HCAR1 lactate treatment: effects on neurogenesis, angiogenesis and anxiety-level of mice
Depression and anxiety disorders have been listed among the ten most common causes of death in almost every country in the entire world (Smith, 2014), but there are still no satisfying treatment. Physical activity has been reported to protect against several neurological and psychological diseases including depression and anxiety disorders. Similar to antidepressants, exercise has also been shown to increase adult neurogenesis, which is a continuous generation of new neurons, in the hippocampus (van Praag et al., 1999, Malberg et al. 2000). One theory is that the new neurons are involved in treatment of depression and anxiety disorders (Jacobs et al., 2000). Exercising muscles produce lactate, and some of the exercise related benefits of high intensity training have recently been mimicked by injection of lactate. Our group identified a lactate receptor, hydroxycarboxylic acid receptor 1 (HCAR1) also called GPR81, in the mammalian brain (Lauritzen et al., 2014; Morland et al., 2015). Recent findings suggest crucial roles of HCAR1 in the brain, linking exercise, increased brain levels of vascular endothelial growth factor and increased formation of blood vessels (angiogenesis) in the hippocampus and cerebral cortex (Morland et al., 2017).
Our hypothesis is that HCAR1 stimulation increases neurogenesis and angiogenesis and reduces anxiety-related behavior in mice at least equal to the most commonly used antidepressant medication. This discovery could potentially be used to develop new and improved antidepressant therapeutics with HCAR1 agonists and is therefore of high interest to the society. We plan to investigate this by treating mice with knockout of HCAR1 (HCAR1 KO) and wild type (wt) mice with a HCAR1 agonist, antidepressant, or saline control (20 wt and 20 HCAR1 KO mice in each group, 120 mice in total). We will analyze markers for neurogenesis and angiogenesis and study the morphology of the newborn neurons in the hippocampus of these mice. We will measure anxiety-like behaviour in the mice by the novelty-suppressed feeding test (Santarelli et al. 2003). We chose this test since it has shown to be sensitive to antidepressant treatment and to be gentle for the mice. The group size is based on our previous experience, which is the least number of animals that can reveal significant differences in anxiety-related behaviour caused by antidepressant treatment.The working team is well trained and able to successfully perform animal research. Ethical concerns will be fully addressed according to law and civil regulations.
Our hypothesis is that HCAR1 stimulation increases neurogenesis and angiogenesis and reduces anxiety-related behavior in mice at least equal to the most commonly used antidepressant medication. This discovery could potentially be used to develop new and improved antidepressant therapeutics with HCAR1 agonists and is therefore of high interest to the society. We plan to investigate this by treating mice with knockout of HCAR1 (HCAR1 KO) and wild type (wt) mice with a HCAR1 agonist, antidepressant, or saline control (20 wt and 20 HCAR1 KO mice in each group, 120 mice in total). We will analyze markers for neurogenesis and angiogenesis and study the morphology of the newborn neurons in the hippocampus of these mice. We will measure anxiety-like behaviour in the mice by the novelty-suppressed feeding test (Santarelli et al. 2003). We chose this test since it has shown to be sensitive to antidepressant treatment and to be gentle for the mice. The group size is based on our previous experience, which is the least number of animals that can reveal significant differences in anxiety-related behaviour caused by antidepressant treatment.The working team is well trained and able to successfully perform animal research. Ethical concerns will be fully addressed according to law and civil regulations.