Specific Brain Nuclei Research Articles

Physiology, Pathophysiology and Clinical Relevance of D-Amino Acids Dynamics: From Neurochemistry to Pharmacotherapy.

Over three decades ago, two independent groups of investigators identified free D-aspartic and later D-serine in specific brain nuclei and endocrine glands. This finding revealed a novel, non-proteinogenic role of these molecules. Moreover, the finding that aged proteins from the human eye crystallin, teeth, bone, blood vessels or the brain incorporate D-aspartic acids to specific primary protein sequences fostered the hypothesis that aging might be related to D-amino acid isomerization of body proteins. The experimental confirmation that schizophrenia and neurodegenerative diseases modify plasma free D-amino acids or tissue levelsnurtured the opportunity of using D-amino acids as therapeutic agents for several disease treatments, a strategy that prompted the successful current application of D-amino acids to human medicine.

Axon guidance during mouse central nervous system regeneration is required for specific brain innervation.

Reconstructing functional neuronal circuits is one major challenge of central nervous system repair. Through activation of pro-growth signaling pathways, some neurons achieve long-distance axon regrowth. Yet, functional reconnection has hardly been obtained, as these regenerating axons fail to resume their initial trajectory and reinnervate their proper target. Axon guidance is considered to be active only during development. Here, using the mouse visual system, we show that axon guidance is still active in the adult brain in regenerative conditions. We highlight that regenerating retinal ganglion cell axons avoid one of their primary targets, the suprachiasmatic nucleus (SCN), due to Slit/Robo repulsive signaling. Together with promoting regeneration, silencing Slit/Robo invivo enables regenerating axons to enter the SCN and form active synapses. The newly formed circuit is associated with neuronal activation and functional recovery. Our results provide evidence that axon guidance mechanisms are required to reconnect regenerating axons to specific brain nuclei.

Recent advances in neural mechanism of general anesthesia induced unconsciousness: insights from optogenetics and chemogenetics.

For over 170years, general anesthesia has played a crucial role in clinical practice, yet a comprehensive understanding of the neural mechanisms underlying the induction of unconsciousness by general anesthetics remains elusive. Ongoing research into these mechanisms primarily centers around the brain nuclei and neural circuits associated with sleep-wake. In this context, two sophisticated methodologies, optogenetics and chemogenetics, have emerged as vital tools for recording and modulating the activity of specific neuronal populations or circuits within distinct brain regions. Recent advancements have successfully employed these techniques to investigate the impact of general anesthesia on various brain nuclei and neural pathways. This paper provides an in-depth examination of the use of optogenetic and chemogenetic methodologies in studying the effects of general anesthesia on specific brain nuclei and pathways. Additionally, it discusses in depth the advantages and limitations of these two methodologies, as well as the issues that must be considered for scientific research applications. By shedding light on these facets, this paper serves as a valuable reference for furthering the accurate exploration of the neural mechanisms underlying general anesthesia. It aids researchers and clinicians in effectively evaluating the applicability of these techniques in advancing scientific research and clinical practice.

The Multifaceted Role of Oxytocinergic System and OXTR Gene.

The article explores the multifaceted role of the neuropeptide oxytocin in human behavior and its connection to the oxytocin receptor ( OXTR ) gene. Oxytocin, produced in specific brain nuclei, is implicated in emotional, social, and maternal behaviors, stress reduction, uterine contraction during childbirth, and lactation. The OXTR gene, located on chromosome 3, encodes oxytocin receptors found in various body parts, including critical brain regions associated with social behaviors. The article delves into studies on rodents, revealing correlations between OXTR gene expression and pair bonding in the prefrontal cortex and social behavior regulation in the amygdala. The discussion extends to the impact of oxytocin on social support-seeking behavior, focusing on a specific genetic variation, rs53576. The article explores how this genetic variation influences empathy, stress reactivity, and susceptibility to disorders such as autism and social anxiety. Furthermore, the article examines structural and functional changes in the brain associated with OXTR gene variations. It discusses the role of DNA methylation in influencing oxytocin receptor availability, affecting social perception and responsiveness to negative stimuli. The article also highlights the oxytocinergic system's involvement in disorders such as autism and social anxiety, emphasizing the interplay between genetics and environmental factors. The article also touches on the potential therapeutic use of exogenous oxytocin in mitigating symptoms associated with these disorders. In summary, the article underscores the intricate relationship between oxytocin, the OXTR gene, and diverse aspects of human behavior, providing insights into social bonding, perception, and the development of behavioral disorders.

