Bmal1 integrates circadian function and temperature sensing in the suprachiasmatic nucleus.

Circadian regulation and temperature dependency are important orchestrators of molecular pathways. How the integration between these two drivers is achieved, is not understood. We monitored circadian- and temperature-dependent effects on transcription dynamics of cold-response protein RNA Binding Motif 3 (Rbm3). Temperature changes in the mammalian master circadian pacemaker, the suprachiasmatic nucleus (SCN), induced Rbm3 transcription and regulated its circadian periodicity, whereas the core clock gene Per2 was unaffected. Rbm3 induction depended on a full Brain And Muscle ARNT-Like Protein 1 (Bmal1) complement: reduced Bmal1 erased Rbm3 responses and weakened SCN circuit resilience to temperature changes. By focusing on circadian and temperature dependency, we highlight weakened transmission between core clock and downstream pathways as a potential route for reduced circadian resilience.

Astrocyte Circadian Timekeeping in Brain Health and Neurodegeneration.

Almost three decades ago, astrocytes neighbouring clock neurons of the suprachiasmatic nucleus, the hypothalamic tissue responsible for synchronising circadian timekeeping in mammals, were found to undergo morphological and protein expression changes in a cyclic 24-h pattern, suggesting that glia could harbour circadian timekeeping mechanisms and that neuron-glia interactions could play a part in the daily organisation of rhythms of physiology and behaviour. Recently, it has become clear that astrocytes are circadian timekeepers, capable of initiating daily patterns of behaviour and imposing their intrinsic circadian tempo in mammals. In this chapter, we will describe properties of intracellular timekeeping of astrocytes and the mechanisms by which astrocytes functionally integrate in brain circuits underlying circadian, sleep, and cognitive behaviours in mammals. We will then discuss how altered astrocyte timekeeping may be involved in early brain vulnerability underpinning neurodegeneration. We will focus on Alzheimer's disease as a template of how altered astrocyte timekeeping may be involved in neurodegeneration, both directly via unbalancing of inflammatory and oxidative stress cellular pathways, and indirectly, by altering sleep and cognitive functions.

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer's Disease.

Alzheimer's Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution.