Biology subjects

Wisden, W.

Publications and source records attributed to Wisden, W..

9 recordsLinked to original sources

bioRxiv2026

Tonic REM sleep EEG components predict better mood, cognition and reduce cortical excitability overnight

Rapid Eye Movement (REM) sleep makes up approximately 20% of sleep in the adult human and is altered in psychiatric and neurodegenerative conditions. REM sleep comprises two substates, during which eye movements do (phasic REM) and do not (tonic REM) occur. Tonic REM makes up 70-90% of REM sleep but its role in regulating brain function, mood and cognition remain underexplored. We investigated how seven nights of insufficient sleep (6 h time in bed), compared to sufficient sleep, alter periodic and aperiodic components of the phasic and tonic REM sleep electroencephalography (EEG), in 542 sleep recordings of 36 young adults. Associations between phasic and tonic REM sleep EEG and mood, cognitive performance, and overnight changes in cortical excitability as indexed by 1/f spectral slopes were assessed. Insufficient sleep predominantly affected tonic REM EEG components, specifically the density of theta, the amplitude, density, and frequency of alpha oscillations and the 1/f slope in the 30 to 45 Hz range. These changes associated with mood and cognitive performances, and with overnight reductions in cortical excitability. These results provide evidence for a role of tonic REM sleep in regulating mood and counteracting cognitive deterioration and excitability changes associated with insufficient sleep.

neuroscience↗

bioRxiv2025

The selective amyloid-driven failure of cholinergic medial septal neurons in aging mice perturbs REM sleep, cognition and emotion, and broadcasts amyloid to other brain regions

In humans, decreases in rapid eye movement sleep (REMS) strongly predict Alzheimers disease (AD), alongside early degeneration of basal forebrain cholinergic neurons. We examined how {beta}-amyloid pathology gradually erodes mouse cholinergic neurons. The familial AppNL-G-F allele was selectively expressed in medial septal (MS) cholinergic neurons of both sexes and compared with mice with global AppNL-G-F expression and selective genetic lesions of MS cholinergic cells. By 14 months, targeted AppNL-G-F allele expression had caused loss of 25% of MS cholinergic neurons and produced amyloid deposition in their terminal fields, particularly the hippocampus. REMS was reduced, together with cognitive and emotional alterations mirroring phenotypes in global mutants, which also showed selective MS cholinergic cell loss. Genetic lesioning of MS cholinergic cells recapitulated most phenotypes, identifying cholinergic loss, not amyloid deposition, as a probable cause of these phenotypes. Nevertheless, broadcasted amyloid from MS cholinergic neurons likely induced hippocampal astrocyte activation and epileptiform spikes. HighlightsO_LIAmyloid in medial septum causes cholinergic neuron loss and Alzheimers symptoms C_LIO_LIAmyloid from medial septal axons may trigger pathology in distant brain regions C_LIO_LILoss of acetylcholine, not amyloid spread, drives REM sleep and cognitive deficits C_LIO_LIBroadcasted septal amyloid induces hippocampal astrogliosis and epileptiform spikes C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/663930v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@147275dorg.highwire.dtl.DTLVardef@69745borg.highwire.dtl.DTLVardef@1560ddborg.highwire.dtl.DTLVardef@a7d8d6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Co-release of histamine and GABA in prefrontal cortex excites fast-spiking interneurons and causes divisive gain change in pyramidal cells; an effect that is enhanced in older mice

We studied how co-release of histamine/GABA from axons originating from the hypothalamic tuberomammillary nucleus (TMN) and projecting to the prefrontal cortex (PFC) influences circuit processing. We opto-stimulated histamine/GABA co-release from genetically defined TMN axons that express the histidine decarboxylase gene (TMNHDC axons). Whole-cell recordings were used to monitor excitability of visually identified PFC neurons in layer 2/3 of prelimbic (PL), anterior cingulate (AC) and infralimbic (IL) regions before and after opto-stimulated histamine/GABA release. We found that histamine-GABA co-release influences the PFC through actions on distinct neuronal types: histamine stimulates fast-spiking interneurons; and co-released GABA enhances tonic (extrasynaptic) inhibition on pyramidal cells (PyrNs). For fast spiking non-accommodating interneurons, opto-stimulation increased excitability, an effect blocked by histamine H1 and H2 receptor antagonists. The excitability of other interneuron types in the PFC was not altered. In contrast, the combined action of histamine and GABA co-release from TMNHDC axons produced predominantly divisive gain changes in PyrNs, increasing their resting input conductance, and decreasing the slope of the input-output relationship. The direct inhibitory effect of TMNHDC axon activation on PyrNs was not blocked by histamine receptor antagonists but was blocked by GABAA receptor antagonists. Across the adult lifespan (from 3 months to over 2 years of age), stimulation of TMNHDC axons in the PFC inhibited PyrN excitability significantly more in older mice. For individuals that maintain cognitive performance into later life, increases in TMNHDC modulation of PyrNs could enhance information processing and be an adaptive mechanism to buttress cognition.

