Michiru Hirasawa

Michiru Hirasawa Laboratory

Our body is constantly exposed to the influence of changing environment externally and internally. The brain is responsible for detecting these changes and countering them to maintain internal stability. Disruptions in these mechanisms can lead to various diseases. To understand how the brain changes under homeostatic challenges, we focus on two brain regions: the hypothalamus, a key brain region that regulates homeostasis, and the hippocampus, involved in learning and memory, that is vulnerable to disrupted homeostasis.

Homeostasis & Hypothalamus

Healthy eating and a good night’s sleep are important facets of healthy life. However, lack of sleep and temptations of fatty foods are highly common in modern society. To understand what happens in the brain during obesity and sleep deprivation, we investigate the molecular and cellular changes in the hypothalamus, the brain region responsible for maintaining homeostasis, during high-fat diet consumption and sleep deprivation.

Ongoing projects:

• Neuroinflammation in obesity: High-fat diet causes inflammation of the hypothalamus, which in turn drives further caloric intake and obesity. On the other hand, hypothalamic inflammation occurs in disease states such as infection and cancer, resulting in loss of appetite and weight. We determined that appetite-promoting melanin-concentrating hormone (MCH) neurons in the hypothalamus can bidirectionally respond to inflammatory mediator prostaglandin E₂ (PGE₂), providing a cellular mechanism by which intense inflammation induces weight loss while mild inflammation causes obesity. We are currently investigating how PGE₂ signaling in MCH neurons contributes to obesity-related conditions in a sex-dependent manner, such as cognitive impairment and anxiety.
  Funded by CIHR
  
  
• Glutamate and GABA transporters in homeostatic circuitry: Glutamate and GABA are the primary excitatory and inhibitory neurotransmitters in the brain, respectively. Following release into the extracellular space, temporal and spatial spread of these neurotransmitters is tightly regulated by glutamate and GABA transporters. We are investigating how these transporters regulate hypothalamic cells involved in energy and sleep homeostasis, namely MCH neurons and orexin neurons, and how these regulatory mechanisms change in response to homeostatic challenges such as high-fat diet, fasting and sleep deprivation.
  Funded by NSERC
  

Chemotherapy effects on the brain

Nearly 1 in 2 Canadians will develop cancer during their lifetime. However, advancements in early detection and treatments have significantly improved the survival rate, placing greater importance on long-term health of cancer patients and survivors. Chemotherapy is effective for many cancers, but it induces often debilitating, long-term neurological side effects for which therapeutic options are scarce. To address this unmet need, we aim to understand the effects of chemotherapy drugs on the brain and to test potential treatments to limit brain damage.

Ongoing projects:

• Chemotherapy-induced fatigue (CIF): Most people receiving chemotherapy experience severe fatigue, which can manifest as physical, mental and affective fatigue. Orexin neurons in the hypothalamus are responsible for keeping us awake and energetic. To determine the role of orexin neurons in CIF, we are investigating the cellular mechanisms by which chemotherapy drugs affect these This study will aid in identifying novel therapeutic approaches for CIF.
  Funded by the Canadian Cancer Society

• Chemotherapy-induced cognitive impairment (chemobrain): Cognitive symptoms are common in chemotherapy, such as impaired memory, attention, information processing, planning, and decision-making, which can persist for many years after the cancer Using a mouse model of chemobrain, we are investigating how chemotherapy drugs impact the functions and structures of the hippocampus, the brain region critical for learning and memory. We are also testing potential treatments to limit the adverse effects of chemotherapy on the hippocampus.
  Funded by the Vitamin Research Fund, Medical Research Fund (MRF)

RECENT PUBLICATIONS

Fang LZ, Linehan V, Licursi M, Alberto CO, Power JL, Parsons MP, Hirasawa M (2023) Prostaglandin E₂ activates melanin-concentrating hormone neurons to drive diet-induced obesity. Proc Natl Acad Sci U S A. 120(31):e2302809120. doi: 10.1073/pnas.2302809120

Fang LZ, Lily Vidal JA, Hawlader O, Hirasawa M (2023) High-fat diet-induced elevation of body weight set point in male mice. Obesity (Silver Spring) 31(4):1000-1010. doi: 10.1002/oby.23650.

Linehan V, Hirasawa M (2022) Short-term Fasting Induces Alternate Activation of Orexin and Melanin-concentrating Hormone Neurons in Rats. Neuroscience 491:156-165. doi: 10.1016/j.neuroscience.2022.04.006.

Linehan V, Fang LZ, Parsons MP, Hirasawa M (2020) High-fat diet induces time-dependent synaptic plasticity of the lateral hypothalamus. Mol Metab 36:100977. doi: 10.1016/j.molmet.2020.100977.

Fifield KE, Rowe TM, Raman-Nair JB, Hirasawa M, Vanderluit JL (2019) Prolonged High Fat Diet Worsens the Cellular Response to a Small, Covert-like Ischemic Stroke. Neuroscience 406:637-652. doi: 10.1016/j.neuroscience.2019.01.050.

Briggs C, Bowes SC, Semba K, Hirasawa M (2019) Sleep deprivation-induced pre- and postsynaptic modulation of orexin neurons. Neuropharmacology 154:50-60. doi: 10.1016/j.neuropharm.2018.12.025

Linehan V, Rowe TM, Hirasawa M (2019) Dopamine modulates excitatory transmission to orexin neurons in a receptor subtype-specific manner. Am J Physiol Regul Integr Comp Physiol 316(1):R68-R75. doi: 10.1152/ajpregu.00150.2018.

Cui D, Peng Y, Zhang C, Li Z, Su Y, Qi Y, Xing M, Li J, Kim GE, Su KN, Xu J, Wang M, Ding W, Piecychna M, Leng L, Hirasawa M, Jiang K, Young L, Xu Y, Qi D, Bucala R.J (2018) Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy. Clin Invest 128(11):4997-5007. doi: 10.1172/JCI93090

Linehan V, Hirasawa M (2018) Electrophysiological Properties of Melanin-Concentrating Hormone and Orexin Neurons in Adolescent Rats. Front Cell Neurosci 12:70. doi: 10.3389/fncel.2018.00070.

Briggs C, Hirasawa M, Semba K (2018) Sleep Deprivation Distinctly Alters Glutamate Transporter 1 Apposition and Excitatory Transmission to Orexin and MCH Neurons. J Neurosci 38(10):2505-2518. doi: 10.1523/JNEUROSCI.2179-17.2018.

Linehan V, Fang LZ, Hirasawa M (2018) Short-term high-fat diet primes excitatory synapses for long-term depression in orexin neurons. J Physiol 596(2):305-316. doi: 10.1113/JP27517