Characterization of tau propagation pattern and cascading hypometabolism from functional connectivity in Alzheimer's disease.

Tau pathology and its spatial propagation in Alzheimer's disease (AD) play crucial roles in the neurodegenerative cascade leading to dementia. However, the underlying mechanisms linking tau spreading to glucose metabolism remain elusive. To address this, we aimed to examine the association between pathologic tau aggregation, functional connectivity, and cascading glucose metabolism and further explore the underlying interplay mechanisms. In this prospective cohort study, we enrolled 79 participants with 18F-Florzolotau positron emission tomography (PET), 18F-fluorodeoxyglucose PET, resting-state functional, and anatomical magnetic resonance imaging (MRI) images in the hospital-based Shanghai Memory Study. We employed generalized linear regression and correlation analyses to assess the associations between Florzolotau accumulation, functional connectivity, and glucose metabolism in whole-brain and network-specific manners. Causal mediation analysis was used to evaluate whether functional connectivity mediates the association between pathologic tau and cascading glucose metabolism. We examined 22 normal controls and 57 patients with AD. In the AD group, functional connectivity was associated with Florzolotau covariance (ß = .837, r = 0.472, p < .001) and glucose covariance (ß = 1.01, r = 0.499, p < .001). Brain regions with higher tau accumulation tend to be connected to other regions with high tau accumulation through functional connectivity or metabolic connectivity. Mediation analyses further suggest that functional connectivity partially modulates the influence of tau accumulation on downstream glucose metabolism (mediation proportion: 49.9%). Pathologic tau may affect functionally connected neurons directly, triggering downstream glucose metabolism changes. This study sheds light on the intricate relationship between tau pathology, functional connectivity, and downstream glucose metabolism, providing critical insights into AD pathophysiology and potential therapeutic targets.

Reelin Regulates Developmental Desynchronization Transition of Neocortical Network Activity.

During the first and second stages of postnatal development, neocortical neurons exhibit a wide range of spontaneous synchronous activity (SSA). Towards the end of the second postnatal week, the SSA is replaced by a more sparse and desynchronized firing pattern. The developmental desynchronization of neocortical spontaneous neuronal activity is thought to be intrinsically generated, since sensory deprivation from the periphery does not affect the time course of this transition. The extracellular protein reelin controls various aspects of neuronal development through multimodular signaling. However, so far it is unclear whether reelin contributes to the developmental desynchronization transition of neocortical neurons. The present study aims to investigate the role of reelin in postnatal cortical developmental desynchronization using a conditional reelin knockout (RelncKO) mouse model. Conditional reelin deficiency was induced during early postnatal development, and Ca2+ recordings were conducted from organotypic cultures (OTCs) of the somatosensory cortex. Our results show that both wild type (wt) and RelncKO exhibited an SSA pattern during the early postnatal week. However, at the end of the second postnatal week, wt OTCs underwent a transition to a desynchronized network activity pattern, while RelncKO activity remained synchronous. This changing activity pattern suggests that reelin is involved in regulating the developmental desynchronization of cortical neuronal network activity. Moreover, the developmental desynchronization impairment observed in RelncKO was rescued when RelncKO OTCs were co-cultured with wt OTCs. Finally, we show that the developmental transition to a desynchronized state at the end of the second postnatal week is not dependent on glutamatergic signaling. Instead, the transition is dependent on GABAAR and GABABR signaling. The results suggest that reelin controls developmental desynchronization through GABAAR and GABABR signaling.

Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice.

