The mission of the Neuromolecular Dynamics Team is to conduct neuroimaging research
on animal models of neuropsychiatric illnesses in conjunction with multimodal
technologies, including neuropathological, behavioral and electrophysiological analyses,
leading to direct insights into early diagnosis and efficacious therapies of the diseases.
In addition, our research projects are committed to elucidating molecular interactions that
underlie visibility of neuroglial components in intravital neuroimaging.
Alzheimer's disease and associated neurodegenerative disorders exhibit characteristic
neuropathological alterations, but definite diagnoses of these diseases cannot be
antemortemly made for living patients. Conversely, psychiatric conditions including
depression and schizophrenia are clinically diagnosed on a symptomatic basis, although
no hallmark lesions have been discovered in the postmortem brains of these illnesses.
Several lines of hypotheses have attempted to link neuropathological changes and clinical
manifestations, by focusing on specific molecules that may be implicated in neuronal
injuries and consequently the onset of neuropsychiatric symptoms. The Molecular Neurobiology
Team is engaged in the following projects on animal models providing potential evidence for
such working theories:
(1) Amyloid hypothesis of Alzheimer's disease pathogenesis
Deposition of pathological fibrils termed amyloid is a hallmark lesion in the Alzheimer's
disease brain, and it is hypothesized to induce neurodegeneration resulting in the clinical
onset of the disease. This view is supported by the fact that genetically engineered mice
overexpressing amyloidogenic molecules develop progressive loss of neuronal integrity,
rationalizing our works on the establishment of diagnostic and therapeutic approaches
targeting brain amyloidosis with the utility of these animal models.
(2) Monoamine hypothesis of psychiatric disorders
A body of evidence has indicated mechanistic association of altered monoamine
(dopamine, serotonin, etc.) neurotransmissions with depression and schizophrenia.
On this theoretical basis, we aim to unravel molecular events that are critically
involved in the pathogenesis of these diseases, by reverse genetics techniques.
Our current investigations include the in vivo imaging of mutant mice behaviorally
recapitulating mental illnesses and the assessment of neurochemical and symptomatic
changes in these animals following pharmacological interventions in monoamine
PET images of brain amyloid in the model mice. In contrast to low-level retention
of radioactive signals in the normal mouse, progressive accumulation of amyloid in
the brains of Alzheimer's disease models is observed as a function of age.
Mapping of dopamine D1 receptors in the living wild-type mouse brain. Intense
expression of the receptors in the striatum is captured by PET.
- Makoto Higuchi
- Team Leader
- Hin Ki, Jun Maeda, Masahiro Maruyama, Naruhiko Sahara, Takashi Horiguchi
- Senior Researcher
- Maiko Ono, Masaki Tokunaga
- Takeharu Minamihisamatsu, Sayuri Sasaki
- Tecnical Staff
- Hiroyuki Kaneko, Barron Anna
- Postdoctoral Fellow
- Kana Osawa