Intrinsic Neuronal Activity Research Articles

Astrocytic Ca2+ Signaling in Epilepsy.

Epilepsy is one of the most common neurological disorders – estimated to affect at least 65 million worldwide. Most of the epilepsy research has so far focused on how to dampen neuronal discharges and to explain how changes in intrinsic neuronal activity or network function cause seizures. As a result, pharmacological therapy has largely been limited to symptomatic treatment targeted at neurons. Given the expanding spectrum of functions ascribed to the non-neuronal constituents of the brain, in both physiological brain function and in brain disorders, it is natural to closely consider the roles of astrocytes in epilepsy. It is now widely accepted that astrocytes are key controllers of the composition of the extracellular fluids, and may directly interact with neurons by releasing gliotransmitters. A central tenet is that astrocytic intracellular Ca2+ signals promote release of such signaling substances, either through synaptic or non-synaptic mechanisms. Accruing evidence suggests that astrocytic Ca2+ signals play important roles in both seizures and epilepsy, and this review aims to highlight the current knowledge of the roles of this central astrocytic signaling mechanism in ictogenesis and epileptogenesis.

ATR regulates neuronal activity by modulating presynaptic firing

Ataxia Telangiectasia and Rad3-related (ATR) protein, as a key DNA damage response (DDR) regulator, plays an essential function in response to replication stress and controls cell viability. Hypomorphic mutations of ATR cause the human ATR-Seckel syndrome, characterized by microcephaly and intellectual disability, which however suggests a yet unknown role for ATR in non-dividing cells. Here we show that ATR deletion in postmitotic neurons does not compromise brain development and formation; rather it enhances intrinsic neuronal activity resulting in aberrant firing and an increased epileptiform activity, which increases the susceptibility of ataxia and epilepsy in mice. ATR deleted neurons exhibit hyper-excitability, associated with changes in action potential conformation and presynaptic vesicle accumulation, independent of DDR signaling. Mechanistically, ATR interacts with synaptotagmin 2 (SYT2) and, without ATR, SYT2 is highly upregulated and aberrantly translocated to excitatory neurons in the hippocampus, thereby conferring a hyper-excitability. This study identifies a physiological function of ATR, beyond its DDR role, in regulating neuronal activity.

Mechanisms of the Effects of Parental Emotional Warmth on Extraversion in Children and Adolescents

The purpose of this study is to probe into the influence mechanism of parental emotional warmth (PEW) on extraversion for children and adolescents, as well as the moderating and mediating role of brain functional activity. Thirty-two children and adolescents underwent functional magnetic resonance imaging (fMRI) scans and completed Egna Minnen av Barndoms Uppfostran (EMBU) and Eysenck Personality Questionnaire (EPQ). Small-worldness (SW) of brain networks, fractional amplitude of low-frequency fluctuations (fALFF), and region-of-interest to region-of-interest (ROI–ROI) functional connectivity were calculated to study intrinsic neuronal activity. We found that PEW had a positive direct effect on extraversion, and all participants in the current study showed an efficient small-world structure. The positive association between PEW and extraversion was mediated by SW. Furthermore, the fALFF and extraversion were significantly and negatively correlated in the right precuneus and dorsolateral superior frontal gyrus. The mediating effect of SW was moderated by the functional connectivity between the right precuneus and the right dorsolateral superior frontal gyrus. The indirect effect was significant with lower level of the functional connectivity between the right precuneus and the right dorsolateral superior frontal gyrus. These findings indicate that SW of brain networks may be a key factor that accounts for the positive association between PEW and extraversion in children and adolescents and the level of the functional connectivity between the right precuneus and the right dorsolateral superior frontal gyrus could moderate the relationship.

Intrinsic Neuronal Activity during Migration Controls the Recruitment of Specific Interneuron Subtypes in the Postnatal Mouse Olfactory Bulb.

Neuronal activity has been identified as a key regulator of neuronal network development, but the impact of activity on migration and terminal positioning of interneuron subtypes is poorly understood. The absence of early subpopulation markers and the presence of intermingled migratory and postmigratory neurons make the developing cerebral cortex a difficult model to answer these questions. Postnatal neurogenesis in the subventricular zone (SVZ) offers a more accessible and compartmentalized model. Neural stem cells regionalized along the border of the lateral ventricle produce two main subtypes of neural progenitors, granule cells and periglomerular neurons that migrate tangentially in the rostral migratory stream (RMS) before migrating radially in the olfactory bulb (OB) layers. Here, we used targeted postnatal electroporation to compare the migration of these two populations in male and female mice. We do not observe any obvious differences regarding the mode of tangential or radial migration between these two subtypes. However, we find a striking increase of intrinsic calcium activity in granule cell precursors (GC-Ps) when they switch from tangential to radial migration. By decreasing neuronal excitability in GC-Ps, we find that neuronal activity has little effect on migration but is required for normal positioning and survival of GC-Ps in the OB layers. Strikingly, decreasing activity of periglomerular neuron precursors (PGN-Ps) did not impact their positioning or survival. Altogether these findings suggest that neuronal excitability plays a subtype specific role during the late stage of migration of postnatally born OB interneurons.SIGNIFICANCE STATEMENT While neuronal activity is a critical factor regulating different aspects of neurogenesis, it has been challenging to study its role during the migration of different neuronal subpopulations. Here, we use postnatal targeted electroporation to label and manipulate the two main olfactory bulb (OB) interneuron subpopulations during their migration: granule cell and periglomerular neuron precursors (PGN-Ps). We find a very striking increase of calcium activity only in granule cell precursors (GC-Ps) when they switch from tangential to radial migration. Interestingly, blocking activity in GC-Ps affected mainly their positioning and survival while PGN-Ps were not affected. These results suggest that neuronal activity is required specifically for the recruitment of GC-Ps in the OB layers.

Intrinsic brain abnormalities of irritable bowel syndrome with diarrhea: a preliminary resting-state functional magnetic resonance imaging study

BackgroundThe aim of the present study was to explore the brain active characteristics of patients with irritable bowel syndrome with diarrhea (IBS-D) using resting-state functional magnetic resonance imaging technology.MethodsThirteen IBS-D patients and fourteen healthy controls (HC) were enrolled. All subjects underwent head MRI examination during resting state. A voxel-based analysis of fractional amplitude of low frequency fluctuation (fALFF) maps between IBS-D and HC was performed using a two-sample t-test. The relationship between the fALFF values in abnormal brain regions and the scores of Symptom Severity Scale (IBS-SSS) were analyzed using Pearson correlation analysis.ResultsCompared with HC, IBS-D patients had lower fALFF values in the left medial superior frontal gyrus and higher fALFF values in the left hippocampus and right precuneus. There was a positive correlation between the duration scores of IBS-SSS and fALFF values in the right precuneus.ConclusionThe altered fALFF values in the medial superior frontal gyri, left hippocampus and right precuneus revealed changes of intrinsic neuronal activity, further revealing the abnormality of gut-brain axis of IBS-D.

Chronic Pharmacological Increase of Neuronal Activity Improves Sensory-Motor Dysfunction in Spinal Muscular Atrophy Mice.

Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our in vivo study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.

Effects of alfaxalone on cerebral blood flow and intrinsic neural activity of rhesus monkeys: A comparison study with ketamine

ObjectiveAlfaxalone has been used increasingly in biomedical research and veterinary medicine of large animals in recent years. However, its effects on the cerebral blood flow (CBF) physiology and intrinsic neuronal activity of anesthetized brains remain poorly understood. MethodsFour healthy adult rhesus monkeys were anesthetized initially with alfaxalone (0.125 mg/kg/min) or ketamine (1.6 mg/kg/min) for 50 min, then administrated with 0.8% isoflurane for 60 min. Heart rates, breathing beats, and blood pressures were continuously monitored. CBF data were collected using pseudo-continuous arterial spin-labeling (pCASL) MRI technique and rsfMRI data were collected using single-shot EPI sequence for each anesthetic. ResultsBoth the heart rates and mean arterial pressure (MAP) remained more stable during alfaxalone infusion than those during ketamine administration. Alfaxalone reduced CBF substantially compared to ketamine anesthesia (grey matter, 65 ± 22 vs. 179 ± 38 ml/100g/min, p<0.001; white matter, 14 ± 7 vs. 26 ± 6 ml/100g/min, p < 0.05); In addition, CBF increase was seen in all selected cortical and subcortical regions of alfaxalone-pretreated monkey brains during isoflurane exposure, very different from the findings in isoflurane-exposed monkeys pretreated with ketamine. Also, alfaxalone showed suppression effects on functional connectivity of the monkey brain similar to ketamine. ConclusionAlfaxalone showed strong suppression effects on CBF of the monkey brain.The residual effect of alfaxalone on CBF of isoflurane-exposed brains was evident and monotonous in all the examined brain regions when used as induction agent for inhalational anesthesia. In particular, alfaxalone showed similar suppression effect on intrinsic neuronal activity of the brain in comparison with ketamine. These findings suggest alfaxalone can be a good alternative to veterinary anesthesia in neuroimaging examination of large animal models. However, its effects on CBF and functional connectivity should be considered.