Implants talk to each-other: RF heating changes when two DBS leads are present simultaneously during MRI.

Deep brain stimulation (DBS) has proven to be an effective treatment for Parkinson's disease and other brain disorders. The procedure often involves implanting two elongated leads aimed at specific brain nuclei in both the left and right hemispheres. However, evaluating the safety of MRI in patients with such implants has only been done on an individual lead basis, ignoring the possibility of crosstalk between the leads. This study evaluates the impact of crosstalk on power deposition at the lead tip through numerical simulation and phantom experiments. We used CT images to obtain patient-specific lead trajectories and compared the power deposition at the lead tip in cases with bilateral and unilateral DBS implants. Our results indicate that the RF power deposition at the lead tip can vary by up to 6-fold when two DBS leads are present together compared to when only one lead is present. Experimental measurements in a simplified case of two lead-only DBS systems confirmed the existence of crosstalk.Clinical Relevance-Our results indicate that RF heating of implanted leads during MRI can be affected by the presence of another lead in the body, which may increase or decrease the power deposition in the tissue depending on the position and configuration of the leads.

Exposure to Morphine and Cocaine Modify the Transcriptomic Landscape in Zebrafish Embryos

Morphine and other opioid analgesics are the drugs of election to treat moderate-to-severe pain, and they elicit their actions by binding to the opioid receptors. Cocaine is a potent inhibitor of dopamine, serotonin, and noradrenaline reuptake, as it blocks DAT, the dopamine transporter, causing an increase in the local concentration of these neurotransmitters in the synaptic cleft. The molecular effects of these drugs have been studied in specific brain areas or nuclei, but the systemic effects in the whole organism have not been comprehensively analyzed. This study aims to analyze the transcriptomic changes elicited by morphine (10 uM) and cocaine (15 uM) in zebrafish embryos. An RNAseq assay was performed with tissues extracts from zebrafish embryos treated from 5 hpf (hours post fertilization) to 72 hpf, and the most representative deregulated genes were experimentally validated by qPCR. We have found changes in the expression of genes related to lipid metabolism, chemokine receptor ligands, visual system, hemoglobins, and metabolic detoxification pathways. Besides, morphine and cocaine modified the global DNA methylation pattern in zebrafish embryos, which would explain the changes in gene expression elicited by these two drugs of abuse.

Selective isolation of mouse glial nuclei optimized for reliable downstream omics analyses

BackgroundIsolation of cell types of interest from the brain for molecular applications presents several challenges, including cellular damage during tissue dissociation or enrichment procedures, and low cell number in the tissue in some cases. Techniques have been developed to enrich distinct cell populations using immunopanning or fluorescence activated cell/nuclei sorting. However, these techniques often involve fixation, immunolabeling and DNA staining steps, which could potentially influence downstream omics applications. New methodTaking advantage of readily available genetically modified mice with fluorescent-tagged nuclei, we describe a technique for the purification of cell-type specific brain nuclei, optimized to decrease sample preparation time and to limit potential artefacts for downstream omics applications. We demonstrate the applicability of this approach for the purification of glial cell nuclei and show that the resulting cell-type specific nuclei obtained can be used effectively for omics applications, including ATAC-seq and RNA-seq. ResultsWe demonstrate excellent enrichment of fluorescently-tagged glial nuclei, yielding high quality RNA and chromatin. We identify several critical steps during nuclei isolation that help limit nuclei rupture and clumping, including quick homogenization, dilution before filtration and loosening of the pellet before resuspension, thus improving yield. Sorting of fluorescent nuclei can be achieved without fixation, antibody labelling, or DAPI staining, reducing potential artifactual results in RNA-seq and ATAC-seq analyses. We show that reproducible glial cell type-specific profiles can be obtained in transcriptomic and chromatin accessibility assays using this rapid protocol. Comparison with existing methodsOur method allows for rapid enrichment of glial nuclei populations from the mouse brain with minimal processing steps, while still providing high quality RNA and chromatin required for reliable omics analyses. ConclusionsWe provide a reproducible method to obtain nucleic material from glial cells in the mouse brain with a quick and limited sample preparation.

