For selected and refractory cases, DBS might be considered.

Neuromodulation for Trigeminal Neuralgia.

Clinical studies on neuromodulation intervention for trigeminal neuralgia have not yet shown promising results. This might be due to the fact that the pathophysiology of chronic trigeminal neuropathy is not yet fully understood. Chronic trigeminal neuropathy includes trigeminal autonomic neuropathy, painful trigeminal neuropathy, and persistent idiopathic facial pain. This disorder is caused by complex abnormalities in the pain processing system, which is comprised of the affective, emotional, and sensory components, rather than mere abnormal sensation. Therefore, integrative understanding of the pain system is necessary for appropriate neuromodulation of chronic trigeminal neuropathy. The possible neuromodulation targets that participate in complex pain processing are as follows : the ventral posterior medial nucleus, periaqueductal gray, motor cortex, nucleus accumbens, subthalamic nucleus, globus pallidus internus, anterior cingulate cortex, hypothalamus, sphenopalatine ganglion, and occipital nerve. In conclusion, neuromodulation interventions for trigeminal neuralgia is yet to be elucidated; future advancements in this area are required

The brain of the tree pangolin (Manis tricuspis). VII. The amygdaloid body.

Here, we describe the cytoarchitecture and chemoarchitecture of the amygdaloid body of the tree pangolin. Our definition of the amygdaloid body includes the pallial portions of the amygdala, and the centromedial group that is a derivative of the subpallium and part of the extended amygdala. The remainder of the extended amygdala is not described herein. Within the amygdaloid body of the tree pangolin, we identified the basolateral group (composed of the lateral, basal, and accessory basal amygdaloid nuclei), the superficial, or cortical nuclei (the anterior and posterior cortical nuclei, the periamygdaloid cortex, and nuclei of the olfactory tract), the centromedial group (the central amygdaloid nucleus and the medial nuclear cluster), and other amygdaloid nuclei (the anterior amygdaloid area, the amygdalohippocampal area, the intramedullary group, and intercalated islands). The location within and relative to each other within the amygdaloid body and the internal subdivisions of these groups were very similar to that reported in other mammalian species, with no clearly derived features specific to the tree pangolin. The only variation was the lack of an insular appearance of the intercalated islands, which in the tree pangolin were observed as a continuous band of neurons located dorsomedial to the basolateral group similar in appearance to and almost continuous with the intramedullary group. In carnivores, the closest relatives of the pangolins, and laboratory rats, a similar appearance of portions of the intercalated islands has been noted.

Female Mice Exposed to Early Life Stress Display Exacerbated Obesity‐Hypertension while Normal Response to Adipose Afferent Reflex Stimulation

The experimental stimulation of afferent excitatory signals from adipose tissue has been shown to contribute with obesity‐induced hypertension as part of a mechanism called the adipose afferent reflex (AAR). Previous studies from our lab have shown that male mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display increased mean arterial pressure (MAP) and sympathetic tone compared to control mice when fed a high fat diet (HF). Also, MSEW‐HF males display exacerbated blood pressure responses to the acute stimulation of the AAR in perigonadal white adipose tissue (gWAT) compared to controls that correlates with increased neuronal activation in the posterior paraventricular nucleus of the hypothalamus and rostroventrolateral medulla. We have identified increased serotonin (5‐HT) levels in eWAT from obese MSEW mice as a potential endogenous factor stimulating sensory neurons. As females MSEW do not show sympathetic activation, the aim of this study was to determine whether their increased blood pressure was independent of exacerbated blood pressure response to AAR stimulation or levels of 5‐HT in gWAT. C57BL/6J mice pups were separated from the dams from postnatal day (PD) 2 to PD 16 and weaned early on PD 17. Control (C) litters remained undisturbed with the dams and were weaned on PD 21. After weaning, Female C and MSEW mice (n=5/group) were placed on low fat diet (LF) or HF (10% and 60% Kcal from fat, respectively). At 16 weeks, subcutaneous (sc) and gWAT depots were exposed for vehicle or 1.5 pmol/μL of capsaicin (8 μL, 2’, 4 sites, bilateral). Vehicle infusions in scWAT or gWAT did not change MAP from baseline in any of the groups. Capsaicin infusions in scWAT slightly increase MAP similarly in all groups (Delta MAP, mmHg: C‐LF: 3±1; MSEW‐LF: 3±1; C‐HF: 2±1; MSEW‐HF: 2±1). In gWAT, capsaicin infusions also increased MAP similarly in all groups (Delta MAP, mmHg: C‐LF: 3±1; MSEW‐LF: 4±1; C‐HF: 3±1; MSEW‐HF: 5±2). None of these changes in MAP were significant. No differences in 5‐HT levels in scWAT (C‐HF: 1801.15±122.26; MSEW‐HF: 1799.17±216.58 ug/mg tissue) and gWAT (C‐HF: 563.51±71.41; MSEW‐HF: 518.31±99.73 ug/mg tissue); were found between groups. Furthermore, stimulation of AAR with 5‐HT (10‐6 M, 4 sites, bilateral) increased blood pressure only in male MSEW mice (p&lt;0.05). These results suggest that the AAR is not exacerbated in obese female MSEW mice, result that is consistent with a lack of sympathetic activation compared to control mice.

