About Dr. Dan Levy

Dan Levy, PhD

Dr. Dan Levy in his labAssociate Professor of Anaesthesia, Harvard Medical School

Dan Levy's research group is interested in addressing the function of the nociceptive sensory system that innervates the cerebral meninges as well as mechanisms that contribute to its activation, which is considered paramount for the genesis of headaches, such as migraine.

Headache is one of the most common types of pain, yet our understanding of why and how different types of headaches emerge remains incomplete. Acute cases of headache may be the result of a homeostatic response to an abnormal physiological condition, such as the exposure to high altitude, or excessive alcohol consumption (alcohol hangover) and are often reversible. However,neurological disorders such as migraine involve recurrent headaches that are difficult to treat and carry an enormous burden for individuals and societies due to their high prevalence, significant disability, and considerable economic costs. A major hurdle to the development of novel, evidence-based treatments for these headache conditions is the poor understanding of their underlying pathology. The major goal of the Levy lab is to define the mechanisms underlying the onset of headaches that are vital for the development of therapeutic approaches for prevention of the onset of headaches.

To address this fundamental question, research in the Levy lab focuses on the intracranial meninges (the dura, arachnoid and pia mater layers that cover and protect the brain) and its sensory innervation - the peripheral neuronal population whose activation has been most directly implicated in the genesis of headaches. The responses of meningeal sensory afferents are being studied using in vivo extracellular single-unit electrophysiology in anesthetized animals, as well as in awake animals using a state-of-the-art two-photon calcium imaging approach. To decipher the triggering mechanisms of headache, the Levy lab combines these approaches with pharmacological and genetic tools to investigate key cellular and molecular processes that modulate the responses of these headache-producing neurons under conditions that have been linked to headache genesis in humans.

Studies of the mechanosensitivity of meningeal sensory neurons are of particular importance to better understand the mechanisms underlying the exacerbation of certain types of headache (e.g. migraine) during physical activities, such as climbing stairs. Dr. Levy and colleagues already identified several endogenous mediators and intracellular signaling cascades (e.g. cAMP-PKA, NO-cGMP, pERK) that contribute to the enhancement or inhibition of these sensory neurons. Dr. Levy’s team further revealed the role of meningeal immune cells (i.e. mast cells, which are also implicated in allergies) as key endogenous factors that can lead to the activation and increased mechanosensitivity of the meningeal sensory system and also identified the inhibition of meningeal afferent responses as a key mechanism that contribute to the headache abortive properties of a key over-the-counter analgesic, naproxen.

To study specifically mechanisms underlying migraine headache, the Levy lab employs different triggering models, including cortical spreading depression (CSD), and systemic administration of nitroglycerin. They also investigate mechanisms of post-traumatic headache, by studying the effects of mild closed head injury, a model of mild brain injury, or concussion. They also use behavioral assays of pain hypersensitivity, such as measurements of cephalic mechanical hypersensitivity, as well as novel approaches to assess headache and migraine-like behaviors in rodents, such as changes in wheel running, open field behavior, and grimacing.

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