bioRxiv Subject Collection: Neuroscience's Journal
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Tuesday, June 25th, 2024
| Time |
Event |
| 1:47a |
An endogenous GLP-1 circuit engages VTA GABA neurons to regulate mesolimbic dopamine neurons and attenuate cocaine seeking
Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate the reinstatement of cocaine-seeking behavior, an animal model of relapse. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius (NTS) that project to the ventral tegmental area (VTA) decreased cocaine reinstatement. Single nuclei transcriptomics and FISH studies revealed GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a novel functional role of GABAergic GLP-1R-expressing midbrain neurons in drug seeking. | | 5:41a |
EEG Signatures of COVID-19 Survival compared to close contacts and the Cuban EEG normative database
BackgroundThe EEG constitutes a powerful neuroimaging technique for assessing functional brain impairment in COVID-19 patients.
ObjectiveThe current investigation compared the EEG among COVID-19 survivors, close contacts and the Cuban EEG normative database, using semi-quantitative visual EEG inspection, quantitative and the current source density measures EEG analysis.
MethodsThe resting-state EEG activity, quantitative QEEG, and VARETA inverse solution, were evaluated in 173 subjects: 87 patients confirmed cases by the positive reverse transcription polymerase chain reaction (RT-PCR), 86 close contacts (negative PCR) and the Cuban EEG normative database. All patients were physical, neurological, and clinically assessed using neurological retrospective survey and version 2.1 of the Schedules for Clinical Assessment in Neuropsychiatry (SCAN).
ResultsThe GTE score showed significant differences in terms of frequency scores of backgrounds rhythmic activity, diffuse slow activity, and focal abnormality. The QEEG analysis showed a pattern of abnormality with respect to the Cuban EEG normative values, displaying an excess of alpha and beta activities in the fronto-central-parietal areas in both groups. The anomalies, of COVID-19 patients and close contacts, differs in the right fronto-centro parietal area. The COVID 19 group differed-s from the close control group in theta band of the right parieto-central. The symptomatic group of COVID-19 patients differs from asymptomatic patients in delta and theta activities of the parieto-central region. The sources of activation using VARETA showed a difference in cortical activation patterns at alpha and beta frequencies in the groups studied with respect to the normative EEG database. In beta frequency were localized in right middle temporal gyrus in both groups and right angular gyrus in Covid 19 group only. In alpha band, the regions were the left supramarginal gyrus for Covid 19 group and the left superior temporal gyrus for Control group. Greater activation was found in the right middle temporal gyrus at alpha frequency in COVID-19 patients than in their close contacts.
ConclusionsBrain functions are impaired in long COVID-19 patients. QEEG and VARETA permit us to comprehend the susceptibility of particular brain regions exposed to viral illness.
HighlightsO_LIBackground frequency abnormalities diffuse slow activity and focal abnormality associated with a pattern of excess oftheta, alpha and beta energies in in the right fronto-centro-parietal regions in QEEG analysis characterizedCOVID-19 patients.
C_LIO_LIPatients with COVID-19 show more alpha and beta EEG activities related to normative EEG database.
C_LIO_LIPatients with COVID-19 and close contacts show high cortical activation in temporo-parietal areas in alpha and beta bands compared to normative EEG database.
C_LIO_LIPatients with COVID-19 (positive PCR) have high activation in the right middle frontal gyrus for alpha band related to close contacts.
C_LI | | 6:45p |
Proteomic Analysis of Dorsal Root Ganglia in a Mouse Model of Paclitaxel-Induced Neuropathic Pain
Paclitaxel is a chemotherapy drug widely used for the treatment of various cancers based on its ability to potently stabilize microtubules blocking division in cancer cells. Paclitaxel-based treatment, however, accumulates in peripheral system sensory neurons and leads to a high incidence rate (over 60%) of chemotherapy induced peripheral neuropathy. Using an established preclinical model of paclitaxel-induced peripheral neuropathy (PIPN), we examined proteomic changes in dorsal root ganglia (DRG) of adult male mice that were treated with paclitaxel (8 mg/kg, at 4 injections every other day) at a concentration shown to induce mechanical and cold allodynia. High throughput proteomic analysis using liquid chromatography electrospray ionization mass spectrometry identified 165 significantly altered proteins within lumbar DRG in response to paclitaxel administration. Gene ontology enrichment and bioinformatic analysis revealed an effect of paclitaxel on key pathways for mitochondrial regulation, axonal function, and inflammatory as well as purinergic signaling. Proteomic findings also confirmed the effect of paclitaxel on microtubule properties within the DRG. Our findings provide insight into molecular mechanisms that can contribute to PIPN in patients. | | 11:46p |
Suppressing phagocyte activation by overexpressing the phosphatidylserine lipase ABHD12 preserves sarmopathic nerves
Programmed axon degeneration (AxD) is a key feature of many neurodegenerative diseases. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of AxD, preventing it from initiating the rapid local NAD+ depletion and metabolic catastrophe that precipitates axon destruction. Because these components of the AxD pathway act within neurons, it was also assumed that the timetable of AxD was set strictly by a cell-intrinsic mechanism independent of neuron-extrinsic processes later activated by axon fragmentation. However, using a rare human disease model of neuropathy caused by hypomorphic NMNAT2 mutations and chronic SARM1 activation (sarmopathy), we demonstrated that neuronal SARM1 can initiate macrophage-mediated axon elimination long before stressed-but-viable axons would otherwise succumb to cell-intrinsic metabolic failure. Investigating potential SARM1-dependent signals that mediate macrophage recognition and/or engulfment of stressed-but-viable axons, we found that chronic SARM1 activation triggers axonal blebbing and dysregulation of phosphatidylserine (PS), a potent phagocyte immunomodulatory molecule. Neuronal expression of the phosphatidylserine lipase ABDH12 suppresses nerve macrophage activation, preserves motor axon integrity, and rescues motor function in this chronic sarmopathy model. We conclude that PS dysregulation is an early SARM1-dependent axonal stress signal, and that blockade of phagocytic recognition and engulfment of stressed-but-viable axons could be an attractive therapeutic target for management of neurological disorders involving SARM1 activation. | | 11:46p |
Ketamine-Induced Unresponsiveness Shows a Harmonic Shift from Global to Localised Functional Organisation.
