Biology subjects

Raven, F.

Publications and source records attributed to Raven, F..

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↗

bioRxiv2025

Dentate gyrus network regulation by somatostatin- and parvalbumin-expressing interneurons differentially impacts hippocampal spatial memory processing

GABAergic interneurons regulate circuit dynamics in hippocampal structures such as CA1 that appear to be essential for memory processing. The dentate gyrus (DG) is known to play a role in pattern recognition and spatial working memory. However, the role of the DG in different stages of long-term spatial memory is poorly understood. Moreover, the roles of the predominant interneuron subtypes within the DG - somatostatin-expressing (SST+) and parvalbumin-expressing (PV+) - in different stages of memory processing are unknown. We tested how chemogenetic manipulation of DG SST+ and PV+ interneurons in mice influences the encoding, consolidation, and retrieval of hippocampus-dependent object-location memory (OLM). We find that activation of DG SST+ interneurons impairs both OLM encoding and retrieval, dramatically suppresses DG granule cell cFos expression, and (in the case of encoding) suppresses downstream CA1 network activity. Among individual mice, the degree of DG granule cell suppression is proportional to the extent of SST+ interneuron activation, and predicts the extent of OLM deficits. In striking contrast, PV+ interneuron activation selectively disrupts encoding, but not retrieval, of OLM, and minimally impacts DG or downstream hippocampal network activity. These findings demonstrate that regulation of the DG network by SST+ and PV+ interneurons differentially contributes to the various stages of spatial memory processing, and suggest that distinct network mechanisms are engaged in the hippocampus during each processing stage. Significance statementNeuronal activity within the dentate gyrus (DG) of the hippocampus is regulated by multiple populations of inhibitory interneurons. To understand how inhibitory regulation contributes to spatial memory processing, we experimentally activated two major classes of DG inhibitory interneurons in mice - either during spatial learning, spatial memory storage, or memory recall. We find spatial learning is disrupted by activation of either SST+ or PV+ interneuron populations, although the two manipulations differentially affect hippocampal activity. Somewhat surprisingly, activation of neither inhibitory population affects spatial memory storage, only SST+ interneuron activation disrupts recall, and the hippocampal activity patterns affected by inhibition differ between learning and recall. These data provide a clearer understanding of the circuits engaged by different steps of spatial memory processing.

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

Reactivation of memory-encoding dentate gyrus neurons during memory consolidation is associated with subregion-specific, learning- and sleep-mediated biosynthetic changes

Post-learning sleep is essential for hippocampal memory processing, including contextual fear memory (CFM) consolidation. We used targeted recombination in activated populations (TRAP) to label context-encoding engram neurons in the hippocampal dentate gyrus (DG) and assessed reactivation of these neurons after fear learning. Post-learning sleep deprivation (SD), which impairs CFM consolidation, selectively disrupted reactivation of inferior blade DG engram neurons. This change was linked to more general suppression of neuronal activity markers in the inferior, but not superior, DG blade by SD. To further characterize how learning and subsequent sleep or SD affect these (and other) hippocampal subregions, we used subregion-specific spatial profiling of transcripts and proteins. We found that transcriptomic responses to sleep loss differed greatly between hippocampal regions CA1, CA3, and DG inferior blade, superior blade, and hilus - with activity-driven transcripts, and those associated with cytoskeletal remodeling, selectively suppressed in the inferior blade. Critically, learning-driven transcriptomic changes, measured 6 h following contextual fear learning, were limited to the two DG blades, differed dramatically between the blades, and were absent from all other regions. These changes suggested an increase in glutamatergic receptor signaling, and a decrease in GABA receptor signaling, during CFM consolidation. Protein abundance across hippocampal subregions was also differentially impacted by learning and sleep, with most alterations to protein expression restricted to DG. Together, these data suggest that the DG is critical for sleep-dependent memory consolidation, and that the effects of sleep loss on the hippocampus are highly subregion-specific, even within the DG itself.

neuroscience↗

bioRxiv2021

Restoring persistent accessibility to memories after sleep deprivation-induced amnesia

It is well established that sleep deprivation after learning impairs hippocampal memory processes and causes amnesia. It is unknown, however, whether it leads to the actual loss of information or merely suppresses the retrievability of this information stored under suboptimal conditions. Here, we reveal that hippocampal memories formed under sleep deprivation conditions can be successfully retrieved multiple days following training using optogenetic memory engram activation or treatment with the clinically-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast. Moreover, when optogenetic memory engram activation and roflumilast treatment were combined two days following training and subsequent sleep deprivation, it resulted in a more persistent memory trace that allowed for natural (i.e., manipulation free) retrieval several days later. Our studies in mice demonstrate that sleep deprivation does not necessarily cause memory loss, but instead leads to the suboptimal storage of information that is difficult to retrieve. We also provide proof of principle that these suboptimally stored memories can be made accessible again far beyond the learning episode and that the clinically-approved PDE4 inhibitor roflumilast may be used to successfully retrieve information thought to be lost.

neuroscience↗