Exendin-4 improves long-term potentiation and neuronal dendritic growth in vivo and in vitro obesity condition

Metabolic syndrome, which increases the risk of obesity and type 2 diabetes has emerged as a significant issue worldwide. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies such as memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells and specific brain nuclei plays multiple roles including regulation of insulin sensitivity, inflammation and synaptic plasticity. Although GLP-1 and GLP-1 receptor agonists appear to have neuroprotective function, the specific mechanism of their action in brain remains unclear. We investigated whether exendin-4, as a GLP-1RA, improves cognitive function and brain insulin resistance in metabolic-imbalanced mice fed a high-fat diet. Considering the result of electrophysiological experiments, exendin-4 inhibits the reduction of long term potentiation (LTP) in high fat diet mouse brain. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons in in vitro metabolic imbalanced condition. Our results showed the improvement of IRS-1 phosphorylation, neuronal complexity, and the mature of dendritic spine shape by exendin-4 treatment in metabolic imbalanced in vitro condition. Here, we provides significant evidences on the effect of exendin-4 on synaptic plasticity, long-term potentiation, and neural structure. We suggest that GLP-1 is important to treat neuropathology caused by metabolic syndrome.

The Opsin 3/Teleost multiple tissue opsin system: mRNA localization in the retina and brain of medaka (Oryzias latipes).

The photoreceptor protein, opsin, is one of the major components for vision and photoreceptive function in animals. Although many opsins have been discovered from animal genomes, only a few non-image-forming functions mediated by opsins have been identified. Understanding the mRNA distribution of photoreceptor proteins is one crucial step in uncovering their photoreceptive function in animals. Here we focus on the medaka fish (Oryzias latipes) Opsin 3 (Opn3)/Teleost multiple opsin (Tmt) system, which constitutes a separate phylogenetic group, having putative blue light photoreceptors for non-image-forming functions. In medaka, there is one opn3 and five tmt-opsin orthologs. The expression pattern of the opn3/tmt-opsins in the retina and brain was investigated by in situ hybridization. mRNAs for opn3/tmt-opsins were distributed in the retinal ganglion cells as well as interneurons and specific brain nuclei. Specifically, hybridization signals were observed in the glutamate decarboxylase 1 (gad1)-expressing amacrine cells for opn3, tmt1a, tmt1b, and tmt2, in the caudal lobe of the cerebellum for tmt1b and tmt2, in the cranial nerve nuclei for opn3, tmt1a, tmt1b, tmt2, and in the rostral pars distalis (adenohypophysis) for opn3. These expression patterns suggest that blue light sensing in the fish retina and brain may be involved in the integration of visual inputs, vestibular function, somatosensation, motor outputs, and pituitary endocrine regulation. This article is protected by copyright. All rights reserved.

Behavioral Genetics: Dissecting a Supergene to Understand Behavior

New research shows how alternative 'supergene' alleles of Estrogen Receptor 1 are differentially expressed in specific brain nuclei causing aggressive behavior in the white-throated sparrow.

PKA functions in metabolism and resistance to obesity: lessons from mouse and human studies.

