Brain Circuitry Research Articles

Prenatal nicotine exposure during pregnancy results in adverse neurodevelopmental alterations and neurobehavioral deficits.

Maternal tobacco use and nicotine exposure during pregnancy have been associated with adverse birth outcomes in infants and can lead to preventable pregnancy complications. Exposure to nicotine and other compounds in tobacco and electronic cigarettes (e-cigarettes) has been shown to increases the risk of miscarriage, prematurity, stillbirth, low birth weight, perinatal morbidity, and sudden infant death syndrome (SIDS). Additionally, recent data provided by clinical and pre-clinical research demonstrates that nicotine exposure during pregnancy may heighten the risk for adverse neurodevelopmental disorders such as Attention-Deficit Hyperactivity (ADHD), anxiety, and depression along with altering the infants underlying brain circuitry, response to neurotransmitters, and brain volume. In the United States, one in 14 women (7.2%) reported to have smoked cigarettes during their pregnancy with the global prevalence of smoking during pregnancy estimated to be 1.7%. Approximately 1.1% of women in the United States also reported to have used e-cigarettes during the last 3months of pregnancy. Due to the large percentage of women utilizing nicotine products during pregnancy in the United States and globally, this review seeks to centralize pre-clinical and clinical studies focused on the neurobehavioral and neurodevelopmental complications associated with prenatal nicotine exposure (PNE) such as alterations to the hypothalamic-pituitary-adrenal (HPA) axis and brain regions such as the prefrontal cortex (PFC), ventral tegmental area (VTA), nucleus accumbens (NA), hippocampus, and caudate as well as changes to nAChR and cholinergic receptor signaling, long-term drug seeking behavior following PNE, and other related developmental disorders. Current literature analyzing the association between PNE and the risk for offspring developing schizophrenia, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety, and obesity will also be discussed.

A mosaic adeno-associated virus vector as a versatile tool that exhibits high levels of transgene expression and neuron specificity in primate brain

Recent emphasis has been placed on gene transduction mediated through recombinant adeno-associated virus (AAV) vector to manipulate activity of neurons and their circuitry in the primate brain. In the present study, we created a novel vector of which capsid was composed of capsid proteins derived from both of the AAV serotypes 1 and 2 (AAV1 and AAV2). Following the injection into the frontal cortex of macaque monkeys, this mosaic vector, termed AAV2.1 vector, was found to exhibit the excellence in transgene expression (for AAV1 vector) and neuron specificity (for AAV2 vector) simultaneously. To explore its applicability to chemogenetic manipulation and in vivo calcium imaging, the AAV2.1 vector expressing excitatory DREADDs or GCaMP was injected into the striatum or the visual cortex of macaque monkeys, respectively. Our results have defined that such vectors secure intense and stable expression of the target proteins and yield conspicuous modulation and imaging of neuronal activity.

Pain control due to botulinum toxin therapy in cervical dystonia relates to the sensorimotor integration process

Background: Botulinum toxin (BoNT) injections have been found to improve pain symptoms of isolated cervical dystonia (CD). In addition to muscle relaxation at the peripheral level, few studies suggest that BoNT has effects on the central brain circuitries. The effects of BoNT on central circuitries that may be pain-related have not been examined. We probed these central effects with transcranial magnetic stimulation (TMS) techniques in a CD cohort presenting with significant pain.Methods: TMS-based measures of sensorimotor integration that are mediated through central processes, such as the short and long latency afferent inhibition (SAI and LAI) and measures for motor cortical excitability including short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were recorded. These measures were recorded at specific interstimulus intervals (ISI) using paired-pulse paradigms before and after the peak effects of BoNT injections. Normative TMS data from age-matched healthy controls were collected for comparisons. Clinical pain symptoms were recorded with Toronto Western spasmodic rating scale (TWSTRS)-pain and a visual analog scale (VAS).Results: Eleven CD subjects (mean age ±SD, 53.1 ± 6.3 years) and 10 age-matched healthy controls were enrolled. SAI was found to be increased in CD patients at baseline, however at the time of peak BoNT effects, it revealed a significant change with normalization to healthy control data (SAI ISI 20 ms, p = 0.001; SAI ISI 30 ms, p = 0.03). The change in SAI correlated with improvements in pain levels assessed with TWSTRS-pain and VAS and the total dose of BoNT injected (corrected for multiple correlations). LAI, SICI, and ICF measures were similar to the healthy controls and remained unchanged with BoNT therapy.Conclusion: Pain control in CD from BoNT therapy relates to modulation of sensorimotor integration at the cortical level.

