Biology subjects

Diering, G. H.

Publications and source records attributed to Diering, G. H..

3 recordsLinked to original sources

bioRxiv2021

Early life sleep disruption drives lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice

BackgroundPatients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life, however the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3{Delta}C). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically-relevant Shank3WT/{Delta}C mice may be at increased risk of lasting deleterious outcomes following early-life sleep disruption. MethodsWe recorded sleep behavior in developing Shank3{Delta}C/{Delta}C, Shank3WT/{Delta}C, and wild type siblings of both sexes using a non-invasive home cage monitoring system. Separately, litters of Shank3WT/{Delta}C and wildtype littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early-life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. ResultsMale and female Shank3{Delta}C/{Delta}C mice slept significantly less than wild type and Shank3WT/{Delta}C siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3WT/{Delta}Cmice, resulting in lasting, sex-specific changes in behavior, whereas wildtype siblings were largely resilient to these effects. Male ELSD Shank3WT/{Delta}Csubjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3WT/{Delta}C subjects had a significant reduction in risk aversion. CON Shank3WT/{Delta}C mice, PASD mice, and all wildtype mice demonstrated typical behavioral responses in most tests. LimitationsThis study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3{Delta}C (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. ConclusionOur study shows that sleep disruption during sensitive periods of early life interact with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

animal behavior and cognition↗

bioRxiv2021

Coordinated regulation of CB1 cannabinoid receptors and anandamide metabolism stabilize network activity during homeostatic scaling down

Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the post-synaptic compartments to regulate synaptic transmission, plasticity, and neuronal excitability primarily through retrograde activation of pre- synaptic cannabinoid receptor type 1 (CB1). The eCB system is well-situated to regulate neuronal network properties and coordinate pre- and post-synaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. To address this issue, we used western blot and targeted lipidomics to measure adaptations in eCB system to bicuculline (BCC)-induced chronic hyperexcitation in mature (>DIV21) cultured rat cortical neurons, and used multielectrode array recording and live-cell imaging of glutamate dynamics to test the effects of pharmacological manipulations of eCB on network activities. We show that BCC-induced chronic hyperexcitation triggers homeostatic downscaling and a coordinated adaptation to enhance tonic eCB signaling. Hyperexcitation triggers first the downregulation of fatty acid amide hydrolase (FAAH), the lipase that degrades the eCB anandamide, then an accumulation of anandamide and related metabolites, and finally a delayed upregulation of surface and total CB1. Additionally, we show that BCC-induced downregulation of surface AMPA-type glutamate receptors (AMPARs) and upregulation of CB1 occur through independent mechanisms. Finally, we show that endocannabinoids support baseline network activities before and after downscaling and is engaged to suppress network activities during adaptation to hyperexcitation. We discuss the implications of our findings in the context of downscaling and homeostatic regulation of oscillatory network activities. Significance statementNeurons are remarkably resilient to perturbations in network activities thanks to the expression of overlapping homeostatic adaptations. In response to network hyperactivity or silencing, neurons respond through regulating excitatory and inhibitory post-synaptic neurotransmitter receptors density, probability of pre-synaptic neurotransmitter release, and/or membrane excitability. The endocannabinoid system is a prominent signaling pathway at many synapses that is known to be involved in multiple forms of short- and long-term synaptic plasticity. Here we find that components of the endocannabinoid system are upregulated in response to chronic hyperexcitation of cultured cortical neurons, and that endocannabinoid signaling is required to maintain network activity but also suppresses network events during hyperexcitation. This work supports a novel tonic homeostatic function for the endocannabinoid system in neurons.

neuroscience↗

bioRxiv2021

Tonic endocannabinoid signaling supports sleep through development in both sexes.

Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in developing and adult mice. We find that eCBs are downregulated in response to acute sleep deprivation in juvenile mice, while in young adults eCBs are upregulated during the sleep phase in a circadian manner. Next we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a non-invasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.

animal behavior and cognition↗