Biology subjects

Ba, W.

Publications and source records attributed to Ba, W..

4 recordsLinked to original sources

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↗

bioRxiv2023

A REM-active basal ganglia circuit that regulates anxiety

REM sleep has been hypothesized to promote emotional resilience, but any neuronal circuits mediating this have not been identified. We find that in mice, somatostatin (Som) neurons in the entopeduncular nucleus (EPSom)/internal globus pallidus are predominantly active selectively during REM sleep. This unique REM activity is necessary and sufficient for maintaining normal REM sleep. Inhibiting or exciting EPSom neurons reduced or increased REM sleep duration, respectively. Activation of the sole downstream target of EPSom neurons, Vglut2 cells in the lateral habenula (LHb), increased sleep via the ventral tegmental area (VTA). A simple chemogenetic scheme to periodically inhibit the LHb over 4 days selectively removed a significant amount of cumulative REM sleep. Chronic REM reduction correlated with mice becoming anxious and more sensitive to aversive stimuli. Therefore, we suggest that REM sleep, in part generated by the EP[->]LHb[->]VTA circuit identified here, could contribute to stabilizing reactions to habitual aversive stimuli.

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.

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).

neuroscience↗