In Parkinson's disease and other synucleinopathies, fibrillar forms of α-synuclein (aSyn) are hypothesized to structurally convert and pathologize endogenous aSyn, which then propagates through the neural connections, forming Lewy pathologies and ultimately causing neurodegeneration. Inoculation of mouse-derived aSyn preformed fibrils (PFFs) into the unilateral striatum of wild-type mice causes widespread aSyn pathologies in the brain through the neural network. Here, we used the local injection of antisense oligonucleotides (ASOs) against Snca mRNA to confine the area of endogenous aSyn protein reduction and not to affect the PFFs properties in this model. We then varied the timing and location of ASOs injection to examine their impact on the initiation and propagation of aSyn pathologies in the whole brain and the therapeutic effect using abnormally-phosphorylated aSyn (pSyn) as an indicator. By injecting ASOs before or 0-14 days after the PFFs were inoculated into the same site in the left striatum, the reduction in endogenous aSyn in the striatum leads to the prevention and inhibition of the regional spread of pSyn pathologies to the whole brain including the contralateral right hemisphere. ASO post-injection inhibited extension from neuritic pathologies to somatic ones. Moreover, injection of ASOs into the right striatum prevented the remote regional spread of pSyn pathologies from the left striatum where PFFs were inoculated and no ASO treatment was conducted. This indicated that the reduction in endogenous aSyn protein levels at the propagation destination site can attenuate pSyn pathologies, even if those at the propagation initiation site are not inhibited, which is consistent with the original concept of prion-like propagation that endogenous aSyn is indispensable for this regional spread. Our results demonstrate the importance of recruiting endogenous aSyn in this neural network propagation model and indicate a possible potential for ASO treatment in synucleinopathies.

Directed physiological networks in the human prefrontal cortex at rest and post transcranial photobiomodulation.

Cerebral infra-slow oscillation (ISO) is a source of vasomotion in endogenic (E; 0.005-0.02 Hz), neurogenic (N; 0.02-0.04 Hz), and myogenic (M; 0.04-0.2 Hz) frequency bands. In this study, we quantified changes in prefrontal concentrations of oxygenated hemoglobin (Δ[HbO]) and redox-state cytochrome c oxidase (Δ[CCO]) as hemodynamic and metabolic activity metrics, and electroencephalogram (EEG) powers as electrophysiological activity, using concurrent measurements of 2-channel broadband near-infrared spectroscopy and EEG on the forehead of 22 healthy participants at rest. After preprocessing, the multi-modality signals were analyzed using generalized partial directed coherence to construct unilateral neurophysiological networks among the three neurophysiological metrics (with simplified symbols of HbO, CCO, and EEG) in each E/N/M frequency band. The links in these networks represent neurovascular, neurometabolic, and metabolicvascular coupling (NVC, NMC, and MVC). The results illustrate that the demand for oxygen by neuronal activity and metabolism (EEG and CCO) drives the hemodynamic supply (HbO) in all E/N/M bands in the resting prefrontal cortex. Furthermore, to investigate the effect of transcranial photobiomodulation (tPBM), we performed a sham-controlled study by delivering an 800-nm laser beam to the left and right prefrontal cortex of the same participants. After performing the same data processing and statistical analysis, we obtained novel and important findings: tPBM delivered on either side of the prefrontal cortex triggered the alteration or reversal of directed network couplings among the three neurophysiological entities (i.e., HbO, CCO, and EEG frequency-specific powers) in the physiological network in the E and N bands, demonstrating that during the post-tPBM period, both metabolism and hemodynamic supply drive electrophysiological activity in directed network coupling of the prefrontal cortex (PFC). Overall, this study revealed that tPBM facilitates significant modulation of the directionality of neurophysiological networks in electrophysiological, metabolic, and hemodynamic activities.

Network-level encoding of local neurotransmitters in cortical astrocytes.

Astrocytes, the most abundant non-neuronal cell type in the mammalian brain, are crucial circuit components that respond to and modulate neuronal activity through calcium (Ca2+) signalling1-7. Astrocyte Ca2+ activity is highly heterogeneous and occurs across multiple spatiotemporal scales-from fast, subcellular activity3,4 to slow, synchronized activity across connected astrocyte networks8-10-to influence many processes5,7,11. However, the inputs that drive astrocyte network dynamics remain unclear. Here we used ex vivo and in vivo two-photon astrocyte imaging while mimicking neuronal neurotransmitter inputs at multiple spatiotemporal scales. We find that brief, subcellular inputs of GABA and glutamate lead to widespread, long-lasting astrocyte Ca2+ responses beyond an individual stimulated cell. Further, we find that a key subset of Ca2+ activity-propagative activity-differentiates astrocyte network responses to these two main neurotransmitters, and may influence responses to future inputs. Together, our results demonstrate that local, transient neurotransmitter inputs are encoded by broad cortical astrocyte networks over a minutes-long time course, contributing to accumulating evidence that substantial astrocyte-neuron communication occurs across slow, network-level spatiotemporal scales12-14. These findings will enable future studies to investigate the link between specific astrocyte Ca2+ activity and specific functional outputs, which could build a consistent framework for astrocytic modulation of neuronal activity.

