bioRxiv Subject Collection: Neuroscience's Journal
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Wednesday, May 22nd, 2024
| Time |
Event |
| 12:46a |
Opioid Modulation of Differential Gene Expression and Neuronal Differentiation in the Ventricular-Subventricular Zone of Adult Male Zebra Finches
The endogenous opioid system modulates diverse functions including pain, physiological functions and motivation. We had earlier demonstrated an increase in cell proliferation in the neurogenic niche of adult male zebra finches, following administration of the general opioid antagonist, naloxone. Since the mechanisms underlying opioid modulation of neurogenesis are poorly understood, we have investigated the molecular mechanisms underlying cell proliferation differentiation induced by the opioid system. Systemic naloxone or vehicle administration in adult male birds was followed by a whole transcriptome microarray assay of the ventricular-subventricular zone (V-SVZ). The analysis revealed 26 differentially expressed transcripts (expression fold change [≥] 1.5), encoding genes important for neuronal functions. The transcriptomics analysis using microarray identified a significant increase in the expression of precursor miRNA tgu-mir-124-201 transcript following inhibition of opioid receptors by naloxone. Our results suggested that the administration of naloxone triggers an increase in the expression of the pro-differentiating microRNA, miR-124, in the brains of adult zebra finches. Using quantitative real-time PCR, we found that the expression of miR-124-3p was higher in the V-SVZ of naloxone-treated versus control birds. Furthermore, the density of neuroblasts was higher in the ventral V-SVZ adjacent to the striatal nucleus Area X, but not in the V-SVZ above the pallial nucleus, HVC, both of which are involved in singing. Since miR-124 targets signalling pathways important for neuronal proliferation and differentiation, our findings suggest that microRNA-124 may be involved in the increase in neurogenesis in adult songbirds induced by altering opioid modulation. | | 1:15a |
Medial temporal lobe atrophy patterns in early- versus late-onset amnestic Alzheimer's disease
Background: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfield volumes and drivers of atrophy in amnestic EOAD is lacking. Methods: BioFINDER-2 participants with memory impairment, abnormal amyloid-beta status and tau-PET were included. Forty-one EOAD individuals aged <65 years and, as comparison, late-onset AD (LOAD, >70 years, n=154) and amyloid-beta-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. Results: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups, although LOAD showed thinner entorhinal cortices compared to EOAD. EOAD showed lower WMH compared to LOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity was found. Conclusions: We found in vivo evidence for MTL atrophy in amnestic EOAD and overall similar levels to LOAD of MTL tau pathology and co-pathologies. | | 1:47a |
Facial expression recognition is modulated by approach-avoidance behavior
Facial expression recognition influences approach-avoidance behaviors, but do approach-avoidance behaviors affect facial expression recognition? We conducted psychophysical experiments to this end, indicating a reverse causal relationship. In a virtual reality space, 3D face stimulus facial expressions varied on seven level, from happy to angry in Experiments 1 and 3 and from happy to fearful in Experiment 2. Participants were asked to perform according to one of the following conditions in response to the stimulus. Participants 1) approached (one-meter forward), 2) avoided (one-meter backward), 3) were approached by, or 4) were avoided by the 3D model. Then, participants selected facial expressions. Experiment 1 revealed that participants recognized the face as angrier when they avoided it rather than when it avoided them. Experiment 2 showed that participants recognized the face as happy when approaching and fearful when avoiding, irrespective of who acted. Experiment 3 revealed that participants recognized the face as angrier when the face approached them rather than when they approached if both parties were physically close. Accordingly, approach-avoidance behavior changes facial expression recognition, indicating a reverse causal relationship. We posit that unconscious learning rooted in biological instincts creates this connection. | | 1:47a |
FDA-Approved MEK1/2 Inhibitor, Trametinib, Protects Mice from Cisplatin and Noise-Induced Hearing Loss
Hearing loss is one of the most common types of disability; however, there is only one FDA-approved drug to prevent any type of hearing loss. Treatment with the highly effective chemotherapy agent, cisplatin, and exposure to high decibel noises are two of the most common causes of hearing loss. The mitogen activated protein kinase (MAPK) pathway, a phosphorylation cascade consisting of RAF, MEK1/2, and ERK1/2, has been implicated in both types of hearing loss. Pharmacologically inhibiting BRAF or ERK1/2 is protective from noise and cisplatin-induced hearing loss in multiple mouse models. Trametinib, a MEK1/2 inhibitor, protects from cisplatin induced outer hair cell death in mouse cochlear explants; however, to the best of our knowledge, inhibiting MEK1/2 has not yet been shown to be protective from hearing loss in vivo. In this study, we demonstrate that trametinib protects from cisplatin-induced hearing loss in a translationally relevant mouse model and does not interfere with cisplatin's tumor killing efficacy in cancer cell lines. Higher doses of trametinib were toxic to mice when combined with cisplatin but lower doses of the drug were protective from hearing loss without any known toxicity. Trametinib also protected mice from noise-induced hearing loss and synaptic damage. This study shows that MEK1/2 inhibition protects from both insults of hearing loss and that targeting all three kinases in the MAPK pathway protect from cisplatin and noise-induced hearing loss in mice. | | 1:47a |
