bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, March 9th, 2024
| Time |
Event |
| 4:44a |
Repeated Binge Alcohol Drinking Leads to Reductions in Corticostriatal Theta Coherence in Female but not Male Mice
Decreased functional connectivity between the striatum and frontal cortex is observed in individuals with alcohol use disorder (AUD), and predicts the probability of relapse in abstinent individuals with AUD. To further our understanding of how repeated alcohol (ethanol; EtOH) consumption impacts the corticostriatal circuit, extracellular electrophysiological recordings (local field potentials; LFPs) were gathered from the nucleus accumbens (NAc) and prefrontal cortex (PFC) of C57BL/6J mice voluntarily consuming EtOH or water using a "drinking-in-the-dark" (DID) procedure. Following a three-day acclimation period wherein only water access was provided during DID, mice were given 15 consecutive days of access to EtOH. Each session consisted of a 30-minute baseline period where water was available and was followed immediately by a 2-hour period where sippers containing water were replaced with new sippers containing either unsweetened 20% (v/v) EtOH (days 4-18; DID) or water (days 1-3; acclimation). Our analyses focused primarily on theta coherence during bouts of drinking, as differences in this band are associated with several behavioral markers of an AUD. Both sexes displayed decreases in theta coherence during the first day of binge EtOH consumption. However, only females displayed further decreases in theta coherence on the 14th day of EtOH access. No differences in theta coherence were observed between the first and final bout on any EtOH drinking days. These results provide additional support for decreases in the functional coupling of corticostriatal circuits as a consequence of alcohol consumption, and suggests that female mice are uniquely vulnerable to these effects following repeated EtOH drinking. | | 5:39a |
Identification of Druggable Binding Sites and Small Molecules as Modulators of TMC1
The sensory hair cells of the inner ear use the mechano-electrical transducer (MET) channels to convert the mechanical stimuli from sound or acceleration into electrical signals, allowing us to perceive sound and maintain balance. The pore-forming subunit of the MET channel is formed by Transmembrane channel-like (TMC) 1 and 2 proteins, which are nonselective cationic channels that also allow the permeation of ototoxic aminoglycosides and cisplatin into hair cells. In search for otoprotective compounds, numerous molecules have been reported to block and modulate the properties of the MET channels. One of them, the styryl fluorescent probe FM1-43, and its analogue AM1-43, are commonly used to evaluate MET channel functionality. However, the mechanism of interaction of these modulators with the TMCs remains largely unknown. In this work, we implemented both computational and experimental approaches to identify novel TMC1 modulators using in silico 3D-pharmacophore approach and free energy binding calculations. Our 3D-pharmacophore contains the structural features necessary for ligands to bind and modulate the activity of TMC1. It consists of two aromatic groups, one acceptor group, and at least one protonatable amine. The pipeline we implemented successfully identified several novel TMC1 compound modulators, which reduced dye uptake in cultured cochlear explants, indicating MET modulation activity. Our molecular docking and MM-GBSA experiments allowed us to identify three potential drug binding sites within the TMC1 pore. Furthermore, our study also supports the ligand-binding relationship between the TMC and TMEM16 proteins, providing novel insights suggesting that these proteins share common 3D-pharmacophoric features for their inhibition. | | 7:31a |
The auditory midbrain mediates tactile vibration sensing
Vibrations are ubiquitous in nature, shaping behavior across the animal kingdom. For mammals, sound waves traveling through air are captured by the cochlea and the neural signals they generate are encoded in the auditory system. Mechanical vibrations acting on the body are detected by mechanoreceptors of the skin and deep tissue and processed by the somatosensory system. As such, the neural pathways that underlie perception and reaction to sound waves and mechanical vibrations are believed to be anatomically distinct and functionally independent. Here, we report that mechanical vibrations are prominently encoded by neurons in the lateral cortex of the inferior colliculus (LCIC) of the auditory midbrain. LCIC responses to environmental vibrations are mediated by A{beta} rapidly adapting (RA)-LTMRs associated with Pacinian corpuscles, which are exquisitely sensitive and unique in their ability to entrain to high frequency (40-1000 Hz) environmental vibrations. Remarkably, most LCIC neurons are dual somatosensory and auditory environmental vibration detectors. Moreover, the LCIC is required for behavioral responses to high frequency mechanical vibrations, but not other somatosensory modalities. Thus, environmental vibrations captured by Pacinian corpuscles of the body are encoded in the auditory midbrain to mediate behavior. | | 7:31a |