neuroscience↗

bioRxiv2021

Disruption of VGLUT1 in cholinergic medial habenula projections increases nicotine self-administration

Cholinergic projections from the medial habenula (MHb) to the interpeduncular nucleus (IPN) have been studied for their complex contributions to nicotine addiction and have been implicated in nicotine reinforcement, aversion, and withdrawal. While it has been established that MHb cholinergic projections co-release glutamate, no direct evidence has demonstrated a role for this specific glutamate projection in nicotine consumption. In the present study, a novel floxed Slc17a7 (VGLUT1) mouse was generated and used to create conditional knockout (cKO) mice that lack VGLUT1 in MHb cholinergic neurons. Histochemical approaches and optogenetics-assisted electrophysiology were used to validate the disruption of VGLUT1 from cholinergic MHb to IPN projections. The mice displayed no gross phenotypic abnormalities and exhibited normal exploratory and locomotor behavior in the open-field assay. However, the loss of VGLUT1-mediated glutamate co-release led to increased nicotine self-administration. These findings indicate that glutamate co-release from ventral MHb cholinergic neurons opposes nicotine consumption and provide additional support for targeting this synapse to develop potential treatments to nicotine addiction.

neuroscience↗

bioRxiv2021

Nitric oxide synthase neurons in the preoptic hypothalamus are sleep-active and contribute to regulating NREM and REM sleep and lowering body temperature.

When mice are exposed to external warmth, nitric oxide synthase (NOS1) neurons in the median and medial preoptic (MnPO/MPO) hypothalamus induce sleep and concomitant body cooling. However, how these neurons regulate baseline sleep and body temperature is unknown. Using calcium photometry, we show that NOS1 neurons in MnPO/MPO are predominantly NREM active. This is the first instance of a predominantly NREM-active population in the PO area, or to our knowledge, elsewhere in the brain. In addition to releasing nitric oxide, NOS1 neurons in MnPO/MPO can release GABA, glutamate and peptides. We expressed tetanus-toxin light-chain in MnPO/MPO NOS1 cells to reduce vesicular release of transmitters. This induced changes in sleep structure: over 24 hours, mice had less NREM sleep in their dark (active) phase, and more NREM sleep in their light (sleep) phase. REM sleep episodes in the dark phase were longer, and there were fewer REM transitions between other vigilance states. REM sleep had less theta power. Mice with synaptically blocked MnPO/MPO NOS1 neurons were also warmer. In particular, mice were warmer than control mice at the dark-light transition (ZT0), as well as during the dark phase siesta (ZT16-20), where there is usually a body temperature dip. Also, at this siesta point of cooled body temperature, mice usually have more NREM, but mice with synaptically blocked MnPO/MPO NOS1 cells showed reduced NREM sleep at this time. Overall, MnPO/MPO NOS1 neurons promote both NREM and REM sleep and contribute to chronically lowering body temperature, particularly at transitions where the mice normally enter NREM sleep.

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bioRxiv2020

Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep

The preoptic hypothalamus regulates both NREM and REM sleep. We found that calcium levels in mouse lateral preoptic (LPO) neurons were highest during REM. Deleting the core GluN1 subunit of NMDA receptors from LPO neurons abolished calcium signals during all vigilance states, and the excitatory drive onto LPO neurons was reduced. Mice had less NREM sleep and were incapable of generating conventionally classified REM sleep episodes: cortical theta oscillations were greatly reduced but muscle atonia was maintained. Additionally, mice lacking NMDA receptors in LPO neurons had highly fragmented sleep-wake patterns. The fragmentation persisted even under high sleep pressure produced by sleep deprivation. Nevertheless, the sleep homeostasis process remained intact, with an increase in EEG delta power. The sedative dexmedetomidine and sleeping medication zolpidem could transiently restore consolidated sleep. High sleep-wake fragmentation, but not sleep loss, was also produced by selective GluN1 knock-down in GABAergic LPO neurons. We suggest that NMDA glutamate receptor signalling stabilizes the firing of "GABAergic NREM sleep-on" neurons and is also essential for the theta rhythm in REM sleep.