Intrinsic low-frequency oscillation changes in multiple-frequency bands in stable patients with chronic obstructive pulmonary disease

Abnormal local spontaneous brain activity during the resting state has been observed in chronic obstructive pulmonary disease (COPD). However, it is still largely unclear whether the abnormalities are related to specific frequency bands. Our purpose was to explore intrinsic neural activity changes in different frequency bands by using the amplitude of low-frequency fluctuation (ALFF) method in stable COPD patients. Nineteen stable COPD patients and twenty gender-, age- and education-matched normal controls (NCs) underwent functional magnetic resonance imaging scans, cognitive function tests and lung function tests. Two different frequency bands (slow-4: 0.027-0.073Hz; slow-5: 0.01-0.027Hz) were calculated and analyzed for frequency-dependent intrinsic neural activity by using the ALFF method. A two-way analysis of variance test was used to compare the main effects of the groups and the frequency bands in the ALFF method. Further post-hoc t-tests were used to compare the differences between COPD patients and NCs in terms of the different frequency bands. A Pearson's correlation analysis was performed to explore the relationship between the altered ALFF brain areas in the different frequency bands and the clinical evaluations in the COPD patients. There were main effects of the groups including significantly higher ALFF values in the right superior temporal gyrus (STG), the bilateral cerebellum posterior lobe (CPL), the right lingual gyrus (LG) and the right brainstem, and as well as significantly decreased ALFF values in the right inferior parietal lobule (IPL) and the angular. The main effect of frequency was demonstrated in the CPL, the STG, the prefrontal cortex and the middle cingulate gyrus. Furthermore, COPD patients exhibited more widespread alterations in intrinsic brain activity in the slow-5 band than in the slow-4 band. Moreover, the abnormal intrinsic brain activity in the slow-4 and slow-5 bands were associated with PaCO2 in COPD patients. These current results indicated that COPD patients showed abnormal intrinsic brain activity in two different frequency bands, and abnormal intrinsic neuronal activity in different brain regions could be better detected by slow-5 band. These observations may provide a neoteric view into understanding the local neural psychopathology in stable COPD patients.

Detection of functional networks within white matter using independent component analysis

Spontaneous fluctuations in MRI signals from gray matter (GM) in the brain are interpreted as originating from variations in neural activity, and their inter-regional correlations may be analyzed to reveal functional connectivity. However, most studies of intrinsic neuronal activity have ignored the spontaneous fluctuations that also arise in white matter (WM). In this work, we explore spontaneous fluctuations in resting state MRI signals in WM based on spatial independent component analyses (ICA), a data-driven approach that separates signals into independent sources without making specific modeling assumptions. ICA has become widely accepted as a valuable approach for identifying functional connectivity within cortex but has been rarely applied to derive equivalent structures within WM. Here, BOLD signal changes in WM of a group of subjects performing motor tasks were first detected using ICA, and a spatial component whose time course was consistent with the task was found, demonstrating the analysis is sensitive to evoked BOLD signals in WM. Secondly, multiple spatial components were derived by applying ICA to identify those voxels in WM whose MRI signals showed similar temporal behaviors in a resting state. These functionally-related structures are grossly symmetric and coincide with corresponding tracts identified from diffusion MRI. Finally, functional connectivity was quantified by calculating correlations between pairs of structures to explore the synchronicity of resting state BOLD signals across WM regions, and the experimental results revealed that there exist two distinct groupings of functional correlations in WM tracts at rest. Our study provides further insights into the nature of activation patterns, functional responses and connectivity in WM, and support previous suggestions that BOLD signals in WM show similarities with cortical activations and are characterized by distinct underlying structures in tasks and at rest.