Mapping Brain Structure Variability in Chronic Pain: The Role of Widespreadness and Pain Type and Its Mediating Relationship With Suicide Attempt

BackgroundChronic pain affects nearly 20% of the U.S. population. It is a leading cause of disability globally and is associated with a heightened risk for suicide. The role of the central nervous system in the perception and maintenance of chronic pain has recently been accepted, but specific brain circuitries involved have yet to be mapped across pain types in a large-scale study. MethodsWe used data from the UK Biobank (N = 21,968) to investigate brain structural alterations in individuals reporting chronic pain compared with pain-free control participants and their mediating effect on history of suicide attempt. ResultsChronic pain and, more notably, chronic multisite pain was associated with, on average, lower surface area throughout the cortex after adjusting for demographic, clinical, and neuropsychiatric confounds. Only participants with abdominal pain showed lower subcortical volumes, including the amygdala and brainstem, and lower cerebellum volumes. Participants with chronic headaches showed a widespread thicker cortex compared with control participants. Mediation analyses revealed that precuneus thickness mediated the relationship of chronic multisite pain and history of suicide attempt. Mediating effects were also identified specific to localized pain, with the strongest effect being amygdala volume in individuals with chronic abdominal pain. ConclusionsResults support a widespread effect of chronic pain on brain structure and distinct brain structures underlying chronic musculoskeletal pain, visceral pain, and headaches. Mediation effects of regions in the extended ventromedial prefrontal cortex subsystem suggest that exacerbated negative internal states, negative self-referencing, and impairments in future planning may underlie suicidal behaviors in individuals with chronic pain.

Along-Tract Statistical Mapping of Microstructural Abnormalities in Bipolar Disorder: A Pilot Study.

Investigating brain circuitry involved in bipolar disorder (BD) is key to discovering brain biomarkers for genetic and interventional studies of the disorder. Even so, prior research has not provided a fine-scale spatial mapping of brain microstructural differences in BD. In this pilot diffusion MRI dataset, we used BUndle ANalytics (BUAN)-a recently developed analytic approach for tractography-to extract, map, and visualize the profile of microstructural abnormalities on a 3D model of fiber tracts in people with BD (N=38) and healthy controls (N=49), and investigate along-tract white matter (WM) microstructural differences between these groups. Using the BUAN pipeline, BD was associated with lower mean fractional anisotropy (FA) in fronto-limbic and interhemispheric pathways and higher mean FA in posterior bundles relative to controls.Clinical Relevance- BUAN combines tractography and anatomical information to capture distinct along-tract effects on WM microstructure that may aid in classifying diseases based on anatomical differences.

Central sensitization in alcohol use disorder: correlates of pain, addiction and health-related quality of life

Background Central sensitization is an important mechanism underlying many chronic pain conditions. Chronic pain and alcohol use disorder (AUD) are highly comorbid. Despite great scientific interest in brain mechanisms linking chronic pain and AUD, progress has been impeded by difficulty assessing central sensitization in AUD. Objective The present study is the first to employ a validated surrogate measure to describe central sensitization in a clinical sample with AUD. Methods Participants with AUD (n = 99) were recruited from an academic addiction treatment center. A well-established surrogate measure of central sensitization, The American College of Rheumatology Fibromyalgia Survey Criteria (ACRFMS) was administered. Participants also responded to questions about quality of life (RAND-36), and AUD. Descriptive analyses and Spearman’s rho correlations were performed. Results Chronic pain and evidence of central sensitization were prevalent. Greater central sensitization was associated with worse health-related quality of life. Participants higher in central sensitization expressed greater endorsement of pain as a reason for AUD onset, maintenance, escalation, treatment delay, and relapse. Conclusion The present study bolsters prior assertions that AUD and chronic pain might compound one another via progressive sensitization of shared brain circuitry. These results may inform future mechanistic research and precision AUD treatment.