Both direct and indirect evidence demonstrate a central role for the cAMP-dependent protein kinase (PKA) signaling pathway in the regulation of energy balance and metabolism across multiple systems. However, the ubiquitous pattern of PKA expression across cell types poses a challenge in pinpointing its tissue-specific regulatory functions and further characterizing its many downstream effects in certain organs or cells. Mouse models of PKA deficiency and over-expression and studies in living cells have helped clarify PKA function in adipose tissue (AT), liver, adrenal, pancreas, and specific brain nuclei, as they pertain to energy balance and metabolic dysregulation. Limited studies in humans suggest differential regulation of PKA in AT of obese compared to lean individuals and an overall dysregulation of PKA signaling in obesity. Despite its complexity, under normal physiologic conditions, the PKA system is tightly regulated by changes in cAMP concentrations upstream via adenylate cyclase and downstream by phosphodiesterase-mediated cAMP degradation to AMP and by changes in PKA holoenzyme stability. Adjustments in the PKA system appear to be important to the development and maintenance of the obese state and its associated metabolic perturbations. In this review we discuss the important role of PKA in obesity and its involvement in resistance to obesity, through studies in humans and in mouse models, with a focus on the regulation of PKA in energy expenditure, intake behavior, and lipid and glucose metabolism.

Three-dimensional morphometric analysis reveals time-dependent structural changes in microglia and astrocytes in the central amygdala and hypothalamic paraventricular nucleus of heart failure rats

BackgroundCardiovascular diseases, including heart failure, are the most common cause of death globally. Recent studies support a high degree of comorbidity between heart failure and cognitive and mood disorders resulting in memory loss, depression, and anxiety. While neuroinflammation in the hypothalamic paraventricular nucleus contributes to autonomic and cardiovascular dysregulation in heart failure, mechanisms underlying cognitive and mood disorders in this disease remain elusive. The goal of this study was to quantitatively assess markers of neuroinflammation (glial morphology, cytokines, and A1 astrocyte markers) in the central amygdala, a critical forebrain region involved in emotion and cognition, and to determine its time course and correlation to disease severity during the progression of heart failure.MethodsWe developed and implemented a comprehensive microglial/astrocyte profiler for precise three-dimensional morphometric analysis of individual microglia and astrocytes in specific brain nuclei at different time points during the progression of heart failure. To this end, we used a well-established ischemic heart failure rat model. Morphometric studies were complemented with quantification of various pro-inflammatory cytokines and A1/A2 astrocyte markers via qPCR.ResultsWe report structural remodeling of central amygdala microglia and astrocytes during heart failure that affected cell volume, surface area, filament length, and glial branches, resulting overall in somatic swelling and deramification, indicative of a change in glial state. These changes occurred in a time-dependent manner, correlated with the severity of heart failure, and were delayed compared to changes in the hypothalamic paraventricular nucleus. Morphometric changes correlated with elevated mRNA levels of pro-inflammatory cytokines and markers of reactive A1-type astrocytes in the paraventricular nucleus and central amygdala during heart failure.ConclusionWe provide evidence that in addition to the previously described hypothalamic neuroinflammation implicated in sympathohumoral activation during heart failure, microglia, and astrocytes within the central amygdala also undergo structural remodeling indicative of glial shifts towards pro-inflammatory phenotypes. Thus, our studies suggest that neuroinflammation in the amygdala stands as a novel pathophysiological mechanism and potential therapeutic target that could be associated with emotional and cognitive deficits commonly observed at later stages during the course of heart failure.

Neuronal plasticity in the forebrain of the male red-sided garter snake: Effect of season, low temperature dormancy, and hormonal status on dendritic spine density

Numerous studies have reported seasonal variations in regional morphology in the brains of seasonally breeding vertebrates. These alterations of neuronal morphology and dendritic spine density appear to be an active process within specific brain nuclei that regulate seasonal behaviors. In many cases, this neural plasticity has been found to be in response to changes in circulating sex steroid hormone levels and occur within pathways essential for the control of reproductive behaviors. Male red-sided garter snakes (Thamnophis sirtalis parietalis) (RSGS) exhibit a dissociated reproductive pattern where mating is initiated at a time when the gonads and steroidogenesis are inactive. And, although circulating levels of sex steroid hormones are elevated at the initiation of courtship and mating, the only known cue found to initiate courtship behavior and mating, is an extended period of low temperature dormancy (LTD) followed by exposure to warm temperatures. This study was designed to examine the role of seasons, sex steroid hormones, and LTD on neuronal and dendritic spine density within the anterior hypothalamus-preoptic area (AHPOA), a region shown to be critical for the regulation of reproductive behaviors. In the male RSGS, the density of dendritic spines on neurons in the AHPOA was significantly greater in spring, actively courting animals, than summer or fall, non-courting animals. Animals maintained under conditions of LTD exhibited significantly increasing spine density as time maintained in LTD increased. Animals receiving either testosterone or estradiol had a significantly greater density of dendritic spines than control animals. This study offers evidence suggesting that the “set up” of the pathways controlling courtship behavior and mating in the male RSGS, is not due solely to an extended period of LTD, but that an extended period of LTD in conjunction with circulating sex steroid hormones are critical for the initiation of reproductive behavior.

