Biology subjects

Aton, S.

Publications and source records attributed to Aton, S..

6 recordsLinked to original sources

bioRxiv2021

Binocular vs. monocular recovery experience differentially promote recovery from visual deficits in a mouse model of amblyopia

Altered visual experience during monocular deprivation (MD) profoundly changes in ocular dominance (OD) in the developing primary visual cortex (V1). MD-driven changes in OD are an experimental model of amblyopia, where early-life alterations in vision lead visual disruption in adulthood. Current treatments for amblyopia include patching of the dominant eye, and more recently-developed binocular therapies. However, the relative impact of monocular vs. binocular recovery experiences on recovery of function in V1 is not well understood. Using single-unit recording, we compared how binocular recovery [BR] or reverse occlusion [RO] of identical duration and content affects OD and visual response recovery in mouse binocular V1 after a period of MD. We also tested how BR and RO affected MD-driven alterations of parvalbumin expression, and visually-driven expression of cFos in parvalbumin-positive and negative neurons. Finally, we tested how BR and RO affected recovery of normal visual acuity for the two eyes in the context of visually-driven behavior. We find that BR is quantitatively superior with respect to normalization of V1 neurons OD, visually-driven cFos expression, and visual acuity for the two eyes. However, MD-driven changes in the firing rate and response properties of V1 principal neuron and fast-spiking interneuron populations do not recover fully after either BR or RO. Binocular matching of orientation preference also remains disrupted in V1 neurons after both forms of recovery experience. Thus BR and RO, analogs of differing treatment regimens for amblyopia, differentially impact various aspects of visual recovery in a mouse model for amblyopia. Significance StatementAmblyopia resulting from altered childhood eye function is a leading cause of lifelong vision loss. Treatment typically involves patching of the dominant eye (forcing monocular visual experience), and produces only partial recovery of vision. Using a well-established mouse model of amblyopia, we directly compared how two types of visual experiences influence recovery of visual function. Our findings suggest that binocular vs. monocular visual experience differentially effect restoration of normal visual responses in cortical neurons, visually-driven neuronal gene expression, and visual acuity. Understanding how the quality of recovery experience impacts visual system recovery in amblyopia should provide critical insights for clinical strategies for its treatment.

neuroscience↗

bioRxiv2020

Sleep loss disrupts hippocampal memory consolidation via an acetylcholine- and somatostatin interneuron-mediated inhibitory gate

Sleep loss profoundly disrupts consolidation of hippocampus-dependent memory. To better characterize effects of learning and sleep loss on the hippocampal circuit, we quantified activity-dependent phosphorylation of ribosomal subunit S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 in enhanced in the dentate gyrus (DG) following single-trial contextual fear conditioning (CFC), but is reduced throughout the hippocampus after brief sleep deprivation (SD) - a manipulation which disrupts contextual fear memory (CFM) consolidation. To characterize cell populations with activity affected by SD, we used translating ribosome affinity purification (TRAP)-seq to identify cell type-specific transcripts on pS6 ribosomes after SD vs. sleep. Cell type-specific enrichment analysis (CSEA) of these transcripts revealed that hippocampal somatostatin-expressing (Sst+) interneurons, and cholinergic and orexinergic inputs to hippocampus, are selectively activated after SD. We used TRAP targeted to hippocampal Sst+ interneurons to identify cellular mechanisms mediating SD-driven Sst+ interneuron activation. We next used pharmacogenetics to mimic the effects of SD, selectively activating hippocampal Sst+ interneurons while mice slept in the hours following CFC. We find that activation of Sst+ interneurons is sufficient to disrupt CFM consolidation, by gating activity in surrounding pyramidal neurons. Pharmacogenetic inhibition of cholinergic input to hippocampus from the medial septum (MS) promoted CFM consolidation and disinhibited neurons in the DG, increasing pS6 expression. This suggests that state-dependent gating of DG activity is mediated by cholinergic input during SD. Together these data provide evidence for an inhibitory gate on hippocampal information processing, which is activated by sleep loss.

neuroscience↗

bioRxiv2020

Learning and Sleep Have Divergent Effects on Cytosolic and Membrane-Associated Ribosomal mRNA Profiles in Hippocampal Neurons

