Biology subjects

Aton, S. J.

Publications and source records attributed to Aton, S. J..

5 recordsLinked to original sources

bioRxiv2026

DREADD agonist Clozapine-N-oxide, but not Compound 21, impairs spatial memory encoding

Chemogenetic studies using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable the precise manipulation of neuronal activity in specific brain regions and cell types. DREADDs are widely used to dissect neural circuits underlying animal behavior, including learning and memory. Clozapine-N-Oxide (CNO), a metabolite of clozapine and one of the earliest-developed ligands for muscarinic DREADDs, was initially considered pharmacologically inert. However, CNO is now known to undergo back-metabolism to clozapine, leading to undesired off-target behavioral effects, including alterations in locomotion and anxiety-related behaviors. New ligands such as Compound 21 (C21) have been developed to improve selectivity and reduce these effects. However, despite their widespread use, no studies to date have directly compared the effects of CNO and C21 themselves on specific cognitive processes such as hippocampus-dependent memory formation. Here, we measured acute effects of CNO and C21 on spatial memory encoding, using an object-location memory (OLM) paradigm in male and female mice. We also quantified encoding-associated hippocampal principal neuron and parvalbumin (PV+) interneuron activity by measuring cFos expression in these populations. Across dorsal hippocampal subregions, neither ligand altered overall neuronal activity nor PV+ interneuron activity during encoding. Nonetheless, we find that CNO administration impairs OLM encoding, while C21 does not. Together, these findings highlight a previously unrecognized behavioral effect of CNO administration on hippocampus-dependent memory formation--even in the absence of DREADD expression--and indicate that C21 may be a preferable ligand for chemogenetic studies examining memory and hippocampal function.

neuroscience↗

bioRxiv2024

Brief sleep disruption alters synaptic structures among hippocampal and neocortical somatostatin-expressing interneurons

Study objectivesBrief sleep loss alters cognition and synaptic structures of principal neurons in hippocampus and neocortex. However, while in vivo recording and bioinformatic data suggest that inhibitory interneurons are more strongly affected by sleep loss, it is unclear how sleep and sleep deprivation affect interneurons synapses. Disruption of the SST+ interneuron population seems to be a critical early sign of neuropathology in Alzheimers dementia, schizophrenia, and bipolar disorder - and the risk of developing all three is increased by habitual sleep loss. We aimed to test how the synaptic structures of SST+ interneurons in various brain regions are affected by brief sleep disruption. MethodsWe used Brainbow 3.0 to label SST+ interneurons in the dorsal hippocampus, prefrontal cortex, and visual cortex of male SST-CRE transgenic mice, then compared synaptic structures in labeled neurons after a 6-h period of ad lib sleep, or gentle handling sleep deprivation (SD) starting at lights on. ResultsDendritic spine density among SST+ interneurons in both hippocampus and neocortex was altered in a subregion-specific manner, with increased overall and thin spine density in CA1, dramatic increases in spine volume and surface area in CA3, and small but significant changes (primarily decreases) in spine size in CA1, PFC and V1. ConclusionsOur suggest that the synaptic connectivity of SST+ interneurons is significantly altered in a brain region-specific manner by a few hours of sleep loss. This suggests a cell type-specific mechanism by which sleep loss disrupts cognition and alters excitatory-inhibitory balance in brain networks. Significance StatementChanges to the function of somatostatin-expressing (SST+) interneurons have been implicated in the etiology of psychiatric and neurological disorders in which both cognition and sleep behavior are affected. Here, we measure the effects of very brief experimental sleep deprivation on synaptic structures of SST+ interneurons in hippocampus and neocortex, in brain structures critical for sleep-dependent memory processing. We find that only six hours of sleep deprivation restructures SST+ interneurons dendritic spines, causing widespread and subregion-specific changes to spine density and spine size. These changes have the potential to dramatically alter excitatory-inhibitory balance across these brain networks, leading to cognitive disruptions commonly associated with sleep loss.

neuroscience↗

bioRxiv2022

Atypical hypnotic compound ML297 restores sleep architecture following emotionally-valenced learning, to promote memory consolidation and hippocampal network activation during recall