Clinical characteristics and treatment options of hearing impairment caused by hyperbilirubinemia

SummaryNeonatal hyperbilirubinemia is the most common clinical symptom in neonates. When the concentration of free bilirubin in blood is too high, it crosses through the blood-brain barrier and selectively deposits in specific brain nuclei to cause neurotoxicity and bilirubin neurological dysfunction. The auditory nervous system is highly sensitive to bilirubin. Therefore, auditory neuropathy is the most important or even the only clinical symptom of bilirubin neurological dysfunction. Chronic bilirubin encephalopathy can be classified to three types as mild, moderate and severe，according to the audiological manifestations and other neurological sequelae. Early recognition and intervention of bilirubin-induced hearing impairment is of great significance to improve the speech recognition rate of the referred children. This article reviews the most important studies about the clinical characteristics, pathogenesis and treatment of bilirubin-induced hearing impairment.

Neuronal Activity in the Hibernating Brain.

Hibernation is a natural phenomenon in many species which helps them to survive under extreme ambient conditions, such as cold temperatures and reduced availability of food in the winter months. It is characterized by a dramatic and regulated drop of body temperature, which in some cases can be near 0°C. Additionally, neural control of hibernation is maintained over all phases of a hibernation bout, including entrance into, during and arousal from torpor, despite a marked decrease in overall neural activity in torpor. In the present review, we provide an overview on what we know about neuronal activity in the hibernating brain focusing on cold-induced adaptations. We discuss pioneer and more recent in vitro and in vivo electrophysiological data and molecular analyses of activity markers which strikingly contributed to our understanding of the brain’s sensitivity to dramatic changes in temperature across the hibernation cycle. Neuronal activity is markedly reduced with decreasing body temperature, and many neurons may fire infrequently in torpor at low brain temperatures. Still, there is convincing evidence that specific regions maintain their ability to generate action potentials in deep torpor, at least in response to adequate stimuli. Those regions include the peripheral system and primary central regions. However, further experiments on neuronal activity are needed to more precisely determine temperature effects on neuronal activity in specific cell types and specific brain nuclei.

MRI-guided robotic arm drives optogenetic fMRI with concurrent Ca2+ recording

Optical fiber-mediated optogenetic activation and neuronal Ca2+ recording in combination with fMRI provide a multi-modal fMRI platform. Here, we developed an MRI-guided robotic arm (MgRA) as a flexible positioning system with high precision to real-time assist optical fiber brain intervention for multi-modal animal fMRI. Besides the ex vivo precision evaluation, we present the highly reliable brain activity patterns in the projected basal forebrain regions upon MgRA-driven optogenetic stimulation in the lateral hypothalamus. Also, we show the step-wise optical fiber targeting thalamic nuclei and map the region-specific functional connectivity with whole-brain fMRI accompanied by simultaneous calcium recordings to specify its circuit-specificity. The MgRA also guides the real-time microinjection to specific deep brain nuclei, which is demonstrated by an Mn-enhanced MRI method. The MgRA represents a clear advantage over the standard stereotaxic-based fiber implantation and opens a broad avenue to investigate the circuit-specific functional brain mapping with the multi-modal fMRI platform.

The Catalytic Subunit β of PKA Affects Energy Balance and Catecholaminergic Activity.