The homeostatic effects of the RE-1 silencing transcription factor on cortical networks are altered under ictogenic conditions in the mouse.

AIM: The Repressor Element-1 Silencing Transcription Factor (REST) is an epigenetic master regulator playing a crucial role in the nervous system. In early developmental stages, REST downregulation promotes neuronal differentiation and the acquisition of the neuronal phenotype. In addition, postnatal fluctuations in REST expression contribute to shaping neuronal networks and maintaining network homeostasis. Here we investigate the role of the early postnatal deletion of neuronal REST in the assembly and strength of excitatory and inhibitory synaptic connections. METHODS: We investigated excitatory and inhibitory synaptic transmission by patch-clamp recordings in acute neocortical slices in a conditional knockout mouse model (RestGTi) in which Rest was deleted by delivering PHP.eB adeno-associated viruses encoding CRE recombinase under the control of the human synapsin I promoter in the lateral ventricles of P0-P1 pups. RESULTS: We show that, under physiological conditions, Rest deletion increased the intrinsic excitability of principal cortical neurons in the primary visual cortex and the density and strength of excitatory synaptic connections impinging on them, without affecting inhibitory transmission. Conversely, in the presence of a pathological excitation/inhibition imbalance induced by pentylenetetrazol, Rest deletion prevented the increase in synaptic excitation and decreased seizure severity. CONCLUSION: The data indicate that REST exerts distinct effects on the excitability of cortical circuits depending on whether it acts under physiological conditions or in the presence of pathologic network hyperexcitability. In the former case, REST preserves a correct excitatory/inhibitory balance in cortical circuits, while in the latter REST loses its homeostatic activity and may become pro-epileptogenic.

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signalling.

Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition, which is essential for neuronal computation1,2. Deviations from a balanced state have been linked to neurodevelopmental disorders, and severe disruptions result in epilepsy3-5. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here we identify a signalling pathway in the adult mouse neocortex that is activated in response to increased neuronal network activity. Overactivation of excitatory neurons is signalled to the network through an increase in the levels of BMP2, a growth factor that is well known for its role as a morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of perineuronal nets. PV-interneuron-specific disruption of BMP2-SMAD1 signalling is accompanied by a loss of glutamatergic innervation in PV cells, underdeveloped perineuronal nets and decreased excitability. Ultimately, this impairment of the functional recruitment of PV interneurons disrupts the cortical excitation-inhibition balance, with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signalling is repurposed to stabilize cortical networks in the adult mammalian brain.

Link Protein 1 Is Involved in the Activity-Dependent Modulation of Perineuronal Nets in the Spinal Cord.

One of the challenges of the mature nervous system is to maintain the stability of neural networks while providing a degree of plasticity to generate experience-dependent modifications. This plasticity-stability dynamism is regulated by perineuronal nets (PNNs) and is crucial for the proper functioning of the system. Previously, we found a relation between spinal PNNs reduction and maladaptive plasticity after spinal cord injury (SCI), which was attenuated by maintaining PNNs with activity-dependent therapies. Moreover, transgenic mice lacking the cartilage link protein 1 (Crtl1 KO mice) showed aberrant spinal PNNs and increased spinal plasticity. Therefore, the aim of this study is to evaluate the role of link protein 1 in the activity-dependent modulation of spinal PNNs surrounding motoneurons and its impact on the maladaptive plasticity observed following SCI. We first studied the activity-dependent modulation of spinal PNNs using a voluntary wheel-running protocol. This training protocol increased spinal PNNs in WT mice but did not modify PNN components in Crtl1 KO mice, suggesting that link protein 1 mediates the activity-dependent modulation of PNNs. Secondly, a thoracic SCI was performed, and functional outcomes were evaluated for 35 days. Interestingly, hyperreflexia and hyperalgesia found at the end of the experiment in WT-injured mice were already present at basal levels in Crtl1 KO mice and remained unchanged after the injury. These findings demonstrated that link protein 1 plays a dual role in the correct formation and in activity-dependent modulation of PNNs, turning it into an essential element for the proper function of PNN in spinal circuits.