Sleep plays a critical role in consolidating many forms of hippocampus-dependent memory. While various classes of hypnotic drugs have been developed in recent years, it remains unknown whether, or how, some of them affect sleep-dependent memory consolidation mechanisms. We find that ML297, a recently-developed candidate hypnotic agent targeting a new mechanism (activating GIRK1-subunit containing G-protein coupled inwardly rectifying potassium [GIRK] channels), alters sleep architecture in mice over the first 6 h following a single-trial learning event. Following contextual fear conditioning (CFC), ML297 reversed post-CFC reductions in NREM sleep spindle power and REM sleep amounts and architecture, renormalizing sleep features to what was observed at baseline, prior to CFC. Renormalization of post-CFC REM sleep latency, REM sleep amounts, and NREM spindle power were all associated with improved contextual fear memory (CFM) consolidation. We find that improvements in CFM consolidation due to ML297 are sleep-dependent, and are associated with increased numbers of highly-activated dentate gyrus (DG), CA1, and CA3 neurons during CFM recall. Together our findings suggest that GIRK1 channel activation restores normal sleep architecture - including REM sleep, which is normally suppressed following CFC - and increases the number of hippocampal neurons incorporated into the CFM engram during memory consolidation. Significance StatementBoth REM and NREM sleep are thought to be important for consolidating hippocampus-dependent memories. We find that GIRK1 activator ML297, administered after single-trial fear learning, restores REM sleep that is normally suppressed after learning fearful associations. This restoration is associated with improvements in fear memory storage, resulting in more robust hippocampus activation in the context of subsequent memory recall. Thus this drug, which also has antiepileptic and anxiolytic properties, may be useful for promoting normal, restorative sleep that benefits memory storage.

neuroscience↗

bioRxiv2022

Binocular visual experience and sleep promote visual cortex plasticity and restore binocular vision in a mouse model of amblyopia

Amblyopia arises from an altered balance of input from the two eyes to the binocular zone of primary visual cortex (bV1) during childhood, causing long-lasting visual impairment. Amblyopia is commonly treated by patching the dominant eye, however, the relative impacts of monocular vs. binocular visual experiences on restoration of bV1 function remains unclear. Moreover, while sleep has been implicated in V1 plasticity in response to vision loss, its role in recovery from amblyopia is unknown. We used monocular deprivation (MD) in juvenile mice to model amblyopia in bV1. We compared recovery of visual responses for the two eyes among bV1 regular spiking (RS, putative principal) neurons and fast-spiking (FS, putative parvalbumin-expressing [PV+]) interneurons after identical-duration, identical-quality binocular recovery (BR) or monocular, reverse occlusion (RO) experiences. We find that BR is quantitatively superior to RO with respect to renormalizing both bV1 populations visual responses. However, this recovery was seen only in freely-sleeping mice; post-BR sleep deprivation prevented functional recovery. Thus, both binocular visual experience and subsequent sleep are required to optimally renormalize bV1 responses in a mouse model of amblyopia.

neuroscience↗

bioRxiv2017

Sub-threshold resonance organizes activity and optimizes learning in neural networks.

Network oscillations across and within brain areas are critical for learning and performance in memory tasks. While a large amount of work has focused on the generation of neural oscillations, their effects on neuronal populations spiking activity and information encoding is less known. Here, we use computational modeling and in vivo recording to demonstrate that a shift in sub-threshold resonance can interact with oscillating input to ensure that networks of neurons properly encode new information represented in external inputs to the weights of recurrent synaptic connections. Using a neuronal network model, we find that due to an input-current dependent shift in their resonance response, individual neurons in a network will arrange their phases of firing to represent varying strengths of their respective inputs. As networks encode information, neurons fire more synchronously, and this effect limits the extent to which further \"learning\" (in the form of changes in synaptic strength) can occur. We also demonstrate that sequential patterns of neuronal firing can be accurately stored in the network; these sequences are later reproduced without external input (in the context of sub-threshold oscillations) in both the forward and reverse directions (as has been observed following learning in vivo). To test whether a similar mechanism could act in vivo, we show that periodic stimulation of hippocampal neurons coordinates network activity and functional connectivity in a frequency-dependent manner. We conclude that sub-threshold resonance provides a plausible network-level mechanism to accurately encode and retrieve information without over-strengthening connections between neurons.

neuroscience↗