Dysthyroid Optic Neuropathy: Short- and Long-Term Effects on Brain Circuitry.

Dysthyroid Optic Neuropathy: Short- and Long-Term Effects on Brain Circuitry.

Functional Connectivity Between Auditory and Medial Temporal Lobe Networks in Antipsychotic-Naïve Patients With First-Episode Schizophrenia Predicts the Effects of Dopamine Antagonism on Auditory Verbal Hallucinations

BackgroundUnderstanding how antipsychotic medication ameliorates auditory verbal hallucinations (AVHs) through modulation of brain circuitry is pivotal for understanding the pathophysiology of psychosis and for predicting treatment response. MethodsThis case-control study included examinations at baseline and at follow-up after 6 weeks. Initially, antipsychotic-naïve patients with first-episode schizophrenia who were experiencing AVHs were recruited together with healthy control participants. Antipsychotic treatment with the relatively selective D2 receptor antagonist amisulpride was administered as monotherapy. Functional connectivity measured by resting-state functional magnetic resonance imaging between networks of interest was used to study the effects of D2 blockade on brain circuitry and predict clinical treatment response. Hallucinations were rated with the Positive and Negative Syndrome Scale. ResultsThirty-two patients experiencing AVHs and 34 healthy control participants were scanned at baseline. Twenty-two patients and 34 healthy control participants were rescanned at follow-up. Connectivity between the auditory network and the medial temporal lobe network was increased in patients at baseline (p = .002) and normalized within 6 weeks of D2 blockade (p = .018). At baseline, the connectivity between these networks was positively correlated with ratings of hallucinations (t = 2.67, p = .013). Moreover, baseline connectivity between the auditory network and the medial temporal lobe network predicted reduction in hallucinations (t = 2.34, p = .032). ConclusionsFunctional connectivity between the auditory network and the medial temporal lobe predicted response to initial antipsychotic treatment. These findings demonstrate that connectivity between networks involved in auditory processing, internal monitoring, and memory is associated with the clinical effect of dopamine antagonism.

Lipid peroxidation and neuroinflammation: A possible link between maternal fructose intake and delay of acquisition of neonatal reflexes in Wistar female rats.

Fructose is a common sweetener found in the daily diet supplemented to many processed and ultra-processed foods and beverages. Consumption of fructose-sweetened beverages has drastically increased in the last decades and is widely associated with metabolic disease, systemic pro-inflammatory status, and adverse transgenerational effects. To date, the impact of maternal fructose intake in brain function of the offspring is less explored. Therefore, the aim of this study was first, to investigate adverse effects in developmental milestones of the progeny of mothers with metabolic syndrome (MetS), induced by ad libitum consumption of a 20% fructose solution, and second to identify possible molecular changes in the nervous system of the newborns associated with maternal fructose intake. Wistar rats were randomly separated into two groups with access to water or fructose (20% w/v in water) for 10 weeks. After MetS was confirmed, dams were mated with control males and continued drinking water or fructose solution during gestation. At postnatal day (PN) 1, a subgroup of offspring of each sex was sacrificed and brains were dissected for oxidative stress and inflammatory status analysis. Changes in the developmental milestones due to maternal fructose consumption were studied (PN3-PN21) in another subgroup of offspring. Sexually dimorphic effects were found on the progeny's acquisition of neurodevelopmental milestones, in brain lipid peroxidation, neuroinflammation, and antioxidative defensive response. Our results suggest that dams' MetS, induced by fructose intake, disrupts brain redox homeostasis in female offspring and affects sensorimotor brain circuitry which may have a translational value for studying neurodevelopmental diseases.

The inevitability of visual interruption.

For successful adaptive behavior, exogenous environmental events must be sensed and reacted to as efficiently as possible. In the lab, the mechanisms underlying such efficiency are often studied with eye movements. Using controlled trials, careful measures of eye movement reaction times, directions, and kinematics suggest a form of "exogenous" oculomotor capture by external events. However, even in controlled trials, exogenous onsets necessarily come asynchronously to internal brain state. We argue that variability in the effectiveness of "exogenous" capture is inevitable. We review an extensive set of evidence demonstrating that before orienting must come interruption, a process that partially explains such variability. More importantly, we present a novel neural mechanistic account of interruption, leveraging the presence of early sensory processing capabilities in the very final stages of oculomotor control brain circuitry.

