HCAR1 in mood disorders
Major depressive disorder, a disorder characterised by a lack of joy along with other cognitive symptoms like worsened memory, is a leading cause of disability in the world for which exercise has a therapeutic effect. One of the effects of exercise in humans is improved volume of and blood flow to the hippocampus, a brain region involved in memory and mood. We have previously shown that lactate, produced in muscles during exercise, stimulates the formation of new blood vessels in the hippocampus in mice. The aim of this experiment is to better understand the role of lactate in improving hippocampal health by comparing depression-like behaviour and measuring patterns of brain activity in the hippocampus of mice that have undergone interventions with either exercise or injections of lactate to a control group.
The experiments require 30 homozygous knock-out and 30 wild type mice which statistically requires the breeding of 120 mice (174 mice in total, including the breeders). In the exercise protocol, the animals will undergo a maximal exercise-capacity test that is classified as "betydelig belastende". The rest of the tests are classified as "lett belastende" due to precautions taken to minimise stress. None of the exercise or behavioural tests are likely to induce pain.
By better understanding the effects of exercise and lactate on behavior and the function of the hippocampus it will be possible to refine the treatment of depression through exercise therapy or novel therapies, which could help many people suffering from the disorder.
Studying phenotypes requires the use of animals and cannot be replaced by cell cultures or computer models. In these experiments the least amount of animals necessary to show statistical significance is used. Through previous work the methods have been improved to induce as little stress and pain as possible in the animals.
The daily exercise experiments are NOT likely to induce pain or stress in the animals, but the maximum endurance capacity (performed twice for each animal; two weeks apart) is stressful. During the exercise and injections procedures, each animal is closely watched by the operators and their wellbeing will be scored according to the attached score scheme. Should an animal display serious signs of distress or disease, like fur changes, altered behaviour or other signs of distress, it will be euthanized by cervical dislocation and decapitated.
We have extensive experience with this type of exercise and lactate interventions in mice. Intraperitoneal injections of lactate does has not cause lesions or damage to the skin in our previous experiments. Most animals chose to run, even during the brakes, suggesting that the exercise regime is not painful or stressful. We have sometimes allowed single mice to have extra rest during the interwalls if they perform below expectations. Through these precautions, withdrawal of animals form the exercise regime due to injuries or exhaustion has not been necessary in our previous studies, but the need to do so will be continuously judged in this project, as described.
After the intervention period the mice will be euthanised and used in experiments as described in the application. As an addition to the application, mice may be euthanised while deeply anesthetized by isoflurane.
The experiments require 30 homozygous knock-out and 30 wild type mice which statistically requires the breeding of 120 mice (174 mice in total, including the breeders). In the exercise protocol, the animals will undergo a maximal exercise-capacity test that is classified as "betydelig belastende". The rest of the tests are classified as "lett belastende" due to precautions taken to minimise stress. None of the exercise or behavioural tests are likely to induce pain.
By better understanding the effects of exercise and lactate on behavior and the function of the hippocampus it will be possible to refine the treatment of depression through exercise therapy or novel therapies, which could help many people suffering from the disorder.
Studying phenotypes requires the use of animals and cannot be replaced by cell cultures or computer models. In these experiments the least amount of animals necessary to show statistical significance is used. Through previous work the methods have been improved to induce as little stress and pain as possible in the animals.
The daily exercise experiments are NOT likely to induce pain or stress in the animals, but the maximum endurance capacity (performed twice for each animal; two weeks apart) is stressful. During the exercise and injections procedures, each animal is closely watched by the operators and their wellbeing will be scored according to the attached score scheme. Should an animal display serious signs of distress or disease, like fur changes, altered behaviour or other signs of distress, it will be euthanized by cervical dislocation and decapitated.
We have extensive experience with this type of exercise and lactate interventions in mice. Intraperitoneal injections of lactate does has not cause lesions or damage to the skin in our previous experiments. Most animals chose to run, even during the brakes, suggesting that the exercise regime is not painful or stressful. We have sometimes allowed single mice to have extra rest during the interwalls if they perform below expectations. Through these precautions, withdrawal of animals form the exercise regime due to injuries or exhaustion has not been necessary in our previous studies, but the need to do so will be continuously judged in this project, as described.
After the intervention period the mice will be euthanised and used in experiments as described in the application. As an addition to the application, mice may be euthanised while deeply anesthetized by isoflurane.