COUP-TFI/Nr2f1 Orchestrates Intrinsic Neuronal Activity during Development of the Somatosensory Cortex.

The formation of functional cortical maps in the cerebral cortex results from a timely regulated interaction between intrinsic genetic mechanisms and electrical activity. To understand how transcriptional regulation influences network activity and neuronal excitability within the neocortex, we used mice deficient for Nr2f1 (also known as COUP-TFI), a key determinant of primary somatosensory (S1) area specification during development. We found that the cortical loss of Nr2f1 impacts on spontaneous network activity and synchronization of S1 cortex at perinatal stages. In addition, we observed alterations in the intrinsic excitability and morphological features of layer V pyramidal neurons. Accordingly, we identified distinct voltage-gated ion channels regulated by Nr2f1 that might directly influence intrinsic bioelectrical properties during critical time windows of S1 cortex specification. Altogether, our data suggest a tight link between Nr2f1 and neuronal excitability in the developmental sequence that ultimately sculpts the emergence of cortical network activity within the immature neocortex.

Loss of Snord116 alters cortical neuronal activity in mice: a preclinical investigation of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder that is characterized by metabolic alteration and sleep abnormalities mostly related to rapid eye movement (REM) sleep disturbances. The disease is caused by genomic imprinting defects that are inherited through the paternal line. Among the genes located in the PWS region on chromosome 15 (15q11-q13), small nucleolar RNA 116 (Snord116) has been previously associated with intrusions of REM sleep into wakefulness in humans and mice. Here, we further explore sleep regulation of PWS by reporting a study with PWScrm+/p- mouse line, which carries a paternal deletion of Snord116. We focused our study on both macrostructural electrophysiological components of sleep, distributed among REMs and nonrapid eye movements. Of note, here, we study a novel electroencephalography (EEG) graphoelements of sleep for mouse studies, the well-known spindles. EEG biomarkers are often linked to the functional properties of cortical neurons and can be instrumental in translational studies. Thus, to better understand specific properties, we isolated and characterized the intrinsic activity of cortical neurons using in vitro microelectrode array. Our results confirm that the loss of Snord116 gene in mice influences specific properties of REM sleep, such as theta rhythms and, for the first time, the organization of REM episodes throughout sleep-wake cycles. Moreover, the analysis of sleep spindles present novel specific phenotype in PWS mice, indicating that a new catalog of sleep biomarkers can be informative in preclinical studies of PWS.

Acute Hyperglycemia Increases Brain Pregenual Anterior Cingulate Cortex Glutamate Concentrations in Type 1 Diabetes.

The brain mechanisms underlying the association of hyperglycemia with depressive symptoms are unknown. We hypothesized that disrupted glutamate metabolism in pregenual anterior cingulate cortex (ACC) in type 1 diabetes (T1D) without depression affects emotional processing. Using proton MRS, we measured glutamate concentrations in ACC and occipital lobe cortex (OCC) in 13 subjects with T1D without major depression (HbA1c 7.1 ± 0.7% [54 ± 7 mmol/mol]) and 11 healthy control subjects without diabetes (HbA1c 5.5 ± 0.2% [37 ± 3 mmol/mol]) during fasting euglycemia followed by a 60-min +5.5 mmol/L hyperglycemic clamp (HG). Intrinsic neuronal activity was assessed using resting-state blood oxygen level-dependent functional MRI to measure the fractional amplitude of low-frequency fluctuations in slow-4 band (fALFF4). Emotional processing and depressive symptoms were assessed using emotional tasks (emotional Stroop task, self-referent encoding task [SRET]) and clinical ratings (Hamilton Depression Rating Scale [HAM-D], Symptom Checklist-90 Revised [SCL-90-R]), respectively. During HG, ACC glutamate increased (1.2 mmol/kg, 10% P = 0.014) while ACC fALFF4 was unchanged (-0.007, -2%, P = 0.449) in the T1D group; in contrast, glutamate was unchanged (-0.2 mmol/kg, -2%, P = 0.578) while fALFF4 decreased (-0.05, -13%, P = 0.002) in the control group. OCC glutamate and fALFF4 were unchanged in both groups. T1D had longer SRET negative word response times (P = 0.017) and higher depression rating scores (HAM-D P = 0.020, SCL-90-R depression P = 0.008). Higher glutamate change tended to associate with longer emotional Stroop response times in T1D only. Brain glutamate must be tightly controlled during hyperglycemia because of the risk for neurotoxicity with excessive levels. Results suggest that ACC glutamate control mechanisms are disrupted in T1D, which affects glutamatergic neurotransmission related to emotional or cognitive processing. Increased prefrontal glutamate during acute hyperglycemic episodes could explain our previous findings of associations among chronic hyperglycemia, cortical thinning, and depressive symptoms in T1D.