A new idea to study the target of scalp acupuncture stimulation

Scalp acupuncture, an important modern acupuncture branch that combines acupuncture stimulation and neuroscience, is gaining popularity in the clinic. It is believed that scalp acupuncture can modulate the function of certain brain areas through stimulation of specific scalp areas corresponding to the related cortical areas, thereby providing therapeutic benefits for a wide scope of diseases. In recent decades, there has been remarkable progress in our understanding of the brain circuitry of many brain-related disorders through cutting-edge brain imaging techniques. Unfortunately, these findings have not been incorporated into scalp acupuncture protocols. Thus, identifying surface cortical regions associated with these disorders would expand stimulation target selections of scalp acupuncture. In this manuscript, we aim to 1) propose the idea and methods to incorporate neuroimaging findings and scalp acupuncture; and 2) introduce scalp acupuncture stimulation targets for some psychological and neurological disorders based on recent brain imaging findings. We hope this manuscript can inspire innovation on this topic to help further develop scalp acupuncture.

A 16-channel loop array for in vivo macaque whole-brain imaging at 7 T

Combining multimodal approaches with functional magnetic resonance imaging (fMRI) has catapulted the research on brain circuitries of non-human primates (NHPs) into a new era. However, many studies are constrained by a lack of appropriate RF coils. In this study, a single loop transmit and 16-channel receive array coil was constructed for brain imaging of macaques at 7 Tesla (7 T). The 16 receive channels were mounted on a 3D-printed helmet-shaped form closely fitting the macaque head, with fourteen openings arranged for multimodal devices around the cortical regions. Coil performance was evaluated by quantifying and comparing signal-to-noise ratio (SNR) maps, noise correlations, g-factor maps and flip-angle maps with a 28-channel commercial knee coil. The in vivo results suggested that the macaque coil has higher SNR in cortical regions and better acceleration ability in parallel imaging, which may benefit revealing mesoscale organizations in the brain.

Gastric vagal afferent signaling to the basolateral amygdala mediates anxiety-like behaviors in experimental colitis mice.

Inflammatory bowel disease (IBD) is a relapsing-remitting disorder characterized by chronic inflammation of the gastrointestinal (GI) tract. Anxiety symptoms are commonly observed in patients with IBD, but the mechanistic link between IBD and anxiety remains elusive. Here, we sought to characterize gut-to-brain signaling and brain circuitry responsible for the pathological expression of anxiety-like behaviors in male dextran sulfate sodium-induced (DSS-induced) experimental colitis mice. We found that DSS-treated mice displayed increased anxiety-like behaviors, which were prevented by bilateral GI vagal afferent ablation. The locus coeruleus (LC) is a relay center connecting the nucleus tractus solitarius to the basolateral amygdala (BLA) in controlling anxiety-like behaviors. Chemogenetic silencing of noradrenergic LC projections to the BLA reduced anxiety-like behaviors in DSS-treated mice. This work expands our understanding of the neural mechanisms by which IBD leads to comorbid anxiety and emphasizes a critical role of gastric vagal afferent signaling in gut-to-brain regulation of emotional states.

Chronic infection by atypical Toxoplasma gondii strain induces disturbance in microglia population and altered behaviour in mice