Mapping brain metabolism, connectivity and neurotransmitters topography in early and late onset dementia with lewy bodies.

INTRODUCTION: Early-onset dementia with Lewy bodies (EO-DLB) is associated with rapid cognitive decline and severe neuropsychiatric symptoms at onset. METHODS: Using FDG-PET imaging for 62 patients (21 EO-DLB, 41 LO (late-onset)-DLB), we explored brain hypometabolism, and metabolic connectivity in the whole-brain network and resting-state networks (RSNs). We also evaluated the spatial association between brain hypometabolism and neurotransmitter pathways topography. RESULTS: Direct comparisons between the two clinical subgroups showed that EO-DLB was characterized by a lower metabolism in posterior cingulate/precuneus and occipital cortex. Metabolic connectivity analysis revealed significant alterations in posterior regions in both EO-DLB and LO-DLB. The EO-DLB, however, showed more severe loss of connectivity between occipital and parietal nodes and hyperconnectivity between frontal and cerebellar nodes. Spatial topography association analysis indicated significant correlations between neurotransmitter maps (i.e. acetylcholine, GABA, serotonin, dopamine) and brain hypometabolism in both EO and LO-DLB, with significantly higher metabolic correlation in the presynaptic serotonergic system for EO-DLB, supporting its major dysfunction. CONCLUSIONS: Our study revealed greater brain hypometabolism and loss of connectivity in posterior brain region in EO- than LO-DLB. Serotonergic mapping emerges as a relevant factor for further investigation addressing clinical differences between DLB subtypes.

Differential Expression Analysis Identifies Candidate Synaptogenic Molecules for Wiring Direction-Selective Circuits in the Retina.

An organizational feature of neural circuits is the specificity of synaptic connections. A striking example is the direction-selective (DS) circuit of the retina. There are multiple subtypes of DS retinal ganglion cells (DSGCs) that prefer motion along one of four preferred directions. This computation is mediated by selective wiring of a single inhibitory interneuron, the starburst amacrine cell (SAC), with each DSGC subtype preferentially receiving input from a subset of SAC processes. We hypothesize that the molecular basis of this wiring is mediated in part by unique expression profiles of DSGC subtypes. To test this, we first performed paired recordings from isolated mouse retinas of both sexes to determine that postnatal day 10 (P10) represents the age at which asymmetric synapses form. Second, we performed RNA sequencing and differential expression analysis on isolated P10 ON-OFF DSGCs tuned for either nasal or ventral motion and identified candidates which may promote direction-specific wiring. We then used a conditional knock-out strategy to test the role of one candidate, the secreted synaptic organizer cerebellin-4 (Cbln4), in the development of DS tuning. Using two-photon calcium imaging, we observed a small deficit in directional tuning among ventral-preferring DSGCs lacking Cbln4, though whole-cell voltage-clamp recordings did not identify a significant change in inhibitory inputs. This suggests that Cbln4 does not function primarily via a cell-autonomous mechanism to instruct wiring of DS circuits. Nevertheless, our transcriptomic analysis identified unique candidate factors for gaining insights into the molecular mechanisms that instruct wiring specificity in the DS circuit.

A model of human neural networks reveals NPTX2 pathology in ALS and FTLD.

Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies1, which involve human-specific mechanisms2-5 that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors6. Single-cell transcriptomics and comparison to independent neural stem cells7 showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks (which we designate iNets). Neuronal and glial maturation in iNets was similar to that of cortical organoids8. Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3' untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity.

Loss of CNTNAP2 Alters Human Cortical Excitatory Neuron Differentiation and Neural Network Development.