Discriminating neural ensemble patterns through dendritic computations in randomly connected feedforward networks
Co-active or temporally ordered neural ensembles are a signature of salient sensory, motor, and cognitive events. Local convergence of such patterned activity as synaptic clusters on dendrites could help single neurons harness the potential of dendritic nonlinearities to decode neural activity patterns. We combined theory and simulations to assess the likelihood of whether projections from neural ensembles could converge onto synaptic clusters even in networks with random connectivity. Using rat hippocampal and cortical network statistics, we show that clustered convergence of axons from 3-4 different co-active ensembles is likely even in randomly connected networks, leading to representation of arbitrary input combinations in at least ten target neurons in a 100,000 population. In the presence of larger ensembles, spatiotemporally ordered convergence of 3-5 axons from temporally ordered ensembles is also likely. These active clusters result in higher neuronal activation in the presence of strong dendritic nonlinearities and low background activity. We mathematically and computationally demonstrate a tight interplay between network connectivity, spatiotemporal scales of subcellular electrical and chemical mechanisms, dendritic nonlinearities, and uncorrelated background activity. We suggest that dendritic clustered and sequence computation is pervasive, but its expression as somatic selectivity requires confluence of physiology, background activity, and connectomics. | | 2:16a |
Melanin-concentrating hormone promotes feeding through the lateral septum
Feeding is necessary for survival but can be hindered by anxiety or fear, thus neural systems that can regulate anxiety states are key to elucidating the expression of food-related behaviors. Melanin-concentrating hormone (MCH) is a neuropeptide produced in the lateral hypothalamus that promotes feeding and anxiogenesis. The orexigenic actions of MCH that prolong ongoing homeostatic or hedonic feeding are context-dependent and more prominent in male than female rodents, but it is not clear where MCH acts to initiate feeding. The lateral septum (LS) promotes feeding and suppresses anxiogenesis when inhibited, and it comprises the densest projections from MCH neurons. However, it is not known whether the LS is a major contributor to MCH-mediated feeding. As MCH inhibits LS cells by MCH receptor (MCHR1) activation, MCH may promote feeding via the LS. We bilaterally infused MCH into the LS and found that MCH elicited a rapid and long-lasting increase in the consumption of standard chow and a palatable, high sugar diet in male and female mice; these MCH effects were blocked by the co-administration of a MCHR1 antagonist TC- MCH 7c. Interestingly, the orexigenic effect of MCH was abolished in a novel, anxiogenic environment even when presented with a food reward, but MCH did not induce anxiety-like behaviors. These findings indicated the LS as a novel region underlying orexigenic MCH actions, which stimulated and enhanced feeding in both sexes in a context -dependent manner that was most prominent in the homecage. | | 10:17a |
Temporal Coherence Shapes Cortical Responses to Speech Mixtures in a Ferret Cocktail Party
Segregation of complex sounds such as speech, animal vocalizations, and music simultaneously emanating from multiple sources, referred to as the cocktail party problem is a remarkable ability that is common in humans and animals alike. The neural underpinnings of this process have been extensively studied behaviorally and physiologically in non-human animals primarily with simplified sounds (tones and noise sequences). In humans, segregation experiments utilizing more complex speech mixtures are common; but physiological experiments have relied on EEG/MEG/ECoG recordings that sample activity from many thousands of neurons, often obscuring the detailed processes that give rise to the observed segregation. The present study combines the insights attainable from animal single-unit physiology with segregation of speech- like mixtures. Ferrets were trained to attend to a female voice in a mixture of two simultaneous, equally salient male and female voices. The animals reliably detected a target female word, both when present in the female stream alone, or when embedded in a male/female voice mixture. Neural representation of the stimuli was recorded in single neurons in the primary and secondary ferret auditory cortical fields, as well as in the frontal cortex. During task performance, representation of the female words became more enhanced relative to those of the (distractor) male in all the cortical regions, especially in the higher auditory cortical field. Analysis of the temporal and spectral response characteristics during task performance reveals how speech segregation gradually emerges in the auditory cortex. A computational model evaluated on the same voice mixtures replicates and extends these results to different attentional targets (attention to female or male voices). These findings are consistent with the temporal coherence theory whereby attention to a target voice anchors neural activity in cortical networks hence binding together channels that are coherent with the target, and ultimately forming a common auditory stream. The experimental and modeling results shed light on neural correlates of streaming percepts. | | 10:17a |