The hippocampus plays an essential role in consolidating transient experiences into long-lasting memories. Memory consolidation can be facilitated by post-learning sleep, although the underlying cellular mechanisms are undefined. Here, we addressed this question using a mouse model of hippocampally-mediated, sleep-dependent memory consolidation (contextual fear memory; CFM), which is known to be disrupted by post-learning sleep loss. We used translating ribosome affinity purification (TRAP) to quantify ribosome-associated RNAs in different subcellular compartments (cytosol and membrane) and in different hippocampal cell populations (either whole hippocampus, Camk2a+ excitatory neurons, or highly active neurons expressing phosphorylated ribosomal subunit S6 [pS6+]). Using RNA-seq, we examined how these transcript profiles change as a function of sleep vs. sleep deprivation (SD) and as a function of prior learning (contextual fear conditioning; CFC). Surprisingly, we found that while many mRNAs on cytosolic ribosomes were altered by sleep loss, almost none were altered by learning. Of the few changes in cytosolic ribosomal transcript abundance following CFC, almost all were occluded by subsequent SD. This effect was particularly pronounced in pS6+ neurons with the highest level of neuronal activity following CFC, suggesting SD-induced disruption of post-learning transcript changes in putative "engram" neurons. In striking contrast, far fewer transcripts on membranebound (MB) ribosomes were altered by SD, and many more mRNAs (and lncRNAs) were altered on MB ribosomes as a function of prior learning. For hippocampal neurons, cellular pathways most significantly affected by CFC were involved in structural remodeling. Comparisons of post-CFC transcript profiles between freely-sleeping and SD mice implicated changes in cellular metabolism in Camk2a+ neurons, and increased protein synthesis capacity in pS6+ neurons, as biological processes disrupted by post-learning sleep loss.

neuroscience↗

bioRxiv2020

Sleep loss drives brain region- and cell type-specific alterations in ribosome-associated transcripts involved in synaptic plasticity and cellular timekeeping

Sleep and sleep loss are thought to impact synaptic plasticity, and recent studies have shown that sleep and sleep deprivation (SD) differentially affect gene transcription and protein translation in the mammalian forebrain. However, much less is known regarding how sleep and SD affect these processes in different microcircuit elements within the hippocampus and neocortex - for example, in inhibitory vs. excitatory neurons. Here we use translating ribosome affinity purification (TRAP) and in situ hybridization to characterize the effects of sleep vs. SD on abundance of ribosome-associated transcripts in Camk2a-expressing (Camk2a+) pyramidal neurons and parvalbumin-expressing (PV+) interneurons in mouse hippocampus and neocortex. We find that while both Camk2a+ neurons and PV+ interneurons in neocortex show concurrent SD-driven increases in ribosome-associated transcripts for activity-regulated effectors of plasticity and transcriptional regulation, these transcripts are minimally affected by SD in hippocampus. Similarly we find that while SD alters several ribosome-associated transcripts involved in cellular timekeeping in neocortical Camk2a+ and PV+ neurons, effects on circadian clock transcripts in hippocampus are minimal, and restricted to Camk2a+ neurons. Taken together, our results indicate that SD effects on transcripts destined for translation are both cell type- and brain region-specific, and that these effects are substantially more pronounced in the neocortex than the hippocampus. We conclude that SD-driven alterations in the strength of synapses, excitatory-inhibitory balance, and cellular timekeeping are likely more heterogeneous than previously appreciated. Significance StatementSleep loss-driven changes in transcript and protein abundance have been used as a means to better understand the function of sleep for the brain. Here we use translating ribosome affinity purification (TRAP) to characterize changes in abundance of ribosome-associated transcripts in excitatory and inhibitory neurons in mouse hippocampus and neocortex after a brief period of sleep or sleep loss. We show that these changes are not uniform, but are generally more pronounced in excitatory neurons than inhibitory neurons, and more pronounced in neocortex than in hippocampus.

neuroscience↗

bioRxiv2020

Non-REM sleep facilitates consolidation of contextual fear memory through temporal coding among hippocampal neurons

Sleep plays a critical role in memory consolidation, although the exact mechanisms mediating this process are unknown. Combining computational and in vivo experimental approaches, we test the hypothesis that reduced cholinergic input to the hippocampus during non-rapid eye movement (NREM) sleep generates stable spike timing relationships between neurons. We find that the order of firing among neurons during a period of NREM sleep reflects their relative firing rates during prior wake, and changes as a function of prior learning. We show that learning-dependent pattern formation (e.g. "replay") in the hippocampus during NREM, together with spike timing dependent plasticity (STDP), restructures network activity in a manner similar to that observed in brain circuits across periods of sleep. This suggests that sleep actively promotes memory consolidation by switching the network from rate-based to firing phase-based information encoding.

neuroscience↗

bioRxiv2020

Causal role for sleep-dependent reactivation of learning-activated sensory ensembles for fear memory consolidation

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation.

neuroscience↗