Biology subjects

Bell, B. J.

Publications and source records attributed to Bell, B. J..

3 recordsLinked to original sources

bioRxiv2024

An Amygdalar Oscillator Coordinates Cellular and Behavioral Rhythms

Circadian rhythms are generated by the master pacemaker suprachiasmatic nucleus (SCN), in concert with local clocks throughout the body. While many brain regions exhibit cycling clock gene expression, the identity of a discrete extra-SCN brain oscillator that produces rhythmic behavior has remained elusive. Here, we show that an extra-SCN oscillator in the lateral amygdala (LA) is defined by expression of the clock-output molecule mWAKE/ANKFN1. mWAKE is enriched in the anterior/dorsal LA (adLA), and strikingly, selective disruption of clock function or excitatory signaling in adLAmWAKE neurons abolishes Period2 (Per2) rhythms throughout the LA. mWAKE levels rise at night and promote rhythmic excitability of adLAmWAKE neurons by upregulating Ca2+-activated K+ channel activity specifically at night. adLAmWAKE neurons coordinate rhythmic sensory perception and anxiety in a clock-dependent and WAKE-dependent manner. Together, these data reveal the cellular identity of an extra-SCN brain oscillator and suggest a multi-level hierarchical system organizing molecular and behavioral rhythms.

neuroscience↗

bioRxiv2020

Characterization of mWake expression in the murine brain

Structure-function analyses of the mammalian brain have historically relied on anatomically-based approaches. In these investigations, physical, chemical, or electrolytic lesions of anatomical structures are applied, and the resulting behavioral or physiological responses assayed. An alternative approach is to focus on the expression pattern of a molecule whose function has been characterized and then use genetic intersectional methods to optogenetically or chemogenetically manipulate distinct circuits. We previously identified WIDE AWAKE (WAKE) in Drosophila, a clock output molecule that mediates the temporal regulation of sleep onset and sleep maintenance. More recently, we have studied the mouse homolog, mWAKE/ANKFN1, and found that its role in the circadian regulation of arousal is conserved. Here, we perform a systematic analysis of the expression pattern of mWake mRNA, protein, and cells throughout the adult mouse brain. We find that mWAKE labels neurons in a restricted, but distributed manner, in multiple regions of the hypothalamus (including the suprachiasmatic nucleus), the limbic system, sensory processing nuclei, and additional specific brainstem, subcortical, and cortical areas. Interestingly, mWAKE is also observed in non-neuronal ependymal cells. In addition, to describe the molecular identities and clustering of mWake+ cells, we provide detailed analyses of single cell RNA sequencing data from the hypothalamus, a region with particularly significant mWAKE expression. These findings lay the groundwork for future studies into the potential role of mWake+ cells in the rhythmic control of diverse behaviors and physiological processes.

neuroscience↗

bioRxiv2020

A Clock-Driven Neural Network Critical for Arousal

The daily cycling of sleep and arousal states is among the most prominent biological rhythms under circadian control. While much is known about the core circadian clock1,2, how this clock tunes sleep and arousal remains poorly understood3. In Drosophila, we previously characterized WIDE AWAKE (WAKE), a clock-output molecule that promotes sleep at night4,5. Here, we show that the function of WAKE in regulating circadian-dependent neural excitability and arousal is conserved in mice. mWake+ cells are found in the suprachiasmatic nucleus (SCN) and dorsomedial hypothalamus (DMH). mWakeDMH neurons drive wakefulness and exhibit rhythmic spiking, with greater firing during the night vs the day. Loss of mWAKE leads to increased spiking of mWake+ SCN and DMH neurons and prominent behavioural arousal, specifically during the night. Single-cell sequencing, imaging, and patch-clamp experiments reveal that mWakeDMH neurons constitute a glutamatergic/GABAergic population that projects widely, receives neuromodulatory input, and acts on neuromodulatory neurons. Strikingly, broad chemogenetic silencing of mWake+ cells leads to profound loss of behavioural responsiveness and low amplitude, low frequency electroencephalography waveforms. These findings suggest that the genetic mechanisms regulating circadian control of sleep and arousal are conserved across >500 million years of evolution and define a clock-regulated neural network critical for arousal.

neuroscience↗