Torpor enhances synaptic strength and restores memory performance in a mouse model of Alzheimer’s disease

Abstract

Hibernation induces neurodegeneration-like changes in the brain, which are completely reversed upon arousal. Hibernation-induced plasticity may therefore be of great relevance for the treatment of neurodegenerative diseases, but remains largely unexplored. Here we show that a single torpor and arousal sequence in mice does not induce dendrite retraction and synapse loss as observed in seasonal hibernators. Instead, it increases hippocampal long-term potentiation and contextual fear memory. This is accompanied by increased levels of key postsynaptic proteins and mitochondrial complex I and IV proteins, indicating mitochondrial reactivation and enhanced synaptic plasticity upon arousal. Interestingly, a single torpor and arousal sequence was also sufficient to restore contextual fear memory in an APP/PS1 mouse model of Alzheimer’s disease. Our study demonstrates that torpor in mice evokes an exceptional state of hippocampal plasticity and that naturally occurring plasticity mechanisms during torpor provide an opportunity to identify unique druggable targets for the treatment of cognitive impairment.

The hibernation-derived compound SUL-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an Alzheimer’s disease mouse model

“…It has been shown previously that SUL-138 also increases the activity of complexes I and IV [23]. The same complexes are upregulated during daily torpor in mice [18]. This points to an additional beneficial effect of SUL-138 by raising protonmotive force via these complexes [58].…”

“…Mitochondria shut down during torpor whereas arousals restore mitochondrial activity. These changes coincide with extensive structural and functional neuronal plasticity in the hippocampus, ranging from changes in synaptic plasticity during daily torpor in mice to complete dendritic retraction and restoration in seasonal hibernators [13][14][15][16][17][18]. Inspired by the effects of hibernation on mitochondria, and the associated boost in neuronal plasticity, 6-chromanol derived small molecules were developed that mimic the action of endogenous mediators conferring organ protection in hibernation [19][20][21] by phenotypical screening of cooled and rewarmed cells [22].…”

Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1

“…Body temperature was measured to investigate α2‐adrenergic effects. Telemetric temperature probes (Anipill, Animals Monitoring, Hérouville, France) were implanted into the abdominal cavities of 2‐month‐old male WT and 2b4 he 2b5 ho mice 30 . Animals were injected subcutaneously with 0.05 mg/kg buprenorphine 30 min prior to surgery.…”

“…Telemetric temperature probes (Anipill, Animals Monitoring, H erouville, France) were implanted into the abdominal cavities of 2-month-old male WT and 2b4 he 2b5 ho mice. 30 Animals were injected subcutaneously with 0.05 mg/kg buprenorphine 30 min prior to surgery. Full anesthesia was applied during surgery (1.5%-3% isoflurane in oxygen).…”

Opportunities and barriers to translating the hibernation phenotype for neurocritical care

“…Although some forms of learning acquired prior to the onset of the hibernation season are compromised after final arousal in spring (64), we and others have reported evidence of enhanced cognitive capacities after interbout arousal (65, 66). Arousal from torpor in mice also enhances synaptic strength and improves memory in a mouse model of Alzheimer's disease (67). Hibernation and cooling in non-hibernating species increase expression of cold-shock, RNA binding proteins such as RBM3 which promotes synaptogenesis (68-70) and skeletal muscle hypertrophy (71).…”