Chemogenetic Modulation of the Posterior Insular Cortex Alters Both Affective and Sensory Pain-related Behavior

The insula is a multimodal cortical area involved in interoception, and somatic and autonomic control. Human imaging studies have consistently shown that the insula is activated during noxious somatosensory stimulation. However, the distinct function of the insula in processing noxious stimuli is poorly understood. The purpose of this study is to investigate how bidirectional chemogenetic modulation of the insula influences sensory and affective behaviors. Selective targeting of the posterior insula (PIC) was determined by anatomical labeling from the sensory thalamus. Modulation of the PIC was performed using excitatory and inhibitory designer receptors exclusively activated by designer drugs (DREADDs), with the agonists compound 21 or clozapine-N-oxide for transient activation. Affective behaviors were evaluated through conditioned place aversion (CPA), thermal preference assay, and hot plate test. Sensory threshold tests performed were Hargreaves and von Frey. The PIC, not the anterior insula, receives direct projections from the thalamic posterior triangular nucleus (PoT), a target of an ascending somatosensory tract. Activating the PIC produced a place aversion in naive mice and a heightened aversion to warmth without altering thermal or mechanical threshold. Conversely, inhibiting the PIC in naive mice increased hot plate latency. Interestingly, activating only the PoT to PIC projections produced thermal hyperalgesia. Our results show that the PIC is an important region for both affective and sensory processing of somatosensory stimuli. Activation of the PIC alone produced negative valence in CPA and an aversion to warmth without altering sensory threshold, while activating the PoT to PIC circuit produced a decrease in thermal threshold. These results suggest that the PIC could be involved in a separate circuit to generate negative affect. Overall, the PIC contributes to the multidimensional experience of pain and thus therapeutics aimed at reducing PIC activity could be effective in alleviating the suffering associated with pain. Grant support from R01 NS107356.

Cognitive outcome is related to functional thalamo-cortical connectivity after paediatric stroke

The thalamus has complex connections with the cortex and is involved in various cognitive processes. Despite increasing interest in the thalamus and the underlying thalamo-cortical interaction, little is known about thalamo-cortical connections after paediatric arterial ischaemic stroke. Therefore, the aim of this study was to investigate thalamo-cortical connections and their association with cognitive performance after arterial ischaemic stroke. Twenty patients in the chronic phase after paediatric arterial ischaemic stroke (≥2 years after diagnosis, diagnosed <16 years; aged 5–23 years, mean: 15.1 years) and 20 healthy controls matched for age and sex were examined in a cross-sectional study design. Cognitive performance (selective attention, inhibition, working memory, and cognitive flexibility) was evaluated using standardized neuropsychological tests. Resting-state functional magnetic resonance imaging was used to examine functional thalamo-cortical connectivity. Lesion masks were integrated in the preprocessing pipeline to ensure that structurally damaged voxels did not influence functional connectivity analyses. Cognitive performance (selective attention, inhibition, and working memory) was significantly reduced in patients compared to controls. Network analyses revealed significantly lower thalamo-cortical connectivity for the motor, auditory, visual, default mode network, salience, left/right executive, and dorsal attention network in patients compared with controls. Interestingly, analyses additionally revealed higher thalamo-cortical connectivity in some subdivisions of the thalamus for the default mode network (medial nuclei), motor (lateral nuclei), dorsal attention (anterior nuclei), and the left executive network (posterior nuclei) in patients compared with controls. Increased and decreased thalamo-cortical connectivity strength within the same networks was, however, found in different thalamic subdivisions. Thus, alterations in thalamo-cortical connectivity strength after paediatric stroke seem to point in both directions, with stronger as well as weaker thalamo-cortical connectivity in patients compared with controls. Multivariate linear regression, with lesion size and age as covariates, revealed significant correlations between cognitive performance (selective attention, inhibition, and working memory) and the strength of thalamo-cortical connectivity in the motor, auditory, visual, default mode network, posterior default mode network, salience, left/right executive, and dorsal attention network after childhood stroke. Our data suggest that the interaction between different sub-nuclei of the thalamus and several cortical networks relates to post-stroke cognition. The variability in cognitive outcomes after paediatric stroke might partly be explained by functional thalamo-cortical connectivity strength.

FV 13 Transcranial direct current stimulation modulates stroke-induced secondary thalamic neurodegeneration in mice

Introduction: Transcranial direct current stimulation (tDCS) non-invasively promotes recovery after stroke ( Braun et al. Exp. Neurol. 2016; Hummel et al. Brain 2005 ). Stroke affects entire networks beyond the focal lesion, impacting post-stroke impairment ( Blaschke et al. Stroke 2021 ). The thalamus constitutes a central hub due to its numerous functional connections but is also prone to secondary injury ( Cao et al. Front. Neurol. 2020 ). Under the hypothesis that tDCS promotes recovery by supporting neuroprotection, we investigated the effects of tDCS on secondary thalamic neurodegeneration after stroke. Methods: Cortical stroke was induced in the sensory-motor cortex (photothrombosis model in mice). Starting three days after stroke, cathodal tDCS over the ipsilesional somatosensory cortex was performed daily for ten days (39.6 kC/m 2 ), sham-stimulated mice served as control. Behavioral tests over time assessed functional recovery. Secondary degeneration of the ipsilesional thalamus was evaluated ex vivo 28 days after stroke. Using an atlas-based registration pipeline ( Pallast et al. J. Neurosc. Methods 2019 ), the absolute number of GFAP+ astrocytes and relative number of ipsilesional NeuN+ neurons compared to the contralateral unaffected thalamus were evaluated. Lesion maps based on T2-weighted Magnetic Resonance Imaging (MRI) before tDCS were used for voxel-based lesion-symptom mapping (VBLSM) to evaluate the effect of the lesion location on remote neurodegeneration. Functional connectivity (FC) between the lesioned sensorimotor cortex and the ipsilesional thalamus was measured by resting-state functional MRI. Additionally, glucose metabolism after a likewise tDCS regimen in healthy mice was measured by positron emission tomography compared to sham stimulation. Results: Repetitive tDCS decreased the ipsilateral thalamic glucose metabolism in unlesioned animals, while accelerating motor recovery after stroke. Four weeks after cortical stroke, secondary glial scaring was found in the ipsilesional thalamus, most pronounced in the posterior (Po), ventral posterolateral (VPL), and ventral posteromedial (VPM) nucleus, its extent correlating to the cortical lesion size (R 2 =0.3, p<0.01). Neurodegeneration was associated with a lesion cluster (VSBLM, p<0.05) extending laterally and including the callosal white matter tracts as well as deeper primary somatosensory layers. A decrease in FC between the primary somatosensory area of the lower limb (SS-LL) and the thalamus correlated with secondary neurodegeneration (R 2 =0.25, p<0.01). Intriguingly, in contrast to glial scaring, tDCS reduced thalamic neurodegeneration by over 60% (p<0.05). Conclusion: Cortical stroke induced network changes and led to remote secondary structural impairment of the thalamus, depending on the affection of corticothalamic connections. TDCS mitigated this remote secondary neurodegeneration. Data suggest previously unknown effects of tDCS on remote brain regions after stroke.

Paradoxical effects of posterior intralaminar thalamic calretinin neurons on hippocampal seizure via distinct downstream circuits

SummaryEpilepsy is a circuit-level brain disorder characterized by hyperexcitatory seizures with unclear mechanisms. Here, we investigated the causal roles of calretinin (CR) neurons in the posterior intralaminar thalamic nucleus (PIL) in hippocampal seizures. Using c-fos mapping and calcium fiber photometry, we found that PIL CR neurons were activated during hippocampal seizures in a kindling model. Optogenetic activation of PIL CR neurons accelerated seizure development, whereas inhibition retarded seizure development. Further, viral-based circuit tracing verified that PIL CR neurons were long-range glutamatergic neurons, projecting toward various downstream regions. Interestingly, selective inhibition of PIL-lateral amygdala CR circuit attenuated seizure progression, whereas inhibition of PIL-zona incerta CR circuit presented an opposite effect. These results indicated that CR neurons in the PIL play separate roles in hippocampal seizures via distinct downstream circuits, which complements the pathogenic mechanisms of epilepsy and provides new insight for the precise medicine of epilepsy.

