bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, September 7th, 2024
| Time |
Event |
| 8:32a |
Electrophysiological responses reveal a dedicated learning mechanism to process salient consonant sounds in human newborns
Isolating relevant sounds in the auditory stream is a crucial feature accomplished by human infants and a pivotal ability for language acquisition. Therefore, it is reasonable to postulate the existence of early mechanisms reorienting attention toward salient acoustic stimuli. Previous studies suggest that infants consider consonant sounds as more salient than dissonant ones, because the former resemble human vocalizations. However, systematic evidence investigating the neural processes underlying consonance tuning in newborns is still scarce. Here, we investigate newborns' ability to recognize and learn salient auditory stimuli by collecting Mismatch Responses (MMRs) to consonant and dissonant sounds and by computing the trial-by-trial correlation of the neural signal with Bayesian Surprise (a theoretical measure of learning). We present 22 healthy newborns (40.4 {+/-} 15.8 hours) with a pseudo-random sequence of deviant and standard auditory events, while we record their electroencephalogram. Our results show that newborns exhibit a neural encoding of auditory regularities for all sound types (consonant and dissonant), as demonstrated by the presence of MMRs and significant correlation of the neural signal with Bayesian Surprise. Furthermore, consonant and dissonant sounds elicited MMRs and correlations with Bayesian Surprise of opposite polarities, with consonant auditory stimulation evoking negative responses, reminiscent of an adult-like MMR. Overall, our findings suggest that newborns display a dedicated perceptual learning mechanism for salient consonant sounds. We speculate that this mechanism might represent an evolutionary-achieved neural tuning to detect and learn salient auditory stimuli with acoustic features resembling human vocalizations. | | 8:32a |
A hippocampal astrocytic sequence emerges during learning and memory
The dorsal hippocampus is a heterogeneous structure with numerous cell types involved in generating and maintaining detailed representations of space and time. Prior work has established that pyramidal cells contribute to these crucial aspects of episodic memory. For example, hippocampal "time cells" encode temporal information through sequential activity. However, the role of non-neuronal cell types are less often explored. In this study, we investigated dorsal hippocampal CA1 astrocytes using one-photon calcium imaging in freely moving animals during a contextual fear conditioning paradigm. To our knowledge, this is the first time a study has successfully performed longitudinal registration of astrocytic cell population using 1p calcium imaging, thus permitting the tracking of a stable population of these cells in freely-moving mice. In response to foot shock, astrocytes generated robust calcium-event sequences with a time-compressed structure akin to canonical hippocampal time cells. Upon re-exposure to the conditioned context, these astrocytic sequences persisted in the absence of shock, maintaining their time-compressed structure. Moreover, astrocytes active on the previous day retained a preserved sequential structure, indicating memory-specific properties. This phenomenon was not observed in a context different from the initial fear conditioning chamber. Taken together, these results present a potentially paradigm-shifting notion that astrocytes play a significant role in the representation of temporal information processing across learning and memory. | | 8:32a |
Like sisters but not twins - vasopressin and oxytocin excite BNST neurons via cell type-specific expression of oxytocin receptor to reduce anxious arousal
Interoceptive signals dynamically interact with the environment to shape appropriate defensive behaviors. Hypothalamic hormones arginine-vasopressin (AVP) and oxytocin (OT) regulate physiological states, including water and electrolyte balance, circadian rhythmicity, and defensive behaviors. Both AVP and OT neurons project to dorsolateral bed nucleus of stria terminalis (BNSTDL), which expresses oxytocin receptors (OTRs) and vasopressin receptors and mediates fear responses. However, understanding the integrated role of neurohypophysial hormones is complicated by the cross-reactivity of AVP and OT and their mutual receptor promiscuity. Here, we provide evidence that the effects of neurohypophysial hormones on BNSTDL excitability are driven by input specificity and cell type-specific receptor selectivity. We show that OTR-expressing BNSTDL neurons, excited by hypothalamic OT and AVP inputs, play a major role in regulating BNSTDL excitability, overcoming threat avoidance, and reducing threat-elicited anxious arousal. Therefore, OTR-BNSTDL neurons are perfectly suited to drive the dynamic interactions balancing external threat risk and physiological needs. | | 8:32a |
Fast and slow synaptic plasticity enables concurrent control and learning
During many tasks the brain receives real-time feedback about performance. What should it do with that information, at the synaptic level, so that tasks can be performed as well as possible? The conventional answer is that it should learn by incrementally adjusting synaptic strengths. We show, however, that learning on its own is severely suboptimal. To maximize performance, synaptic plasticity should also operate on a much faster timescale -- essentially, the synaptic weights should act as a control signal. We propose a normative plasticity rule that embodies this principle. In this, fast synaptic weight changes greedily suppress downstream errors, while slow synaptic weight changes implement statistically optimal learning. This enables near-perfect task performance immediately, efficient task execution on longer timescales, and confers robustness to noise and other perturbations. Applied in a cerebellar microcircuit model, the theory explains longstanding experimental observations and makes novel testable predictions. | | 8:32a |