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bioRxiv2020

Sleep deprivation triggers somatostatin neurons in prefrontal cortex to initiate nesting and sleep via the preoptic and lateral hypothalamus

Animals undertake specific behaviors before sleep. Little is known about whether these innate behaviors, such as nest building, are actually an intrinsic part of the sleep-inducing circuitry. We found, using activity-tagging genetics, that mouse prefrontal cortex (PFC) somatostatin/GABAergic (SOM/GABA) neurons, which become activated during sleep deprivation, induce nest building when opto-activated. These tagged neurons induce sustained global NREM sleep if their activation is prolonged metabotropically. Sleep-deprivation-tagged PFC SOM/GABA neurons have long-range projections to the lateral preoptic (LPO) and lateral hypothalamus (LH). Local activation of tagged PFC SOM/GABA terminals in LPO and the LH induced nesting and NREM sleep respectively. Our findings provide a circuit link for how the PFC responds to sleep deprivation by coordinating sleep preparatory behavior and subsequent sleep.

neuroscience↗

bioRxiv2019

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

The ventral tegmental area (VTA), an important source of dopamine, regulates goal- and reward-directed and social behaviors, wakefulness and sleep. Hyperactivation of dopamine neurons generates behavioral pathologies. But any roles of non-dopamine VTA neurons in psychiatric illness have been little explored. Lesioning or chemogenetically inhibiting VTA GABAergic (VTAVgat) neurons generated persistent wakefulness with mania-like qualities: locomotor activity was increased; sensitivity to D-amphetamine was heightened; immobility times decreased on the tail suspension and forced swim tests; and sucrose preference increased. Furthermore, after sleep deprivation, mice with lesioned VTAVgat neurons did not catch up on the lost NREM sleep, even though they were starting from an already highly sleep-deprived baseline, suggesting that the sleep homeostasis process was bypassed. The mania-like behaviors, including the sleep loss, were reversed by the mood-stabilizing drug valproate, and re-emerged when valproate treatment was stopped. Lithium salts, however, had no effect. The mania like-behaviors partially depended on dopamine, because giving D1/D2/D3 receptor antagonists partially restored the behaviors, but also on VTAVgat projections to the lateral hypothalamus (LH). Optically or chemogenetically inhibiting VTAVgat terminals in the LH elevated locomotion and decreased immobility time during the tail suspension and forced swimming tests. VTAVgat neurons are centrally positioned to help set an animals (and humans) level of mental and physical activity. Inputs that inhibit VTAVgat neurons intensify wakefulness (increased activity, enhanced alertness and motivation), qualities useful for acute survival. Taken to the extreme, however, decreased or failed inhibition from VTAVgat neurons produces mania-like qualities (hyperactivity, hedonia, decreased sleep).

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bioRxiv2019

Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the alpha2 adrenergic agonist dexmedetomidine

Sleep deprivation induces a characteristic rebound in NREM sleep accompanied by an immediate increase in the power of delta (0.5 - 4 Hz) oscillations, proportional to the prior time awake. To test the idea that galanin neurons in the mouse lateral preoptic hypothalamus (LPO) regulate this sleep homeostasis, they were selectively genetically ablated. The baseline sleep architecture of LPO-{Delta}Gal mice became heavily fragmented, their average core body temperature permanently increased (by about 2{degrees}C) and the diurnal variations in body temperature across the sleep-wake cycle also markedly increased. Additionally, LPO-{Delta}Gal mice showed a striking spike in body temperature and increase in wakefulness at a time (ZT24) when control mice were experiencing the opposite - a decrease in body temperature and becoming maximally sleepy (start of "lights on"). After sleep deprivation sleep homeostasis was largely abolished in LPO-{Delta}Gal mice: the characteristic increase in the delta power of NREM sleep following sleep deprivation was absent, suggesting that LPO galanin neurons track the time spent awake. Moreover, the amount of recovery sleep was substantially reduced over the following hours. We also found that the 2 adrenergic agonist dexmedetomidine, used for long-term sedation during intensive care, requires LPO galanin neurons to induce both the NREM-like state with increased delta power and the reduction in body temperature, characteristic features of this drug. This suggests that dexmedetomidine over-activates the natural sleep homeostasis pathway via galanin neurons. Collectively, the results emphasize that NREM sleep and the concurrent reduction in body temperature are entwined at the circuit level. SignificanceCatching up on lost sleep (sleep homeostasis) is a common phenomenon in mammals, but there is no circuit explanation for how this occurs. We have discovered that galanin neurons in the hypothalamus are essential for sleep homeostasis as well as for the control of body temperature. This is the first time that a neuronal cell type has been identified that underlies sleep homeostasis. Moreover, we show that activation of these galanin neurons are also essential for the actions of the 2 adrenergic agonist dexmedetomidine, which induces both hypothermia together with powerful delta oscillations resembling NREM sleep. Thus, sleep homeostasis, temperature control and sedation by 2 adrenergic agonists can all be linked at the circuit level by hypothalamic galanin neurons.

neuroscience↗