The protein kinase A (PKA) signaling system mediates the effects of numerous hormones, neurotransmitters, and other molecules to regulate metabolism, cardiac function, and more. PKA defects may lead to diverse phenotypes that largely depend on the unique expression profile of the affected subunit. Deletion of the Prkarcb gene, which codes for PKA catalytic subunit β (Cβ), protects against diet-induced obesity (DIO), yet the mechanism for this phenotype remains unclear. We hypothesized that metabolic rate would be increased in Cβ knockout (KO) mice, which could explain DIO resistance. Male, but not female, CβKO mice had increased energy expenditure, and female but not male CβKO mice had increased subcutaneous temperature and increased locomotor activity compared with wild-type (WT) littermates. Urinary norepinephrine (NE) and normetanephrine were elevated in female CβKO mice. CβKO mice had increased heart rate (HR); blocking central NE release normalized HR to that of untreated WT mice. Basal and stimulated PKA enzymatic activities were unchanged in adipose tissue and heart and varied in different brain regions, suggesting that Prkacb deletion may mediate signaling changes in specific brain nuclei and may be less important in the peripheral regulation of PKA expression and activity. This is a demonstration of a distinct effect of the PKA Cβ catalytic subunit on catecholamines and sympathetic nerve signaling. The data provide an unexpected explanation for the metabolic phenotype of CβKO mice. Finally, the sexual dimorphism is consistent with mouse models of other PKA subunits and adds to the importance of these findings regarding the PKA system in human metabolism.

Effects of vitamin D3 supplementation on cognition and blood lipids: a 12-month randomised, double-blind, placebo-controlled trial

Alzheimer’s disease (AD) is the leading cause of dementia and loss of autonomy and independency in the elderly.1 Currently, no effective pharmacological interventions change the onset or progression of AD.2...

Tinnitus and temporary hearing loss result in differential noise-induced spatial reorganization of brain activity.

Loud noise frequently results in hyperacusis or hearing loss (i.e., increased or decreased sensitivity to sound). These conditions are often accompanied by tinnitus (ringing in the ears) and changes in spontaneous neuronal activity (SNA). The ability to differentiate the contributions of hyperacusis and hearing loss to neural correlates of tinnitus has yet to be achieved. Towards this purpose, we used a combination of behavior, electrophysiology, and imaging tools to investigate two models of noise-induced tinnitus (either with temporary hearing loss or with permanent hearing loss). Manganese (Mn2+) uptake was used as a measure of calcium channel function and as an index of SNA. Manganese uptake was examined in vivo with manganese-enhanced magnetic resonance imaging (MEMRI) in key auditory brain regions implicated in tinnitus. Following acoustic trauma, MEMRI, the SNA index, showed evidence of spatially dependent rearrangement of Mn2+ uptake within specific brain nuclei (i.e., reorganization). Reorganization of Mn2+ uptake in the superior olivary complex and cochlear nucleus was dependent upon tinnitus status. However, reorganization of Mn2+ uptake in the inferior colliculuswas dependent upon hearing sensitivity. Furthermore, following permanent hearing loss, reduced Mn2+ uptake was observed. Overall, by combining testing for hearing sensitivity, tinnitus, and SNA, our data move forward the possibility of discriminating the contributions of hyperacusis and hearing loss to tinnitus.

Comparison of subthalamic nucleus planning coordinates in 1Tesla and 3Tesla MRI for deep brain stimulation targeting

Deep brain stimulation (DBS) involves placing electrodes within specific deep brain nuclei. For movement disorders the most common indications are tremors, Parkinsons disease and dystonias. Surgeons mostly employ MR imaging for preoperative target selection. MR field geometrical distortion may contribute to target-selection error in the MR scan which can contribute to error in electrode placement. In this paper we compared the STN target planning coordinates in six parkinsonian DBS patients. Each patient underwent target planning in 1T and 3T MRI. We statistically compared and analysed the target-, and the fiducial coordinates in two different magnetic fileds. The target coordinates showed no significant differences (Mann-Whitney test, p > 0.05), however we found significant difference in fiducial coordinates (p < 0.01), in 3T MRI it was more pronounced (mean ± SD: 0.8 ± 0.3 mm) comparing to 1T (mean ± SD: 0.4 ± 0.2 mm). Preliminary results showed no significant differences in planning of target coordinates comparing 1T to 3T magnetic fields.