Differences in Net Information Flow and Dynamic Connectivity Metrics Between Physically Active and Inactive Subjects Measured by Functional Near-Infrared Spectroscopy (fNIRS) During a Fatiguing Handgrip Task.

Twenty-three young adults (4 Females, 25.13 ± 3.72 years) performed an intermittent maximal handgrip force task using their dominant hand for 20 min (3.5 s squeeze/6.5 s release, 120 blocks) with concurrent cortical activity imaging by functional Near-Infrared Spectroscopy (fNRIS; OMM-3000, Shimadzu Corp., 111 channels). Subjects were grouped as physically active (n = 10) or inactive (n = 12) based on a questionnaire (active-exercise at least four times a week, inactive- exercise less than two times a week). We explored how motor task fatigue affected the vasomotion-induced oscillations in ΔHbO as measured by fNIRS at each hemodynamic frequency band: endothelial component (0.003–0.02 Hz) associated to microvascular activity, neurogenic component (0.02–0.04 Hz) related to intrinsic neuronal activity, and myogenic component (0.04–0.15 Hz) linked to activity of smooth muscles of arterioles. To help understand how these three neurovascular regulatory mechanisms relate to handgrip task performance we quantified several dynamic fNIRS metrics, including directional phase transfer entropy (dPTE), a computationally efficient and data-driven method used as a marker of information flow between cortical regions, and directional connectivity (DC), a means to compute directionality of information flow between two cortical regions. The relationship between static functional connectivity (SFC) and functional connectivity variability (FCV) was also explored to understand their mutual dependence for each frequency band in the context of handgrip performance as fatigued increased. Our findings ultimately showed differences between subject groups across all fNIRS metrics and hemodynamic frequency bands. These findings imply that physical activity modulates neurovascular control mechanisms at the endogenic, neurogenic, and myogenic frequency bands resulting in delayed fatigue onset and enhanced performance. The dynamic cortical network metrics quantified in this work for young, healthy subjects provides baseline measurements to guide future work on older individuals and persons with impaired cardiovascular health.

Hippocampal epileptogenesis in autoimmune encephalitis.

ObjectiveAutoantibody‐mediated forms of encephalitis (AE) include neurological disorders characterized by subacute memory loss, movement disorders, and, often, frequent, focal epileptic seizures. Yet, the electrophysiological effects of these autoantibodies on neuronal function have received little attention. In this study, we assessed the effects of CSF containing autoantibodies on intrinsic and extrinsic properties of hippocampal neurons, to define their epileptogenic potential.MethodsWe compared the effects of CSF containing leucine‐rich glioma inactivated 1 (LGI1), contactin‐associated protein‐like 2 (CASPR2), and γ‐aminobutyric acid receptor B (GABABR) antibodies on ex vivo electrophysiological parameters after stereotactic hippocampal inoculation into mice. Whole‐cell patch‐clamp and extracellular recordings from CA1 pyramidal neurons and CA3‐CA1 field recordings in ex vivo murine brain slices were used to study neuronal function.ResultsBy comparison to control CSF, AE CSFs increased the probability of glutamate release from CA3 neurons. In addition, LGI1‐ and CASPR2 antibodies containing CSFs induced epileptiform activity at a population level following Schaffer collateral stimulation. CASPR2 antibody containing CSF was also associated with higher spontaneous firing of CA1 pyramidal neurons. On the contrary, GABABR antibody containing CSF did not elicit changes in intrinsic neuronal activity and field potentials.InterpretationUsing patient CSF, we have demonstrated that the AE‐associated antibodies against LGI1 and CASPR2 are able to increase hippocampal CA1 neuron excitability, facilitating epileptiform activity. These findings provide in vivo pathogenic insights into neuronal dysfunction in these conditions.

