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(http://www.niehs.nih.gov//portfolio/index.cfm?do=portfolio.grantdetail&&grant_number=R01ES035827&format=word)
| Principal Investigator: Guilarte, Tomas R | |
|---|---|
| Institute Receiving Award | Florida International University |
| Location | Miami, FL |
| Grant Number | R01ES035827 |
| Funding Organization | National Institute of Environmental Health Sciences |
| Award Funding Period | 08 Feb 2024 to 30 Nov 2028 |
| DESCRIPTION (provided by applicant): | Abstract: Childhood lead (Pb2+) exposure results in cognitive function deficits and is associated with neuropsychiatric disorders such as schizophrenia (SZ) later in life. Deficits in cognitive function and sensorimotor gating represent core symptoms of chronic early life Pb2+ exposure (CELLE) and psychiatric disease resulting in life-long disability that is currently untreatable. To develop effective treatments, it is critical to understand and integrate neurobiological deficits at multiple levels of analysis. Our proposed studies aim to further understand the effects of CELLE at the cellular level and the resulting effects on brain networks and circuits, regional brain volume and connectivity, and how these changes result in behavioral deficits filling gaps in knowledge on the neurobiology of CELLE as a risk factor for psychiatric disease. Our central hypothesis is that CELLE alters the maturation and function of parvalbumin (PV)-positive GABAergic interneurons (PVGI), disrupting the excitatory/inhibitory (E/I) balance, producing networks and circuits abnormalities and brain dysconnectivity, leading to behavioral and cognitive deficits. We will also test the hypothesis that the brain- derived neurotrophic factor (BDNF)-mimetic and blood-brain-barrier permeable nutraceutical 7,8-dihydroxyflavone (7,8-DHF) is effective in mitigating the negative effects of CELLE with translational implications for the treatment of Pb2+-exposed children. To test these hypotheses, we propose the following specific aims (SA): SA1 will determine the effects of CELLE on behavior and cognitive function and the developmental trajectory of PVGI in the middle prefrontal cortex (mPFC) and hippocampus (HIPP). Behaviors will include reference and working memory in the 8-arm radial arm maze (8-RAM) and pre-pulse inhibition of the startle response (PPI) using a life course approach. We will also examine PVGI development using cell markers including PV (cell identification), GAD67, and perineuronal nets (PNN) in the mPFC and HIPP. SA2 will determine the effect of CELLE in mPFC-HIPP at the network and circuit levels during active 8-RAM and PPI behaviors and relate them to the PVGI markers. CELLE-induced electrophysiological network abnormalities will be examined in delta (1-4Hz), theta (4-8Hz), and gamma (30-120Hz) ranges during behavior. Circuitry contributing to abnormal network activity will be tested in mPFC-HIPP circuitry using a viral-based inhibitory designer receptors specifically activated by a designer drug (DREAADs; retroAAV-hM4Di) approach. We will also perform volumetric MRI and fiber tractography to understand CELLE effects that will complement and augment the electrophysiology studies on brain connectivity. SA3 will test a strategy to restore normal function in CELLE rats. We will use the nutraceutical 7,8-DHF, a BDNF mimetic and TrkB agonist, as a potential therapy for CELLE effects across several levels of analysis as described in SA1 and SA2. The proposed studies will provide new foundational knowledge about the neurobiology of CELLE as a risk factor for psychiatric disease. Furthermore, they will assess the effectiveness of 7,8-DHF as a therapy for translational studies with potential benefits to millions of Pb2+-exposed children. |
| Science Code(s)/Area of Science(s) |
Primary: 61 - Neurodevelopmental Secondary: 03 - Carcinogenesis/Cell Transformation |
| Publications | No publications associated with this grant |
| Program Officer | Jonathan Hollander |