Monitoring myelin lipid composition and structure of myelinated fibers reveals a maturation delay in CMT1A
Findings accumulated over time show that neurophysiological, neuropathological, and molecular alterations are present in CMT1A and support the dysmyelinating rather than demyelinating nature of this neuropathy. Moreover, uniform slowing of nerve conduction velocity is already manifest in CMT1A children and does not improve throughout their life. This evidence and our previous studies displaying aberrant myelin composition and structure in adult CMT1A rats prompt us to hypothesize a myelin and axon developmental defect in the CMT1A peripheral nervous system. Peripheral myelination begins during the early stages of development in mammals and, during this process, chemical and structural features of myelinated fibers (MFs) evolve towards a mature phenotype; deficiencies within this self-modulating circuit can cause its blockage. Therefore, to shed light on pathophysiological mechanisms that occur during development, and to investigate the relationship among axonal, myelin, and lipidome deficiencies in CMT1A, we extensively analyzed the evolution of both myelin lipid profile and MF structure in WT and CMT1A rats. Lipidomic analysis revealed a delayed maturation of CMT1A myelin already detectable at P10 characterized by deprivation of sphingolipid species such as hexosylceramides and long-chain sphingomyelins, whose concentration physiologically increases in WT, and an increase in lipids typical of unspecialized plasma membranes, including phosphatidylcholines and phosphatidylethanolamines. Consistently, advanced morphometric analysis on more than 130.000 MFs revealed a delay in the evolution of CMT1A axon and myelin geometric parameters, appearing concomitantly with lipid impairment. We here demonstrate that, during normal development, MFs undergo a continuous maturation process in both chemical composition and physical structure, but these processes are delayed in CMT1A. | | 7:31a |
Neurobiological Changes Across Pregnancy: A Longitudinal Investigation
Pregnancy is a period of profound biological transformation. However, we know remarkably little about pregnancy-related brain changes. To address this gap, we charted longitudinal changes in brain structure during pregnancy and explored potential mechanisms driving these changes. Ten participants (Mean age = 28.97 years) were assessed 1-6 times (median = 3) during their pregnancy. Each visit included anatomical and diffusion-weighted MRI, and assessments of waking salivary hormones, hair hormones, and inflammatory cytokines. Reductions in gray matter volume were found by gestational week. Neurite Density Index (NDI), a proxy of axon density, in white matter tracts increased across pregnancy, especially in tracts linked to sensorimotor processing. Progesterone levels were associated with reductions in brain volumetric measurements, and both progesterone and estradiol levels were linked to increases in NDI in white matter tracts. This study highlights the profound neurobiological changes experienced by pregnant individuals and provides insight on neuroplasticity in adulthood. | | 7:31a |
Diffusion kurtosis MRI tracks gray matter myelin content in the primate cerebral cortex
Diffusion magnetic resonance imaging (dMRI) has been widely employed to model the trajectory of myelinated fiber bundles in white matter. Increasingly, dMRI is also used to assess local tissue properties throughout the brain. In the cerebral cortex, myelin content is a critical indicator of the maturation, regional variation, and disease related degeneration of gray matter tissue. Gray matter myelination can be measured and mapped using several non-diffusion MRI strategies; however, first order diffusion statistics such as fractional anisotropy (FA) show only weak spatial correlation with cortical myelin content. Here we show that a simple higher order diffusion parameter, the mean diffusion kurtosis (MK), is strongly correlated with the laminar and regional variation of myelin in the primate cerebral cortex. We carried out ultra-high resolution, multi-shelled dMRI in ex vivo marmoset monkey brains and compared dMRI parameters from a number of higher order models (diffusion kurtosis, NODDI and MAP MRI) to the distribution of myelin obtained using histological staining, and via Magnetization Transfer Ratio MRI (MTR), a non-diffusion MRI method. In contrast to FA, MK closely matched the myelin content assessed by histology and by MTR in the same sample. The parameter maps from MAP-MRI and NODDI also showed good correspondence with cortical myelin content. The results demonstrate that dMRI can be used to assess the variation of local myelin content in the primate cortical cortex, which may be of great value for assessing tissue integrity and tracking disease in living human patients. | | 7:31a |
Blocking Src-PSD-95 interaction rescues glutamatergic signaling dysregulation in schizophrenia.