BACKGROUND: Loss-of-function mutations in the contactin-associated protein-like 2 (CNTNAP2) gene are causal for neurodevelopmental disorders, including autism, schizophrenia, epilepsy, and intellectual disability. CNTNAP2 encodes CASPR2, a single-pass transmembrane protein that belongs to the neurexin family of cell adhesion molecules. These proteins have a variety of functions in developing neurons, including connecting presynaptic and postsynaptic neurons, and mediating signaling across the synapse. METHODS: To study the effect of loss of CNTNAP2 function on human cerebral cortex development, and how this contributes to the pathogenesis of neurodevelopmental disorders, we generated human induced pluripotent stem cells from one neurotypical control donor null for full-length CNTNAP2, modeling cortical development from neurogenesis through to neural network formation in vitro. RESULTS: CNTNAP2 is particularly highly expressed in the first two populations of early-born excitatory cortical neurons, and loss of CNTNAP2 shifted the relative proportions of these two neuronal types. Live imaging of excitatory neuronal growth showed that loss of CNTNAP2 reduced neurite branching and overall neuronal complexity. At the network level, developing cortical excitatory networks null for CNTNAP2 had complex changes in activity compared with isogenic controls: an initial period of relatively reduced activity compared with isogenic controls, followed by a lengthy period of hyperexcitability, and then a further switch to reduced activity. CONCLUSIONS: Complete loss of CNTNAP2 contributes to the pathogenesis of neurodevelopmental disorders through complex changes in several aspects of human cerebral cortex excitatory neuron development that culminate in aberrant neural network formation and function.

Conditional deletion of Neurexin-2 alters neuronal network activity in hippocampal circuitries and leads to spontaneous seizures.

Neurexins (Nrxns) have been extensively studied for their role in synapse organization and have been linked to many neuropsychiatric disorders, including autism spectrum disorder (ASD), and epilepsy. However, no studies have provided direct evidence that Nrxns may be the key regulator in the shared pathogenesis of these conditions largely due to complexities among Nrxns and their non-canonical functions in different synapses. Recent studies identified NRXN2 mutations in ASD and epilepsy, but little is known about Nrxn2's role in a circuit-specific manner. Here, we report that conditional deletion of Nrxn2 from the hippocampus and cortex (Nrxn2 cKO) results in behavioral abnormalities, including reduced social preference and increased nestlet shredding behavior. Electrophysiological recordings identified an overall increase in hippocampal CA3→CA1 network activity in Nrxn2 cKO mice. Using intracranial electroencephalogram recordings, we observed unprovoked spontaneous reoccurring electrographic and behavioral seizures in Nrxn2 cKO mice. This study provides the first evidence that conditional deletion of Nrxn2 induces increased network activity that manifests into spontaneous recurrent seizures and behavioral impairments.

Esketamine increases neurotransmitter releases but simplifies neurotransmitter networks in mouse prefrontal cortex.

General anesthesia induces a profound but reversible unconscious state, which is accompanied by changes in various neurotransmitters in the cortex. Unlike the "brain silencing" effect of γ-aminobutyric acid (GABA) receptor potentiator anesthesia, ketamine anesthesia leads the brain to a paradoxical active state with higher cortical activity, which is manifested as dissociative anesthesia. However, how the overall neurotransmitter network evolves across conscious states after ketamine administration remains unclear. Using in vivo microdialysis, high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis, and electroencephalogram (EEG) recording technique, we continuously measured the concentrations of six neurotransmitters and the EEG signals during anesthesia with esketamine, an S-enantiomer of ketamine racemate. We found that there was an increase in the release of five cortical neurotransmitters after the administration of esketamine. The correlation of cortical neurotransmitters was dynamically simplified along with behavioral changes until full recovery after anesthesia. The esketamine-increased gamma oscillation power was positively correlated only with the concentration of 5-hydroxytryptamine (5-HT) in the medial prefrontal cortex. This study suggests that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.NEW & NOTEWORTHY In this study, we found that esketamine significantly increased the cortical concentration of multiple neurotransmitters in mice. However, esketamine dynamically simplified the overall network of cortical neurotransmitters at different behavioral states during the perianesthesia period. The concentration of 5-HT in the medial prefrontal cortex (mPFC) was highly correlated with the esketamine-increased gamma oscillation. These findings suggested that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.

Cortical diurnal rhythms remain intact with microglial depletion.

