Circadian rhythms are generated by the master pacemaker suprachiasmatic nucleus (SCN) in concert with local clocks throughout the body. Although 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 adLA neurons abolishes Period2 (PER2) rhythms throughout the LA. mWAKE levels rise at night and promote rhythmic excitability of adLA neurons by upregulating Ca-activated K channel activity specifically at night. adLA 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.
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http://dx.doi.org/10.1016/j.neuron.2024.08.013 | DOI Listing |
Neuron
November 2024
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:
Circadian rhythms are generated by the master pacemaker suprachiasmatic nucleus (SCN) in concert with local clocks throughout the body. Although 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.
View Article and Find Full Text PDFbioRxiv
September 2024
Laboratory of Addiction Genetics, Department of Pharmaceutical Sciences and Center for Drug Discovery, Northeastern University, Boston, MA USA.
Opioid use disorder is heritable, yet its genetic etiology is largely unknown. C57BL/6J and C57BL/6NJ mouse substrains exhibit phenotypic diversity in the context of limited genetic diversity which together can facilitate genetic discovery. Here, we found C57BL/6NJ mice were less sensitive to oxycodone (OXY)-induced locomotor activation versus C57BL/6J mice in a conditioned place preference paradigm.
View Article and Find Full Text PDFJ Steroid Biochem Mol Biol
May 2024
Dept. of Neurosteroids, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague 6, Czech Republic. Electronic address:
Endogenous neurosteroids (NS) and their synthetic analogs, neuroactive steroids (NAS), are potentially useful drug-like compounds affecting the pathophysiology of miscellaneous central nervous system disorders (e.g. Alzheimer´s disease, epilepsy, depression, etc.
View Article and Find Full Text PDFJ Steroid Biochem Mol Biol
May 2019
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nam. 2, Prague 6 - Dejvice, 16610, Czech Republic.
A broad variety of central nervous system diseases have been associated with glutamate induced excitotoxicity under pathological conditions. The neuroprotective effects of neurosteroids can combat this excitotoxicity. Herein, we have demonstrated the neuroprotective effect of novel steroidal N-methyl-D-aspartate receptor inhibitors against glutamate- or NMDA- induced excitotoxicity.
View Article and Find Full Text PDFFront Pharmacol
November 2018
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czechia.
Herein, we report the synthesis, structure-activity relationship study, and biological evaluation of neurosteroid inhibitors of -methyl-D-aspartate receptors (NMDARs) receptors that employ an amide structural motif, relative to pregnanolone glutamate (PAG) - a compound with neuroprotective properties. All compounds were found to be more potent NMDAR inhibitors (IC values varying from 1.4 to 21.
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