Elucidating torpor's effects on brain activity and behaviour and investigating its neuroprotective properties against acute ischaemic stroke
Lead Research Organisation:
University of Oxford
Department Name: RDM Radcliffe Department of Medicine
Abstract
Stroke is a leading cause of adult disability and death globally. It occurs when a clot forms in blood vessels in the brain. The affected area of brain is starved of oxygen, leading to the death of brain cells. The result is often life-changing disability or death.
Thrombolysis, a drug treatment that dissolves the clot, has proven to be very effective against stroke. However, the time window in which it can be used is short (4.5 hours). Therefore, stroke scientists have been researching new methods of treating stroke that may complement thrombolysis and improve outcome in post-stroke patients. Research in animals shows that hypothermia is the most effective neuroprotective therapy (i.e. a treatment that protects brain cells from damage e.g. due to a stroke). However, current ways of triggering hypothermia (e.g. cooling the body's surface using a cooling blanket) lead to thermogenesis. This is a response that involves shivering (which is unpleasant for the patient) and, more importantly, increases the body's production of heat and which opposes the effect of cooling. However, in nature there is a way of triggering hypothermia that reduces thermogenesis: torpor.
Torpor is a reversible regulated state of reduced body temperature and metabolism. It occurs naturally in some animals in response to food shortage. Hibernation is the name of one form of profound torpor that occurs seasonally. However, recent research has shown that particular drugs can be used to trigger torpor in animals that do not naturally go into torpor. Other research has shown that even some primates naturally go into torpor. As a result, there is growing promise that the neuroprotective properties of torpor can be harnessed to develop new effective treatments for stroke. However, before this can happen, several questions need to be answered:
1) How does torpor affect brain activity?
2) How does torpor affect brain function?
3) Does inducing torpor using drugs protect the brain against damage resulting from a stroke?
In order to investigate these questions, the following experiments will be performed in mice:
1) Recording of brain activity during torpor
2) Assessing how performance in a tests of brain function is affected by torpor
3) Assessing how torpor affects the extent of brain damage and impairment of function that would be caused by a stroke
Thrombolysis, a drug treatment that dissolves the clot, has proven to be very effective against stroke. However, the time window in which it can be used is short (4.5 hours). Therefore, stroke scientists have been researching new methods of treating stroke that may complement thrombolysis and improve outcome in post-stroke patients. Research in animals shows that hypothermia is the most effective neuroprotective therapy (i.e. a treatment that protects brain cells from damage e.g. due to a stroke). However, current ways of triggering hypothermia (e.g. cooling the body's surface using a cooling blanket) lead to thermogenesis. This is a response that involves shivering (which is unpleasant for the patient) and, more importantly, increases the body's production of heat and which opposes the effect of cooling. However, in nature there is a way of triggering hypothermia that reduces thermogenesis: torpor.
Torpor is a reversible regulated state of reduced body temperature and metabolism. It occurs naturally in some animals in response to food shortage. Hibernation is the name of one form of profound torpor that occurs seasonally. However, recent research has shown that particular drugs can be used to trigger torpor in animals that do not naturally go into torpor. Other research has shown that even some primates naturally go into torpor. As a result, there is growing promise that the neuroprotective properties of torpor can be harnessed to develop new effective treatments for stroke. However, before this can happen, several questions need to be answered:
1) How does torpor affect brain activity?
2) How does torpor affect brain function?
3) Does inducing torpor using drugs protect the brain against damage resulting from a stroke?
In order to investigate these questions, the following experiments will be performed in mice:
1) Recording of brain activity during torpor
2) Assessing how performance in a tests of brain function is affected by torpor
3) Assessing how torpor affects the extent of brain damage and impairment of function that would be caused by a stroke
Technical Summary
BACKGROUND
Stroke is a leading cause of adult disability and mortality globally. Hypothermia is the most potent experimental neuroprotective therapy for stroke. However, the thermogenic response to hypothermia has limited its progress in clinical trials. Thermogenesis is suppressed in torpor - a state of regulated hypothermia occurring naturally in some animals in response to food shortage. Recent studies show torpor can be pharmacologically-induced via activation of A1 adenosine receptors (A1AR) in the central nervous system, even in animals incapable of natural torpor. Consequently, there is growing promise that neuroprotective properties of torpor can be harnessed to develop novel therapies for acute stroke. However, key aspects of torpor are not well-understood and require further investigation as per below.
OBJECTIVES
To investigate in mice:
1) The precise temporal dynamics of brain activity during torpor, and whether single neurons are less excitable and more resistant to excitotoxic damage;
2) Torpor's effect on subsequent behavioural performance;
3) The neuroprotective properties of pharmacologically-induced torpor in stroke models, comparing these with adenosine's hypothermia-independent neuroprotective effects.
METHODS
1) Electrically-evoked local field potentials will be measured during torpor in mice; spike-sorting algorithms will be used to distil individual neurons' activity profiles.
2) Performance of mice in a battery of behavioural tests will be measured before, during and after torpor.
3) Stroke will be induced via insertion of a carotid intraluminal suture under anaesthesia (a minimally-invasive and reproducible method well-established in mice). Torpor will subsequently be induced by intracerebroventricular-infusion of A1AR agonist cyclohexyladenosine. Infarct size and behavioural performance of mice will be quantified. Experiments will be repeated in mice artificially-maintained at normal body temperature.
Stroke is a leading cause of adult disability and mortality globally. Hypothermia is the most potent experimental neuroprotective therapy for stroke. However, the thermogenic response to hypothermia has limited its progress in clinical trials. Thermogenesis is suppressed in torpor - a state of regulated hypothermia occurring naturally in some animals in response to food shortage. Recent studies show torpor can be pharmacologically-induced via activation of A1 adenosine receptors (A1AR) in the central nervous system, even in animals incapable of natural torpor. Consequently, there is growing promise that neuroprotective properties of torpor can be harnessed to develop novel therapies for acute stroke. However, key aspects of torpor are not well-understood and require further investigation as per below.