Microglia are subject to change in tandem with the endogenously generated biological oscillations known as our circadian rhythm. Studies have shown microglia harbor an intrinsic molecular clock which regulates diurnal changes in morphology and influences inflammatory responses. In the adult brain, microglia play an important role in the regulation of condensed extracellular matrix structures called perineuronal nets (PNNs), and it has been suggested that PNNs are also regulated in a circadian and diurnal manner. We sought to determine whether microglia mediate the diurnal regulation of PNNs via CSF1R inhibitor dependent microglial depletion in C57BL/6J mice, and how the absence of microglia might affect cortical diurnal gene expression rhythms. While we observe diurnal differences in microglial morphology, where microglia are most ramified at the onset of the dark phase, we do not find diurnal differences in PNN intensity. However, PNN intensity increases across many brain regions in the absence of microglia, supporting a role for microglia in the regulation of PNNs. Here, we also show that cortical diurnal gene expression rhythms are intact, with no cycling gene changes without microglia. These findings demonstrate a role for microglia in the maintenance of PNNs, but not in the maintenance of diurnal rhythms.

Activation of noradrenergic locus coeruleus and social behavior network nuclei varies with duration of male midshipman advertisement calls.

Vocal courtship is vital to the reproductive success of many vertebrates and is therefore a highly-motivated behavioral state. Catecholamines have been shown to play an essential role in the expression and maintenance of motivated vocal behavior, such as the coordination of vocal-motor output in songbirds. However, it is not well-understood if this relationship applies to anamniote vocal species. Using the plainfin midshipman fish model, we tested whether specific catecholaminergic (i.e., dopaminergic and noradrenergic) nuclei and nodes of the social behavior network (SBN) are differentially activated in vocally courting (humming) versus non-humming males. Herein, we demonstrate that tyrosine hydroxylase immunoreactive (TH-ir) neuron number in the noradrenergic locus coeruleus (LC) and induction of cFos (an immediate early gene product and proxy for neural activation) in the preoptic area differentiated humming from non-humming males. Furthermore, we found relationships between activation of the LC and SBN nuclei with the total amount of time that males spent humming, further reinforcing a role for these specific brain regions in the production of motivated reproductive-related vocalizations. Finally, we found that patterns of functional connectivity between catecholaminergic nuclei and nodes of the SBN differed between humming and non-humming males, supporting the notion that adaptive behaviors (such as the expression of advertisement hums) emerge from the interactions between various catecholaminergic nuclei and the SBN.

Distribution and daily oscillation of GABA in the circadian system of the cockroach Rhyparobia maderae.

Gamma-aminobutyric acid (GABA) is the prevalent inhibitory neurotransmitter in nervous systems promoting sleep in both mammals and insects. In the Madeira cockroach, sleep-wake cycles are controlled by a circadian clock network in the brain's optic lobes, centered in the accessory medulla (AME) with its innervating pigment-dispersing factor (PDF) expressing clock neurons at the anterior-ventral rim of the medulla. GABA is present in cell clusters that innervate different circuits of the cockroach's AME clock, without colocalizing in PDF clock neurons. Physiological, immunohistochemical, and behavioral assays provided evidence for a role of GABA in light entrainment, possibly via the distal tract that connects the AME's glomeruli to the medulla. Furthermore, GABA was implemented in clock outputs to multiple effector systems in optic lobe and midbrain. Here, GABAergic brain circuits were analyzed further, focusing on the circadian system in search for sleep/wake controlling brain circuits. All GABA-immunoreactive neurons of the cockroach brain were also stained with an antiserum against the GABA-synthesizing enzyme glutamic acid decarboxylase. We found strong overlap of the distribution of GABA-immunoreactive networks with PDF clock networks in optic lobes and midbrain. Neurons in five of the six soma groups that innervate the clock exhibited GABA immunoreactivity. The intensity of GABA immunoreactivity in the distal tract showed daily fluctuations with maximum staining intensity in the middle of the day and weakest staining at the end of the day. Quantification via enzyme-linked immunosorbent assay and quantitative liquid chromatography coupled to electrospray ionization tandem mass spectrometry, likewise, showed higher GABA levels in the optic lobe during the inactivity phase of the cockroach during the day and lower levels during its activity phase at dusk. Our data further support the hypothesis that light- and PDF-dependently the circadian clock network of the cockroach controls GABA levels and thereby promotes sleep during the day.

The impact of COVID-19 lockdown on brain metabolism.

This study aims to evaluate the impact of French national lockdown of 55 days on brain metabolism of patients with neurological disorders. Whole-brain voxel-based PET analysis was used to correlate 18 F-FDG metabolism to the number of days after March 17, 2020 (in 95 patients; mean age: 54.3 years ± 15.7; 59 men), in comparison to the same period in 2019 before the SARS-CoV-2 outbreak (in 212 patients; mean age: 59.5 years ± 15.8; 114 men), and to the first 55 days of deconfinement (in 188 patients; mean age: 57.5 years ± 16.5; 93 men). Lockdown duration was negatively correlated to the metabolism of the sensory-motor cortex with a prevailing effect on the left dominant pyramidal tract and on younger patients, also including the left amygdala, with only partial reversibility after 55 days of deconfinement. Weak overlap was found with the reported pattern of hypometabolism in long COVID (<9%). Restriction of physical activities, and possible related deconditioning, and social isolation may lead to functional disturbances of sensorimotor and emotional brain networks. Of note, this metabolic pattern seems distinct to those reported in long COVID. Further longitudinal studies with longer follow-up are needed to evaluate clinical consequences and relationships on cognitive and mental health against functional deactivation hypothesis, and to extend these findings to healthy subjects in the context of lockdown.

Neural underpinnings of food choice and consumption in obesity.

BACKGROUND/OBJECTIVES: Obesity is associated with unhealthy food choices. Food selection is driven by the subjective valuation of available options, and the perceived and actual rewards accompanying consumption. These cognitive operations are mediated by brain regions including the ventromedial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), and ventral striatum (vStr). This study investigated the relationship between body mass index (BMI) and functional activations in the vmPFC, dACC, and vStr during food selection and consumption. SUBJECTS/METHODS: After overnight fasting, 26 individuals (BMI: 18-40 kg/m2) performed a food choice task while being scanned with functional magnetic resonance imaging (fMRI). Each trial involved selecting one beverage from a pair of presented options, followed by delivery of a 3 mL aliquot of the selected option using an MR-compatible gustometer. We also tracked subjective preference for each beverage throughout the experiment. RESULTS: During food choice, individuals with greater BMI had less activation in the dorsolateral prefrontal cortex when selecting a high-value option and less vmPFC activation upon its consumption. Independent of BMI, during food choice the dACC and anterior insula elicited higher activation when a less preferred beverage was selected. Activation of the dACC and a broader frontoparietal network was also observed when deciding between options more similar in value. During consumption, receipt of a more preferred beverage was associated with greater vmPFC response, and attenuation of the dACC. CONCLUSIONS: An individual's preference for a food option modulates the brain activity associated with choosing and consuming it. The relationship between food preference and underlying brain activity is altered in obesity, with reduced engagement of cognition-related regions when presented with a highly valued option, but a blunted response in reward-related regions upon consumption.

Neurocircuitry basis of the opioid use disorder-post-traumatic stress disorder comorbid state: conceptual analyses using a dimensional framework.

Understanding the interface between opioid use disorder (OUD) and post-traumatic stress disorder (PTSD) is challenging. By use of a dimensional framework, such as research domain criteria, convergent and targetable neurobiological processes in OUD-PTSD comorbidity can be identified. We hypothesise that, in OUD-PTSD, circuitry that is implicated in two research domain criteria systems (ie, negative valence and cognitive control) underpins dysregulation of incentive salience, negative emotionality, and executive function. We also propose that the OUD-PTSD state might be systematically investigated with approaches outlined within a neuroclinical assessment framework for addictions and PTSD. Our dimensional analysis of the OUD-PTSD state shows how first-line therapeutic approaches (ie, partial µ-type opioid receptor [MOR1] agonism) modulate overlapping neurobiological and clinical features and also provides mechanistic rationale for evaluating polytherapeutic strategies (ie, partial MOR1 agonism, κ-type opioid receptor [KOR1] antagonism, and α-2A adrenergic receptor [ADRA2A] agonism). A combination of these therapeutic mechanisms is projected to facilitate recovery in patients with OUD-PTSD by mitigating negative valence states and enhancing executive control.