Norepinephrine Signals Through Astrocytes To Modulate Synapses
Locus coeruleus (LC)-derived norepinephrine (NE) drives network and behavioral adaptations to environmental saliencies by reconfiguring circuit connectivity, but the underlying synapse-level mechanisms are elusive. Here, we show that NE remodeling of synaptic function is independent from its binding on neuronal receptors. Instead, astrocytic adrenergic receptors and Ca2+ dynamics fully gate the effect of NE on synapses as the astrocyte-specific deletion of adrenergic receptors and three independent astrocyte-silencing approaches all render synapses insensitive to NE. Additionally, we find that NE suppression of synaptic strength results from an ATP-derived and adenosine A1 receptor-mediated control of presynaptic efficacy. An accompanying study from Chen et al. reveals the existence of an analogous pathway in the larval zebrafish and highlights its importance to behavioral state transitions. Together, these findings fuel a new model wherein astrocytes are a core component of neuromodulatory systems and the circuit effector through which norepinephrine produces network and behavioral adaptations, challenging an 80-year-old status quo. | | 10:17a |
How cortico-basal ganglia-thalamic subnetworks can shift decision policies to maximize reward rate
All mammals exhibit flexible decision policies that depend, at least in part, on the cortico-basal ganglia-thalamic (CBGT) pathways. Yet understanding how the complex connectivity, dynamics, and plasticity of CBGT circuits translates into experience-dependent shifts of decision policies represents a longstanding challenge in neuroscience. Here we used a computational approach to address this problem. Specifically, we simulated decisions driven by CBGT circuits under baseline, unrewarded conditions using a spiking neural network, and fit the resulting behavior to an evidence accumulation model. Using canonical correlation analysis, we then replicated the existence of three recently identified control ensembles (responsiveness, pliancy and choice) within CBGT circuits, with each ensemble mapping to a specific configuration of the evidence accumulation process. We subsequently simulated learning in a simple two-choice task with one optimal (i.e., rewarded) target. We find that value-based learning, via dopaminergic signals acting on cortico-striatal synapses, effectively manages the speed-accuracy tradeoff so as to increase reward rate over time. Within this process, learning-related changes in decision policy can be decomposed in terms of the contributions of each control ensemble, and these changes are driven by sequential reward prediction errors on individual trials. Our results provide a clear and simple mechanism for how dopaminergic plasticity shifts specific subnetworks within CBGT circuits so as to strategically modulate decision policies in order to maximize effective reward rate. | | 10:17a |
Temporal-Coherence Induces Binding in Responses to Sound Sequences in Ferret Auditory Cortex
Binding the attributes of a sensory source is necessary to perceive it as a unified entity, one that can be attended to and extracted from its surrounding scene. In auditory perception, this is the essence of the cocktail party problem in which a listener segregates one speaker from a mixture of voices, or a musical stream from simultaneous others. It is postulated that coherence of the temporal modulations of a source's features is necessary to bind them. The focus of this study is on the role of temporal-coherence in binding and segregation, and specifically as evidenced by the neural correlates of rapid plasticity that enhance cortical responses among synchronized neurons, while suppressing them among asynchronized ones. In a first experiment, we find that attention to a sound sequence rapidly binds it to other coherent sequences while suppressing nearby incoherent sequences, thus enhancing the contrast between the two. In a second experiment, a sequence of synchronized multi-tone complexes (figure), embedded in a cloud of randomly dispersed desynchronized tones (ground), perceptually and neurally pops-out after a fraction of a second highlighting the binding among its coherent tones against the incoherent background. These findings demonstrate the role of temporal-coherence in binding and segregation. | | 2:00p |
Acute drug induced parkinsonian akinesia is associated with reduced rate and increased regularity of neuronal activity in the pedunculopontine tegmental nucleus of unanesthetized rats
The pedunculopontine tegmental nucleus of the brainstem is important for a wide range of functions, including sensorimotor integration and regulation of locomotion and discrete forelimb movements. Evidence suggests it is structurally disordered as part of the neuropathology of the movement disorder Parkinsons disease. To assess whether neuronal activity is also affected in parkinsonian model animals we used single neuron recordings in free moving rats to determine the effects of acute drug-induced parkinsonism on the firing rate of the neurons. Acute parkinsonian akinesia was associated with reduction in resting firing rate and increased firing regularity, consistent with reduced excitability in this state. |
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