OBJECTIVES
To investigate in mice:
1) The precise temporal dynamics of brain activity during torpor, and whether single neurons are less excitable and more resistant to excitotoxic damage;
2) Torpor's effect on subsequent behavioural performance;
3) The neuroprotective properties of pharmacologically-induced torpor in stroke models, comparing these with adenosine's hypothermia-independent neuroprotective effects.
METHODS
1) Electrically-evoked local field potentials will be measured during torpor in mice; spike-sorting algorithms will be used to distil individual neurons' activity profiles.
2) Performance of mice in a battery of behavioural tests will be measured before, during and after torpor.
3) Stroke will be induced via insertion of a carotid intraluminal suture under anaesthesia (a minimally-invasive and reproducible method well-established in mice). Torpor will subsequently be induced by intracerebroventricular-infusion of A1AR agonist cyclohexyladenosine. Infarct size and behavioural performance of mice will be quantified. Experiments will be repeated in mice artificially-maintained at normal body temperature.
Planned Impact
Impact on UK society and economy will be generated via the following:
1) Benefit to patients
Stroke is a UK and global leading cause of adult disability and mortality. There are over 100,000 strokes annually in the UK, and over 1.2 million stroke survivors. In 2015, stroke killed 6.24 million people worldwide. The aim of the proposed project is to develop a basis for translating the neuroprotective properties of torpor into a therapy for acute ischaemic stroke. Such a therapy could be used either independently or synergistically with established therapies such as thrombolysis or thrombectomy, with the aim of significantly improving clinical outcome following a stroke. Patients (and their carers) would benefit from reduced morbidity, reduced mortality and reduced costs of private care post-stroke.
2) Benefit to the National Health Service
The NHS and social care costs of stroke total approximately £1.7 billion annually in England alone. Direct and indirect care accounts for the vast majority of this, with treatment costs only accounting for 5% of this cost (Stroke Association Statistics, 2017). Clearly, there is an under-met need for advances in both prevention and acute treatment of stroke. Although stroke prevention is effective at reducing the cost of stroke to the NHS, we are still far from full prevention. Therefore, there is a clear benefit to the NHS of novel effective therapies in the context of acute stroke services.
As previously alluded to, other branches of NHS services may also benefit from a novel neuroprotective therapy, e.g. neonatal services (via a neuroprotective therapy for neonatal hypoxaemia), surgery and anaesthetics (e.g. for some trauma and cardiothoracic surgeries which already utilise therapeutic hypothermia).
3) Academic beneficiaries (in a separate section of this application form)
4) Benefits to industry and the overall UK economy
The UK is an international leader in biomedical and biotechnology research. Findings from this project may attract national and international research and development interest e.g. pharmaceutical and biotechnology companies wishing to commercialise induced torpor for medical and non-medical uses. Examples of such companies already exist in the United States, e.g. Space Works. Such funding would contribute to solidifying the UK's position as a global scientific centre of excellence.
1) Benefit to patients
Stroke is a UK and global leading cause of adult disability and mortality. There are over 100,000 strokes annually in the UK, and over 1.2 million stroke survivors. In 2015, stroke killed 6.24 million people worldwide. The aim of the proposed project is to develop a basis for translating the neuroprotective properties of torpor into a therapy for acute ischaemic stroke. Such a therapy could be used either independently or synergistically with established therapies such as thrombolysis or thrombectomy, with the aim of significantly improving clinical outcome following a stroke. Patients (and their carers) would benefit from reduced morbidity, reduced mortality and reduced costs of private care post-stroke.
2) Benefit to the National Health Service
The NHS and social care costs of stroke total approximately £1.7 billion annually in England alone. Direct and indirect care accounts for the vast majority of this, with treatment costs only accounting for 5% of this cost (Stroke Association Statistics, 2017). Clearly, there is an under-met need for advances in both prevention and acute treatment of stroke. Although stroke prevention is effective at reducing the cost of stroke to the NHS, we are still far from full prevention. Therefore, there is a clear benefit to the NHS of novel effective therapies in the context of acute stroke services.
As previously alluded to, other branches of NHS services may also benefit from a novel neuroprotective therapy, e.g. neonatal services (via a neuroprotective therapy for neonatal hypoxaemia), surgery and anaesthetics (e.g. for some trauma and cardiothoracic surgeries which already utilise therapeutic hypothermia).
3) Academic beneficiaries (in a separate section of this application form)
4) Benefits to industry and the overall UK economy
The UK is an international leader in biomedical and biotechnology research. Findings from this project may attract national and international research and development interest e.g. pharmaceutical and biotechnology companies wishing to commercialise induced torpor for medical and non-medical uses. Examples of such companies already exist in the United States, e.g. Space Works. Such funding would contribute to solidifying the UK's position as a global scientific centre of excellence.
People |
ORCID iD |
| Yige Huang (Principal Investigator / Fellow) |
Publications
Huang Y
(2021)
The relationship between fasting-induced torpor, sleep, and wakefulness in laboratory mice
in SLEEP
Huang Y.
(2019)
THE RELATIONSHIP BETWEEN FASTING-INDUCED TORPOR, SLEEP AND WAKEFULNESS IN LABORATORY MICE
in SLEEP MEDICINE
Lo EH
(2021)
Circadian Biology and Stroke.
in Stroke
Northeast R
(2019)
Sleep homeostasis during daytime food entrainment in mice
in Sleep
Yamagata T
(2021)
The hypothalamic link between arousal and sleep homeostasis in mice.
in Proceedings of the National Academy of Sciences of the United States of America