ABBA, a novel tool for whole-brain mapping, reveals brain-wide differences in immediate early genes induction following learning
Unbiased characterization of whole-brain cytoarchitecture represents an invaluable tool for understanding brain function. For this, precise mapping of histological markers from 2D sections onto 3D brain atlases is pivotal. Here, we present two novel software tools facilitating this process: Aligning Big Brains and Atlases (ABBA), designed to streamline the precise and efficient registration of 2D sections to 3D reference atlases, and BraiAn, an integrated suite for multi-marker automated segmentation, whole-brain statistical analysis, and data visualisation. Combining these tools, we performed a comprehensive comparative study of the whole-brain expression of three of the most widely used immediate early genes (IEGs). Thanks to their neural activity-dependent expression, IEGs have been used for decades as a proxy of neural activity to generate unbiased mapping of activity following behaviour, but their respective induction in response to neuronal activation across the entire brain remains unclear. To address this question, we systematically compared the brain-wide expression cFos, Arc and NPAS4, three abundantly used IEGs, across three different behavioural conditions related to memory. Our results highlight major differences in both their distribution and induction patterns, indicating that they do not represent equivalent markers across brain areas or activity states, but can provide instead complementary information. | | 9:49a |
Acetylation of lysine 82 initiates TDP-43 nuclear loss of function by disrupting its nuclear import
The hallmark of a spectrum of age-dependent neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), is a TDP-43 proteinopathy that includes nuclear loss of function and cytoplasmic aggregation. Here, reduced proteasome activity, as naturally occurs during aging, is shown to inhibit nuclear import of TDP-43. Quantitative mass spectrometry is used to determine that TDP-43 is the protein whose nuclear localization is most perturbed upon reduction in proteasome activity, culminating in elevated cytoplasmic TDP-43. Interaction of importin-a1 with the bipartite classical nuclear localization sequence (cNLS) of TDP-43 is shown to be disrupted by partial proteasome inhibition but maintained by replacement with a PY-NLS that is recognized by importin-b2. Mechanistically, this nuclear depletion of TDP-43 is shown to be driven by ubiquitination or acetylation of lysines 79, 82, and 84 within the cNLS when proteasome activity is reduced in human neurons. Specifically, acetylation at lysine 82 is sufficient to abolish TDP-43 binding to importin-a1 and subsequent nuclear import of TDP-43. Moreover, using acetylation-specific TDP-43 antibodies, we detected acetylation of lysine 82 in the motor cortex of sporadic ALS patients but not control subjects. Our findings demonstrate that post-translational acetylation at lysine 82 of TDP-43 drives disruption of its importin-a1-mediated nuclear import and is sufficient to initiate TDP-43 nuclear loss of function and cytoplasmic accumulation, evidence supporting acetylation as a plausible initiator of TDP-43 proteinopathies. | | 4:18p |
Remote ischemic conditioning attenuates transneuronal degeneration and promotes stroke recovery via CD36-mediated efferocytosis.
BACKGROUND: Remote ischemic limb conditioning (RIC) has been implicated in cross-organ protection in cerebrovascular disease, including stroke. However, the lack of a consensus protocol and controversy over the clinical therapeutic outcomes of RIC suggest inadequate mechanistic understanding of RIC. The current study identifies RIC-induced molecular and cellular events in the blood that enhance long-term functional recovery in experimental cerebral ischemia. METHODS: Naive mice or mice subjected to transient ischemic stroke were randomly selected to receive sham conditioning or RIC in the hind limb at 2 h post-stroke. At 3d post-stroke, monocyte composition in the blood was analyzed, and brain tissue was examined for monocyte-derived macrophages (Mphi), levels of efferocytosis, and CD36 expression. Mouse with conditional deletion of CD36 in Mphi (cKOMMphi) was used to establish the role of CD36 in RIC-mediated modulation of efferocytosis, transneuronal degeneration, and recovery following stroke. RESULTS: RIC applied 2h after stroke increased entry of monocytes into the injured brain. In the post-ischemic brain, M? had increased levels of CD36 expression and efferocytosis. These changes in brain Mphi were derived from RIC-induced changes in circulating monocytes. In the blood, RIC increased CD36 expression in circulating monocytes and shifted monocytes to a proinflammatory LY6CHigh state. Conditional deletion of CD36 in Mphi abrogated the RIC-induced monocyte shift in the blood and efferocytosis in the brain. During the recovery phase of stroke, RIC rescued the loss of the volume and of tyrosine hydroxylase+ neurons in substantia nigra (SN) as well as behavioral deficits in WT mice, but not in cKOMMphi mice. CONCLUSIONS: RIC induces a shift in monocytes to a proinflammatory state with elevated CD36 levels, and this is associated with CD36-dependent efferocytosis in Mphis that rescues delayed transneuronal degeneration in the post-ischemic brain and promotes stroke recovery. Together, these findings provide novel insight into our mechanistic understanding of how RIC improves in post-stroke recovery. |
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