Toxoplasma gondii chronic infection is characterized by the establishment of tissue cysts in the brain and increased levels of IFN-γ, which can lead to brain circuitry interference and consequently abnormal behaviour in mice. In this sense, the study presented here sought to investigate the impact of chronic infection by two T. gondii strains in the brain of infection-resistant mice, as a model for studying the involvement of chronic neuroinflammation with the development of behavioural alterations. For that, male BALB/c mice were divided into three groups: non-infected (Ni), infected with T. gondii ME49 clonal strain (ME49), and infected with TgCkBrRN2 atypical strain (CK2). Mice were monitored for 60 days to establish the chronic infection and then submitted to behavioural assessment. The enzyme-linked immunosorbent assay was used for measurement of specific IgG in the blood and levels of inflammatory cytokines and neurotrophic factors in the brain, and the cell's immunophenotype was determined by multiparametric flow cytometry. Mice infected with ME49 clonal strain displayed hyperlocomotor activity and memory deficit, although no signs of depressive- and/or anxiety-like behaviour were detected; on the other hand, chronic infection with CK2 atypical strain induced anxiety- and depressive-like behaviour. During chronic infection by CK2 atypical strain, mice displayed a higher number of T. gondii brain tissue cysts and inflammatory infiltrate, composed mainly of CD3+ T lymphocytes and Ly6Chi inflammatory monocytes, compared to mice infected with the ME49 clonal strain. Infected mice presented a marked decrease of microglia population compared to non-infected group. Chronic infection with CK2 strain produced elevated levels of IFN-γ and TNF-ɑ in the brain, decreased NGF levels in the prefrontal cortex and striatum, and altered levels of fractalkine (CX3CL1) in the prefrontal cortex and hippocampus. The persistent inflammation and the disturbance in the cerebral homeostasis may contribute to altered behaviour in mice, as the levels of IFN-γ were shown to be correlated with the behavioural parameters assessed here. Considering the high incidence and life-long persistence of T. gondii infection, this approach can be considered a suitable model for studying the impact of chronic infections in the brain and how it impacts in behavioural responses.

Determination of steady-state transcriptome modifications associated with repeated homotypic stress in the rat rostral posterior hypothalamic region.

Chronic stress is epidemiologically correlated with physical and psychiatric disorders. Whereas many animal models of chronic stress induce symptoms of psychopathology, repeated homotypic stressors to moderate intensity stimuli typically reduce stress-related responses with fewer, if any, pathological symptoms. Recent results indicate that the rostral posterior hypothalamic (rPH) region is a significant component of the brain circuitry underlying response reductions (habituation) associated with repeated homotypic stress. To test whether posterior hypothalamic transcriptional regulation associates with the neuroendocrine modifications induced by repeated homotypic stress, RNA-seq was performed in the rPH dissected from adult male rats that experienced either no stress, 1, 3, or 7 stressful loud noise exposures. Plasma samples displayed reliable increases of corticosterone in all stressed groups, with the smallest increase in the group exposed to 7 loud noises, indicating significant habituation compared to the other stressed groups. While few or no differentially expressed genes were detected 24-h after one or three loud noise exposures, relatively large numbers of transcripts were differentially expressed between the group exposed to 7 loud noises when compared to the control or 3-stress groups, respectively, which correlated with the corticosterone response habituation observed. Gene ontology analyses indicated multiple significant functional terms related to neuron differentiation, neural membrane potential, pre- and post-synaptic elements, chemical synaptic transmission, vesicles, axon guidance and projection, glutamatergic and GABAergic neurotransmission. Some of the differentially expressed genes (Myt1l, Zmat4, Dlx6, Csrnp3) encode transcription factors that were independently predicted by transcription factor enrichment analysis to target other differentially regulated genes in this study. A similar experiment employing in situ hybridization histochemical analysis in additional animals validated the direction of change of the 5 transcripts investigated (Camk4, Gabrb2, Gad1, Grin2a and Slc32a) with a high level of temporal and regional specificity for the rPH. In aggregate, the results suggest that distinct patterns of gene regulation are obtained in response to a repeated homotypic stress regimen; they also point to a significant reorganization of the rPH region that may critically contribute to the phenotypic modifications associated with repeated homotypic stress habituation.

Extension of mRNA poly(A) tails and 3'UTRs during neuronal differentiation exhibits variable association with post-transcriptional dynamics.

