Abstract
In this study we investigated the role of the circadian mechanism on cognition-relevant brain regions and neurobiological impairments associated with heart failure (HF), using murine models. We found that the circadian mechanism is an important regulator of healthy cognitive system neurobiology. Normal Clock∆19/∆19 mice had neurons with smaller apical dendrite trees in the medial prefrontal cortex (mPFC), and hippocampus, showed impaired visual-spatial memory, and exhibited lower cerebrovascular myogenic tone, versus wild types (WT). We then used the left anterior descending coronary artery ligation model to investigate adaptations in response to HF. Intriguingly, adaptations to neuron morphology, memory, and cerebrovascular tone occurred in differing magnitude and direction between Clock∆19/∆19 and WT mice, ultimately converging in HF. To investigate this dichotomous response, we performed microarrays and found genes crucial for growth and stress pathways that were altered in Clock∆19/∆19 mPFC and hippocampus. Thus these data demonstrate for the first time that (i) the circadian mechanism plays a role in neuron morphology and function; (ii) there are changes in neuron morphology and function in HF; (iii) CLOCK influences neurobiological gene adaptations to HF at a cellular level. These findings have clinical relevance as patients with HF often present with concurrent neurocognitive impairments. There is no cure for HF, and new understanding is needed to reduce morbidity and improve the quality of life for HF patients.
Highlights
The circadian system coordinates our physiology with the diurnal environment – mammals are awake in the day or at night
We focused on the circadian factor CLOCK, as it is a canonical part of the circadian mechanism, and relatively well characterized in experimental heart disease models
We found that CLOCK is pivotal to maintain normal neuron morphology; Clock∆19/∆19 mice have smaller apical dendrite trees in medial prefrontal cortex (mPFC) layer 2/3 and hippocampus CA1 neurons, versus wild type (WT) mice
Summary
The circadian system coordinates our physiology with the diurnal environment – mammals are awake in the day or at night (reviewed in[33,34]). We investigate the role of the circadian mechanism on normal neurobiology using Clock∆19/∆19 mice, and how the circadian mechanism contributes to neurobiological adaptations within cognition-relevant brain regions in HF. The Clock∆19/∆19 mice show differences in the magnitude and direction of their neurobiological responses, as compared to WTs. despite different neurobiological adaptations, they result in similar end outcomes in terms of neuron morphology, memory, and cerebrovascular tone in HF. To investigate the mechanisms underlying this dichotomous response, we examined gene expression at baseline, MI and HF in the mPFC and hippocampus in Clock∆19/∆19 vs WT mice. We found differential activation of genes important for neural growth, cytoskeleton, signalling and metabolism These data reveal that CLOCK is an important regulator of healthy cognitive system neurobiology, and adaptations in neuron morphology and function in HF.
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