Biology subjects

Katsuki, F.

Publications and source records attributed to Katsuki, F..

6 recordsLinked to original sources

bioRxiv2026

Early Loss of Deep Restorative Sleep and Auditory Stimulus Evoked 40-Hz activity of Hippocampal Parvalbumin Neurons in the APP/PS1 Mouse Model of Alzheimer's Disease

Sleep abnormalities and dysfunction of gamma band (30-80 Hz) activity generated by parvalbumin (PV) interneurons are early characteristics of Alzheimers disease (AD) which correlate with the severity of amyloid-{beta} deposition (A{beta}) and cognitive impairment. However, the timing of these alterations in vivo with respect to disease progression is unclear. Here, in longitudinal recordings from APP/PS1/PV-cre (AD mice) from 3-6 months, we found reduced sleep slow-wave power (0.5-4 Hz) in hippocampus and medial prefrontal cortex in AD mice as young as 3 months old, compared to non-AD (PV-cre) mice, well before overt pathology. This finding was primarily due to reductions in the NREM delta range (1.5-4 Hz), a hallmark of restorative functions of sleep. In contrast, beta (15-30 Hz) power linked to insomnia was significantly higher across all sleep-wake states. Loss of deep NREM sleep was not compensated by an increase in NREM sleep time, instead NREM sleep during the dark (active) phase was slightly but significantly lower in AD mice. 40-Hz auditory steady-state responses and associated evoked calcium responses of hippocampal PV neurons recorded using fiber photometry were also impaired by 3 months old. However, Y-maze performance in 3- and 6-month-old AD mice was not significantly different from non-AD mice. These results reveal reduced deep sleep and PV-associated 40-Hz activity as very early changes amenable to early intervention occurring prior to cognitive deficits. Furthermore, they establish APP/PS1 mice as a good model to causally test the relationship between sleep, PV neuronal activity and amyloid-mediated pathology.

neuroscience↗

bioRxiv2026

Synaptic GABA dysfunction of thalamocortical neurons impairs sleep spindle morphology and recovery from fearful memories.

The neural mechanisms which control the characteristic waxing and waning shape of sleep spindles and their dysregulation in neuropsychiatric illnesses are unresolved. Recent, sparse research shows post-traumatic stress disorder (PTSD) presents with abnormal spindle morphology and dysfunctional synaptic GABAA receptors in midline thalamic regions. We modeled this GABAA receptor dysfunction by localized CRISPR-Cas9-knockdown in mice. In contrast to a control group with intact GABAA receptors, mice with synaptic GABAA receptor knock-down in thalamocortical (TC) neurons lost the characteristic waxing and waning shape of sleep spindles and exhibited a failure to diminish conditioned contextual fear responses. Our results suggest that abnormally shaped sleep spindles may be a marker of synaptic GABA dysfunction in TC neurons and an indicator of disrupted fear extinction.

neuroscience↗

bioRxiv2023

Sleep-Deep-Net learns sleep wake scoring from the end-user and completes each record in their style.

Sleep-wake scoring is a time-consuming, tedious but essential component of clinical and pre-clinical sleep research. Sleep scoring is even more laborious and challenging in rodents due to the smaller EEG amplitude differences between states and the rapid state transitions which necessitate scoring in shorter epochs. Although many automated rodent sleep scoring methods exist, they do not perform as well when scoring new data sets, especially those which involve changes in the EEG/EMG profile. Thus, manual scoring by expert scorers remains the gold-standard. Here we take a different approach to this problem by using a neural network to accelerate the scoring of expert scorers. Sleep-Deep-Net (SDN) creates a bespoke deep convolution neural network model for individual electroencephalographic or local-field-potential records via transfer learning of GoogleNet, by learning from a small subset of manual scores of each EEG/LFP record as provided by the end-user. SDN then automates scoring of the remainder of the EEG/LFP record. A novel REM scoring correction procedure further enhanced accuracy. SDN reliably scores EEG and LFP data and retains sleep-wake architecture in wild-type mice, in sleep induced by the hypnotic zolpidem, in a mouse model of Alzheimers disease and in a genetic knock-down study, when compared to manual scoring. SDN reduced manual scoring time to 1/12. Since SDN uses transfer learning on each independent recording, it is not biased by previously scored existing data sets. Thus, we find SDN performs well when used on signals altered by a drug, disease model or genetic modification. STATEMENT OF SIGNIFICANCESleep medicine is often critically advanced by translational research based on in vivo electrophysiologic mouse data. A necessary but time-consuming step in this field is scoring epochs of recordings into wakefulness, non-rapid-eye-movement sleep and non-rapid-eye-movement sleep. Despite efforts to automate this, manual scoring remains the gold-standard since automatic methods poorly handle data that is not similar enough to data used during development. Here, we describe a novel automated sleep scoring method that involves retraining a deep-convolution-neural-net capable of computer vision to score sleep-wake patterns after learning from a small set of manual scores within a record. This avoids biasing the model to expect data to be the same as its training set from previous records.

neuroscience↗

bioRxiv2023

Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in basal forebrain

Here we describe a novel group of basal forebrain (BF) neurons expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+ neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+ neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+ neurons was high, 5-6 times that of neighboring cholinergic, parvalbumin or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+ neurons to brain regions involved in sleep-wake control, motivated behaviors and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area and olfactory bulb. Chemogenetic activation of BF Npas1+ neurons in the light (inactive) period increased the amount of wakefulness and the latency to sleep for 2-3 hr, due to an increase in long wake bouts and short NREM sleep bouts. Non-REM slow-wave (0-1.5 Hz) and sigma (9-15 Hz) power, as well as sleep spindle density, amplitude and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+ neurons in stress responsiveness, the anatomical projections of BF Npas1+ neurons and the effect of activating them suggest a possible role for BF Npas1+ neurons in motivationally-driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia and other neuropsychiatric conditions involving BF. SIGNIFICANCE STATEMENTWe characterize a group of basal forebrain (BF) neurons in the mouse expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. BF Npas1+ neurons are a major subset of GABAergic neurons distinct and more numerous than cholinergic, parvalbumin or glutamate neurons. BF Npas1+ neurons target brain areas involved in arousal, motivation and olfaction. Activation of BF Npas1+ neurons in the light (inactive) period increased wakefulness and the latency to sleep due to increased long wake bouts. Non-REM sleep slow waves and spindles were reduced reminiscent of findings in several neuropsychiatric disorders. Identification of this major subpopulation of BF GABAergic wake-promoting neurons will allow studies of their role in insomnia, dementia and other conditions involving BF.

neuroscience↗

bioRxiv2020

CRISPR knockdown of GABAA alpha3 subunits on thalamic reticular neurons enhances deep sleep

Identification of mechanisms which increase deep sleep could lead to novel treatments which promote the restorative effects of sleep. Here, knockdown of the 3 GABAA-receptor subunit from parvalbumin neurons in the thalamic reticular nucleus using CRISPR-Cas9 gene editing increased the thalamocortical delta oscillations implicated in many health-promoting effects of sleep. Inhibitory synaptic currents were strongly reduced in vitro. Effects were most pronounced in the mouse sleep (light) period. Further analysis identified a novel deep-sleep state in mice prior to NREM-REM transitions which was preferentially affected by deletion of 3 subunits. Our results identify a functional role for GABAA receptors on Thalamic Reticular Nucleus neurons and suggest antagonism of 3 subunits as a strategy to enhance deep sleep. One Sentence SummarySelective genetic knockdown of the major subunit of GABAA receptors present in the thalamic reticular nucleus enhanced deep sleep in mice.

neuroscience↗

bioRxiv2019

Basal forebrain parvalbumin neurons mediate arousals from sleep induced by hypercarbia or auditory stimuli

Brief arousals from sleep in patients with sleep apnea and other disorders prevent restful sleep, and contribute to cognitive, metabolic and physiologic dysfunction. Little is currently known about which neural systems mediate these brief arousals, hindering the development of treatments. The basal forebrain (BF) receives inputs from many nuclei of the ascending arousal system. These inputs include the brainstem parabrachial neurons which promote arousal in response to elevated blood carbon dioxide levels, as seen in sleep apnea. Optical inhibition of the terminals of parabrachial neurons in the BF impairs cortical arousals to hypercarbia, but which cell types within the BF mediate cortical arousals in response to hypercarbia or other sensory stimuli is unknown. Here using optogenetic techniques in mice, we show that BF parvalbumin (PV) neurons fulfill several criteria for a system mediating brief arousals from sleep. Optical stimulation of BF PV neurons during the light period, when mice normally sleep, caused rapid transitions to wakefulness and increased wake bout durations. Unlike many other ascending arousal systems, arousals induced by stimulation of BF PV neurons were brief, resulting in only a small (13.6%) increase in the total amount of wakefulness. Bilateral optical inhibition of BF PV neurons increased the latency to arousal produced by hypercarbia or auditory stimuli. Thus, BF PV neurons are an important component of the brain circuitry which generates brief arousals from sleep in response to internal and external sensory stimuli.

neuroscience↗