Differentiation of neural progenitor cells into mature neuronal phenotypes relies on extensive temporospatial coordination of mRNA expression to support the development of functional brain circuitry. Cleavage and polyadenylation of mRNA has tremendous regulatory capacity through the alteration of mRNA stability and modulation of microRNA (miRNA) function, however the extent of utilization in neuronal development is currently unclear. Here, we employed poly(A) tail sequencing, mRNA sequencing, ribosome profiling and small RNA sequencing to explore the functional relationship between mRNA abundance, translation, poly(A) tail length, alternative polyadenylation (APA) and miRNA expression in an in vitro model of neuronal differentiation. Differential analysis revealed a strong bias towards poly(A) tail and 3'UTR lengthening during differentiation, both of which were positively correlated with changes in mRNA abundance, but not translation. Globally, changes in miRNA expression were predominantly associated with mRNA abundance and translation, however several miRNA-mRNA pairings with potential to regulate poly(A) tail length were identified. Furthermore, 3'UTR lengthening was observed to significantly increase the inclusion of non-conserved miRNA binding sites, potentially enhancing the regulatory capacity of these molecules in mature neuronal cells. Together, our findings suggest poly(A) tail length and APA function as part of a rich post-transcriptional regulatory matrix during neuronal differentiation.

Emerging Penetrating Neural Electrodes: In Pursuit of Large Scale and Longevity.

Penetrating neural electrodes provide a powerful approach to decipher brain circuitry by allowing for time-resolved electrical detections of individual action potentials. This unique capability has contributed tremendously to basic and translational neuroscience, enabling both fundamental understandings of brain functions and applications of human prosthetic devices that restore crucial sensations and movements. However, conventional approaches are limited by the scarce number of available sensing channels and compromised efficacy over long-term implantations. Recording longevity and scalability have become the most sought-after improvements in emerging technologies. In this review, we discuss the technological advances in the past 5-10 years that have enabled larger-scale, more detailed, and longer-lasting recordings of neural circuits at work than ever before. We present snapshots of the latest advances in penetration electrode technology, showcase their applications in animal models and humans, and outline the underlying design principles and considerations to fuel future technological development.

Brain Circuitry of Consciousness: A Review of Current Models and a Novel Synergistic Model With Clinical Application.

How consciousness arises in the brain has important implications for clinical decision-making. We summarize recent findings in consciousness studies to provide a toolkit for clinicians to assess deficits in consciousness and predict outcomes after brain injury. Commonly encountered disorders of consciousness are highlighted, followed by the clinical scales currently used to diagnose them. We review recent evidence describing the roles of the thalamocortical system and brainstem arousal nuclei in supporting awareness and arousal and discuss the utility of various neuroimaging studies in evaluating disorders of consciousness. We explore recent theoretical progress in mechanistic models of consciousness, focusing on 2 major models, the global neuronal workspace and integrated information theory, and review areas of controversy. Finally, we consider the potential implications of recent research for the day-to-day decision-making of clinical neurosurgeons and propose a simple "three-strikes" model to infer the integrity of the thalamocortical system, which can guide prognosticating return to consciousness.

Correlation of mutated gene and signalling pathways in ASD.

Autism is a complicated spectrum of neurodevelopmental illnesses characterized by repetitive and constrained behaviors and interests, as well as social interaction and communication difficulties that are first shown in infancy. More than 18 million Indians, according to the National Health Portal of India, and 1 in 160 children worldwide, according to the WHO, are diagnosed with autism spectrum disorders. This review aims to discuss the complex genetic architecture that underlies autism and summarizes the role of proteins likely to play in the development of autism. We also consider how genetic mutations can affect convergent signaling pathways and hinder the development of brain circuitry and the role of cognition development and theory of mind with Cognition-behavior therapy benefits in autism.

Natural killer cells and innate lymphoid cells 1 tune anxiety-like behavior and memory in mice via interferon-γ and acetylcholine

The mechanisms of communication between the brain and the immune cells are still largely unclear. Here, we characterize the populations of resident natural killer (NK) cells and innate lymphoid cells (ILC) 1 in the meningeal dura layer of adult mice. We describe that ILC1/NK cell-derived interferon-γ and acetylcholine can contribute to the modulation of brain homeostatic functions, shaping synaptic neuronal transmission and neurotransmitter levels with effects on mice behavior. In detail, the interferon-γ plays a role in the formation of non-spatial memory, tuning the frequency of GABAergic neurotransmission on cortical pyramidal neurons, while the acetylcholine is a mediator involved in the modulation of brain circuitries that regulate anxiety-like behavior. These findings disclose mechanisms of immune-to-brain communication that modulate brain functions under physiological conditions.