Sudden Heart Rate Reduction Upon Optogenetic Release of Acetylcholine From Cardiac Parasympathetic Neurons in Perfused Hearts.

The balance of sympathetic and parasympathetic tone provides exquisite control of heart rate and contractility and has also been shown to modulate coronary flow and inflammation. Understanding how autonomic balance is altered by cardiac disease is an active area of research, and developing new ways to control this balance provides insights into disease therapies. However, achieving acute neuron-specific stimulation of autonomic neurons can be difficult in experiments that measure the acute effects of nerve stimulation on the heart. Conventional electrical and pharmacological approaches can be spatially and temporally non-selective. Cell-specific expression of light-activated channels (channelrhodopsin, ChR2) is a powerful approach that enables control of the timing and distribution of cellular stimulation using light. We present such an optogenetic approach where parasympathetic cardiac neurons are selectively photoactivated at high temporal precision to initiate cholinergic-mediated slowing of heart rate. Mice were crossbred to express ChR2 in peripheral cholinergic neurons using Cre-Lox recombination driven by a choline acetyltransferase (ChAT) promoter. Hearts from adult mice were excised, perfused, and the epicardium was illuminated (peak 460–465 nm) to photoactivate ChR2. In one set of studies, hearts were illuminated using a large-field LED light source. In other studies, a micro LED was placed on the right atrium to selectively illuminate the junction of the superior vena cava (SVC) and right atrium. The ECG was acquired before, during, and after tissue illumination to measure changes in heart rate. Upon illumination, hearts exhibited sudden and dramatic reductions in heart rate with restoration of normal heart rate after cessation of illumination. Delays in atrioventricular conduction were also observed. Heart rate reductions at the highest irradiance levels were similar to heart rate reductions caused by application of bethanechol (10 μM) or acetylcholine (800 μM). Atropine (50 nM) completely blocked the effect of ChR2 photoactivation, confirming cholinergic mediation. Optogenetic activation of intrinsic parasympathetic neurons reduced heart rate in an immediate, dose-dependent fashion, resembling the slowing of sinus rate in response to acetylcholine. Our results demonstrate a new approach for controlling parasympathetic modulation of cardiac function by selectively activating the endogenous release of acetylcholine from intrinsic cardiac cholinergic neurons.Key Message: Optogenetic photoactivation of intrinsic cardiac neurons provides immediate, tissue-specific stimulation with minimal cross-reactivity. Our results demonstrate that selective expression of channelrhodopsin within cardiac cholinergic neurons enables photoactivated release of acetylcholine, thereby instantaneously slowing sinus rate and altering atrioventricular conduction. This provides for in-depth examination of the endogenous interplay between cardiac autonomic neurons and the functional outcomes of downstream post-synaptic receptor activation.

Eating in the absence of hunger in young children is related to brain reward network hyperactivity and reduced functional connectivity in executive control networks.

Recent work has implicated disinhibited eating behaviours (DEB) as a potential pathway toward obesity development in children. However, the underlying neurobiology of disinhibited eating behaviours in young, healthy weight children, prior to obesity development, remains unknown. This study tested the relationship between DEB and intrinsic neuronal activity and connectivity in young children without obesity. Brain networks implicated in overeating including reward, salience and executive control networks, and the default mode network were investigated. DEB was measured by the eating in the absence of hunger (EAH) paradigm with postlunch kilocalories consumed from highly palatable foods (EAH kcal) used as the predictor. Intrinsic neuronal activity within and connectivity between specified networks were measured via resting-state functional magnetic resonance imaging. Eighteen typically developing children (mean age=5.8years) were included. EAH kcal was positively associated with activity of the nucleus accumbens, a major reward network hub (P<0.05, corrected). EAH kcal was negatively associated with intrinsic prefrontal cortex connectivity to the striatum (P<0.01, corrected). These results suggest that neural aspects of DEB are detectable in young children without obesity, providing a potential tool to better understand the development of obesity in this population.

The dark matter of the brain.