The complex and heterogeneous genetic architecture of schizophrenia inspires us to look beyond individual risk genes for therapeutic strategies and target their interactive dynamics and convergence. Postsynaptic NMDA receptor (NMDAR) complexes are a site of such convergence. Src kinase is a molecular hub of NMDAR function, and its protein interaction subnetwork is enriched for risk-genes and altered protein associations in schizophrenia. Previously, Src activity was found to be decreased in post-mortem studies of schizophrenia, contributing to NMDAR hypofunction. PSD-95 suppresses Src via interacting with its SH2 domain. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 via employingacell penetrating andSrc activating PSD-95 inhibitory peptide(TAT-SAPIP). TAT-SAPIPselectively increased post-synaptic Src activity in humans and mice, andenhanced synaptic NMDAR currents in mice.Chronic ICV injection ofTAT-SAPIPrescued deficits intrace fear conditioning in Src hypomorphic mice.We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses. | | 7:31a |
Midbrain Dopaminergic Neuron Development is Regulated by Two Molecularly Distinct Subtypes of Radial Glia Cells
Understanding midbrain dopaminergic (mDA) neuron development is key to advancing cell replacement therapies for Parkinson's disease (PD). Recent single-cell RNA-sequencing (scRNA-seq) studies have identified different subtypes of transient radial glia (Rgl) cell types in the developing mouse and human ventral midbrain. However, their individual functions and their impact on mDA neuron development are unclear. Here we analyze the transcriptome of endogenous mouse and human ventral midbrain Rgl and assess the function of key midbrain floor plate Rgl factors in human stem cells during mDA neuron differentiation. We find that Rgl1 is defined by a neurogenic network centered on Arntl, and that this transcription factor regulates human mDA neurogenesis. Conversely, the transcriptome of Rgl3 is dominated by signaling and extracellular matrix molecules that control different aspects of human mDA neuron development. Thus, our results suggest a function of Rgl1 as a mDA progenitor, and of Rgl3 as a signaling mDA niche cell. Moreover, using human stem cells we demonstrate that new knowledge of cell-type specific intrinsic and extrinsic developmental factors can readily be applied to improve the generation of cells with therapeutic interest, such as human mDA neurons for PD. | | 7:31a |
Striatal Dopamine Modulates Temporal Surprise P3a
Dopamine is vital in forming mental models of 'what' and 'when' sensory events occur that essentially guide goal-directed behaviour. However, it remains largely unknown how variations in temporal predictability are incorporated into such mental models. A better understanding of the underlying mechanisms is important, considering dopaminergic depletion in diseases such as Parkinson's Disease and Schizophrenia, where abnormal temporal processing is observed. Some electroencephalographic (EEG) studies indicate that noradrenergic mechanisms, as reflected in the P3b event-related potential, are modulated by temporal predictability, whereas others indicate that dopaminergic mechanisms as reflected in the P3a, underlie surprise. In this study, resting-state and task-dependent EEG was recorded from 24 healthy participants who were administered a selective D2 agonist or antagonist before they performed a pure tone auditory 'oddball' task. Two oddball sequences included either partially predictable, with inter-stimulus intervals (ISIs) of 400ms/1200ms; or fully temporally predictable tones, with a consistent ISI of 600ms. Tones following 400ms ISIs were perceived as surprising, or 'early', as shown in an enhanced P3a response; tones following a 1200ms ISIs showed a much reduced P3a response ('late'). The agonist accentuated the 'late' effect, demonstrating that drugs targeting D2 receptors modulate temporal prediction. These findings differentiate the role of the dopaminergic system in temporal processing and model-based auditory predictions. | | 7:31a |
Engineering an in vitro retinothalamic nerve model
Understanding the retinothalamic pathway in vitro can offer insights into its development and potential for future therapeutic applications. This study presents a Polydimethylsiloxane-based two-chamber system with axon guidance channels, designed to replicate unidirectional retinothalamic signal transmission in vitro. The system enables the formation of up to 20 identical functional retinothalamic networks on a single transparent microelectrode array. Using embryonic rat retinas, we developed a model where retinal spheroids innervate thalamic targets through up to 6~mm long microfluidic channels. We found that network integrity depends on channel length, with 0.5-2 mm channels maintaining over 90 % morphological and 40 % functional integrity. A reduced network integrity was recorded in longer channels. The results indicate a notable reduction in forward spike propagation in channels longer than 4 mm. Additionally, spike conduction fidelity decreased with increasing channel length. Yet, stimulation-induced thalamic target activity remained unaffected by channel length. Finally, we assessed the impact of stimulation frequency and channel length on the sustainability of the thalamic target spheroid response. The study found that a sustained thalamic calcium response could be elicited with stimulation frequencies up to 31 Hz, with higher frequencies leading to transient responses. In conclusion, this study shows how channel length affects retinothalamic network formation and signal transmission in vitro. |
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