Ketamine is classified as a dissociative anaesthetic that, in sub-anaesthetic doses, can produce an altered state of consciousness characterised by dissociative symptoms, visual and auditory hallucinations, and perceptual distortions. Given the anaesthetic-like and psychedelic-like nature of this compound, it is expected to have different effects on brain dynamics in anaesthetic doses than in low, sub-anaesthetic doses. We investigated this question using connectome harmonic decomposition (CHD), a recently developed method to decompose brain activity in terms of the network organisation of the underlying human structural connectome. Previous research using this method has revealed connectome harmonic signatures of consciousness and responsiveness, with increased influence of global network structure in disorders of consciousness and propofol-induced sedation, and increased influence of localised patterns under the influence of classic psychedelics and sub-anaesthetic doses of ketamine, as compared to normal wakefulness. When we applied the CHD analytical framework to resting-state fMRI data of volunteers during ketamine-induced unresponsiveness, we found increased prevalence of localised harmonics, reminiscent of altered states of consciousness. This is different from traditional GABAergic sedation, where instead the prevalence of global rather than localised harmonics seems to increase with higher doses. In addition, we found that ketamine's harmonic signature shows higher alignment with those seen in LSD- or psilocybin-induced psychedelic states than those seen in unconscious individuals, whether due to propofol sedation or brain injury. Together, the results indicate that ketamine-induced unresponsiveness, which does not necessarily suppress conscious experience, seems to influence the prevalence of connectome harmonics in the opposite way compared to GABAergic hypnotics. We conclude that the CHD framework offers the possibility to track alterations in conscious awareness (e.g., dreams, sensations) rather than behavioural responsiveness - a discovery made possible by ketamine's unique property of decoupling these two facets. | | 11:46p |
Fluorescent identification of axons, dendrites and soma of neuronal retinal ganglion cells with a genetic marker as a tool for facilitating the study of neurodegeneration
This study characterizes a fluorescent Slc17a6-tdTomato neuronal reporter mouse line offering strong labeling in axons throughout the optic nerve, dendrites and soma in 99% of retinal ganglion cells (RGCs). The model facilitates neuronal assessment ex vivo with wholemounts quantified to show neurodegeneration following optic nerve crush or elevated IOP as related to glaucoma, in vitro with robust Ca2+ responses to P2X7 receptor stimulation in neuronal cultures, and in vivo using a confocal scanning laser ophthalmoscope (cSLO). While the tdTomato signal showed strong overlap with RGC markers, BRN3A and RBPMS, there was no cross-labeling of displaced amacrine cells in the ganglion cell layer. Controls indicated no impact of Slc17a6-tdTomato expression on light-dependent neuronal function, as determined with a microelectrode array (MEA), or on structure, as measured with optical coherence tomography (OCT). In summary, this novel neuronal reporter mouse model offers an effective means to increase the efficiency for real-time, specific visualization of retinal ganglion cells. It holds substantial promise for enhancing our understanding of RGC pathology in glaucoma and other diseases of the optic nerve, and could facilitate the screening of targeted therapeutic interventions for neurodegeneration. | | 11:46p |
Onset of α5GABA-A Receptor Dependent Hippocampal Trisynaptic Circuit Dysfunction Is Associated Increased Age and Blood Pressure
Hypertension onset with aging is of widespread clinical significance, predominantly in males, yet the neural circuitry underpinnings for hypertension associated memory dysfunction remains unknown. Sprague Dawley (SD) male but not female rats develop age dependent increases in mean arterial blood pressure (MAP) by 16 months of age. We sought to interrogate the functional integrity of the hippocampal trisynaptic circuit (HTC), which is known to participate in memory, to determine whether age-associated increases in MAP contributes to circuitry dysfunction that may lead to mild-cognitive impairment (MCR). Ripples, and specifically sharp-wave ripple oscillations, play a role in memory replay and consolidation during awake immobility among other behaviors. These synchronous high frequency local field potentials (LFPs) in the ripple band (140 to 200 Hz) serve as an HTC level surrogate marker for circuitry function in rodents, non-human primates, and humans. Thus, we asked whether age-associated increased MAP might alter ripple dynamics. Recognizing that each patient responds in a unique way to hypertension we used a within subject design wherein each animal served as its own control in the investigative model. We surgically implanted high density silicon probe electrodes in HTC CA1 of young and aged SD males to determine whether a nootropic drug, 5IA, a negative allosteric modulator of 5 subunit containing type-A GABA receptors, could detect aberrant modulation of ripples within each subject. Here we report that acute oral administration of 5IA selectively modulated ripple amplitude, but not its duration or frequency during epochs of awake immobility. The response of peak ripple amplitude to 5IA is substantially diminished when chronic MAP exceeds 160 mmHg, corresponding to significant hypertension. The results are consistent with a model in which age-associated increases in MAP is associated with dysfunctional 5 GABA-A receptor modulation of ripple amplitude, but not duration or frequency, as a potential precision biomarker for memory dysfunction. |
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