The bulk of brain energy expenditure is allocated for maintenance of perpetual intrinsic activity of neurons and neural circuits. Long-term electrophysiological and neuroimaging studies in anesthetized and behaving animals show, however, that the great majority of nerve cells in the intact brain do not fire action potentials, i.e., are permanently silent. Herein, I review emerging data suggesting massive redundancy of nerve cells in mammalian nervous system, maintained in inhibited state at high energetic costs. Acquired in the course of evolution, these collections of dormant neurons and circuits evade routine functional undertakings, and hence, keep out of the reach of natural selection. Under penetrating stress and disease, however, they occasionally switch in active state and drive a variety of neuro-psychiatric symptoms and behavioral abnormalities. The increasing evidence for widespread occurrence of silent neurons warrants careful revision of functional models of the brain and entails unforeseen reserves for rehabilitation and plasticity.

Abnormalities in the evoked frontal oscillatory activity of first-episode psychosis: A TMS/EEG study

TMS with simultaneous EEG allows assessing the intrinsic oscillatory activity of cortical neurons. We recently showed reduced frontal cortical oscillations in chronic schizophrenia (SCZ). Here we investigated the oscillatory activity of first-episode psychosis (FEP) patients after TMS of a frontal area, the motor cortex. Compared to healthy controls, FEP patients had significantly reduced beta/low gamma oscillations, which were associated to worse clinical symptoms. Altogether, this study demonstrates that TMS/EEG recordings: 1) are feasible in acute, early-course psychotic patients; and 2) reveal intrinsic oscillatory deficits at illness onset, which may help design more effective, early interventions in SCZ.

Opposing patterns of neuronal variability in the sensorimotor network mediate cyclothymic and depressive temperaments.

Affective temperaments have been described since the early 20th century and may play a central role in psychiatric illnesses, such as bipolar disorder (BD). However, the neuronal basis of temperament is still unclear. We investigated the relationship of temperament with neuronal variability in the resting state signal-measured by fractional standard deviation (fSD) of Blood-Oxygen-Level Dependent signal-of the different large-scale networks, that is, sensorimotor network (SMN), along with default-mode, salience and central executive networks, in standard frequency band (SFB) and its sub-frequencies slow4 and slow5, in a large sample of healthy subject (HC, n = 109), as well as in the various temperamental subgroups (i.e., cyclothymic, hyperthymic, depressive, and irritable). A replication study on an independent dataset of 121 HC was then performed. SMN fSD positively correlated with cyclothymic z-score and was significantly increased in the cyclothymic temperament compared to the depressive temperament subgroups, in both SFB and slow4. We replicated our findings in the independent dataset. A relationship between cyclothymic temperament and neuronal variability, an index of intrinsic neuronal activity, in the SMN was found. Cyclothymic and depressive temperaments were associated with opposite changes in the SMN variability, resembling changes previously described in manic and depressive phases of BD. These findings shed a novel light on the neural basis of affective temperament and also carry important implications for the understanding of a potential dimensional continuum between affective temperaments and BD, on both psychological and neuronal levels.

Peripheral oxytocin and vasopressin modulates regional brain activity differently in men and women with schizophrenia

BackgroundOxytocin (OT) and arginine vasopressin (AVP) exert sexually dimorphic effects on cognition and emotion processing. Abnormalities in these hormones are observed in schizophrenia and may contribute to multiple established sex differences associated with the disorder. Here we examined sex-dependent hormone associations with resting brain activity and their clinical associations in schizophrenia patients. MethodsOT and AVP serum concentrations were assayed in 35 individuals with schizophrenia (23 men) and 60 controls (24 men) from the Chicago BSNIP study site. Regional cerebral function was assessed with resting state fMRI by measuring the amplitude of low-frequency fluctuations (ALFF) which are believed to reflect intrinsic spontaneous neuronal activity. ResultsIn female patients, lower OT levels were associated with lower ALFF in frontal and cerebellar cortices (p's < 0.05) and in female controls AVP levels were inversely associated with ALFF in the frontal cortex (p = 0.01). In male patients, lower OT levels were associated with lower ALFF in the posterior cingulate and lower AVP levels were associated with lower ALFF in frontal cortex (p's < 0.05). In male controls, lower OT levels were associated with lower ALFF in frontal cortex and higher ALFF in the thalamus (p's < 0.05). There were some inverse ALFF-behavior associations in patients. ConclusionsAlterations in peripheral hormone levels are associated with resting brain physiology in a sex-dependent manner in schizophrenia. These effects may contribute to sex differences in psychiatric symptom severity and course of illness in schizophrenia.