Oxytocin Receptor-Expressing Neurons in the Paraventricular Thalamus Regulate Feeding Motivation through Excitatory Projections to the Nucleus Accumbens Core.

Oxytocin receptors (OTR) have been found in the paraventricular thalamus (PVT) for the regulation of feeding and maternal behaviors. However, the functional projections of OTR-expressing PVT neurons remain largely unknown. Here, we used chemogenetic and optogenetic tools to test the role of OTR-expressing PVT neurons and their projections in the regulation of food intake in both male and female OTR-Cre mice. We found chemogenetic activation of OTR-expressing PVT neurons promoted food seeking under trials with a progressive ratio schedule of reinforcement. Using Feeding Experimentation Devices for real-time meal measurements, we found chemogenetic activation of OTR-expressing PVT neurons increased meal frequency but not cumulative food intake because of a compensatory decrease in meal sizes. In combination with anterograde neural tracing and slice patch-clamp recordings, we found optogenetic stimulation of PVT OTR terminals excited neurons in the posterior basolateral amygdala (pBLA) and nucleus accumbens core (NAcC) as well as local PVT neurons through monosynaptic glutamatergic transmissions. Photostimulation of OTR-expressing PVT-NAcC projections promoted food-seeking, whereas selective activation of PVT-pBLA projections produced little effect on feeding. In contrast to selective activation of OTR terminals, photostimulation of a broader population of glutamatergic PVT terminals exerted direct excitation followed by indirect lateral inhibition on neurons in both NAcC and anterior basolateral amygdala. Together, these results suggest that OTR-expressing PVT neurons are a distinct population of PVT glutamate neurons that regulate feeding motivation through projections to NAcC.SIGNIFICANCE STATEMENT The paraventricular thalamus plays an important role in the regulation of feeding motivation. However, because of the diversity of paraventricular thalamic neurons, the specific neuron types promoting food motivation remain elusive. In this study, we provide evidence that oxytocin receptor-expressing neurons are a specific group of glutamate neurons that primarily project to the nucleus accumbens core and posterior amygdala. We found that activation of these neurons promotes the motivation for food reward and increases meal frequency through projections to the nucleus accumbens core but not the posterior amygdala. As a result, we postulate that oxytocin receptor-expressing neurons in the paraventricular thalamus and their projections to the nucleus accumbens core mainly regulate feeding motivation but not food consumption.

Characterization and distribution of kisspeptins, kisspeptin receptors, GnIH, and GnRH1 in the brain of the protogynous bluehead wrasse (Thalassoma bifasciatum)

The kisspeptin and gonadotropin-inhibitory hormone (GnIH) systems regulate the hypothalamic-pituitary-gonadal (HPG) axis in a broad range of vertebrates through direct or indirect effects on hypothalamic/preoptic gonadotropin-releasing hormone (GnRH) neurons and pituitary gonadotropes. These systems are sensitive to environmental factors, including social conditions, and may assist in relaying environmental signals to the HPG axis in a potentially broad range of taxa. In this study, we characterized expression of kisspeptin-system genes (kiss1, kiss2, kissr1, and kissr2), gnih, and gnrh1 in the brain of the bluehead wrasse (Thalassoma bifasciatum), an important teleost model of socially-controlled sex change. We analyzed cDNA sequences and examined transcript distributions in the brain using in situ hybridization (ISH) to determine if expression occurs in reproductively-relevant and conserved regions. Expression of kiss1 was detected in the habenula, lateral hypothalamic nucleus (LHn), and preoptic area (POA), while kiss2 was expressed in the dorsal hypothalamus, with sporadic signal in the POA. Expression of kissr1 was detected in the POA, habenula, and LHn, while kissr2 expression was widespread. Gnih mRNA was detected in the posterior periventricular nucleus (NPPv), and gnrh1 neurons localized to the POA. Neurons expressing kissr2 and gnih co-regionalized in the NPPv, while kissr1, kissr2, and gnrh1 co-regionalized in the POA. Double-label ISH revealed very close proximity between kissr1 and gnrh1 neurons, suggesting potential communication between the kisspeptin and GnRH1 systems through these interneurons. These expression patterns are generally conserved and suggest that if kisspeptins do signal GnRH1 neurons, the interaction is indirect, possibly through neurons adjacent to GnRH1. With this foundation in place, future studies can help determine the interactions among these systems and whether these peptides assist in transducing social changes into a shift from female to male sexual function.

The Importance of Ki67, Glial Fibrillar Acidic Protein and Vitamin D Receptor in the Central Nervous System of Postmortem Suicide Cases

Death by suicide is a tragic public health problem. Major depressive patients constitute some of these deaths. Although the etiology of major depression has not been clarified, there are studies suggesting that the hippocampus and caudate nucleus may be effective. In this study, it was aimed to compare vitamin D receptor (VDR), Ki67 and glial fibrial acidic protein (GFAP) antibodies in the brain tissues (hippocampus and caudate nucleus) of untreated major depression patients who died because of suicide with the control group. Left hippocampus and caudate nuclei of seven patients with untreated major depression who died of suicide in a one-year period and six psychiatrically normal patients were taken during autopsy. The hippocampus was stained with VDR, GFAP and Ki67 antibodies, and the caudate nucleus was stained with VDR and GFAP antibodies. There was no significant difference in the number of Ki67-positive cells in the anterior and posterior dentate gyrus between the major depression and control groups (P > 0.05). In the major depression group, a negative correlation was reported between the number of Ki67-positive cells in the anterior dentate gyrus and age (r: 0.867, P < 0.05). In the anterior dentate gyrus, posterior dentate gyrus and caudate nucleus, there was no significant difference between the suicide and control groups in the fraction of the immunoreactive area with GFAP antibodies (P > 0.05). While the percentage of immunoreactive granular cells for vitamin D receptor in the anterior dentate gyrus was significantly higher than the control group (P <0.05), no significant difference was reported in the posterior dentate gyrus. Vitamin D receptor immunoreactive neuron positivity in the caudate nucleus was not significantly different between the major depression and control groups (P > 0.05). In untreated major depression, additional immunohistochemical changes are observed in the anterior hippocampus, and the vitamin D receptor increases in the granular cells as a protective factor.

Connectomic analysis of unilateral dual-lead thalamic deep brain stimulation for treatment of multiple sclerosis tremor.

Tremor is a common symptom in multiple sclerosis and can present as a severe postural and action tremor, leading to significant disability. Owing to the diffuse and progressive nature of the disease, it has been challenging to characterize the pathophysiology underlying multiple sclerosis tremor. Deep brain stimulation of the ventralis intermedius and the ventralis oralis posterior thalamic nuclei has been used to treat medically refractory multiple sclerosis tremors with variable results. The aim of this study was to characterize multiple sclerosis tremor at the network level by applying modern connectomic techniques to data from a previously completed single-centre, randomized, single-blind prospective trial of 12 subjects who were treated with unilateral dual-lead (ventralis intermedius + ventralis oralis posterior) thalamic deep brain stimulation. Preoperative T1-weighted MRI and postoperative head CTs were used, along with applied programming settings, to estimate the volume of tissue activated for each patient. The volumes of tissue activated were then used to make voxel-wise and structural connectivity correlations with clinically observed tremor suppression. The volume of the tissue-activated analyses identified the optimal region of stimulation at the ventralis oralis posterior ventralis intermedius border intersecting with the dentato-rubro-thalamic tract. A regression model showed strong connectivity to the supplemental motor area was positively associated with tremor suppression (r = 0.66) in this cohort, whereas connectivity to the primary motor cortex was negatively associated with tremor suppression (r = −0.69), a finding opposite to that seen in ventralis intermedius deep brain stimulation for essential tremor. Comparing the structural connectivity to that of an essential tremor cohort revealed a distinct network that lies anterior to the essential tremor network. Overall, the volumes of tissue activated and connectivity observations converge to suggest that optimal suppression of multiple sclerosis tremor will likely be achieved by directing stimulation more anteriorly toward the ventralis oralis posterior and that a wide field of stimulation synergistically modulating the ventralis oralis posterior and ventralis intermedius nuclei may be more effective than traditional ventralis intermedius deep brain stimulation at suppressing the severe tremors commonly seen in complex tremor syndromes such as multiple sclerosis tremor.