- Title Information
- Title
- Targeted Circuit Manipulation for Ameliorating Huntington's Disease Pathogenesis
- Type of Resource (primo)
- images
- Abstract
- Almost 30 years after identifying the genetic mutation underlying Huntington’s disease (HD), treatments remain limited to managing late-stage symptoms of motoric, psychiatric, and cognitive deficits. Findings from patients and mouse models of HD point to pre-symptomatic imbalances in neuronal circuit activity, well before any overt symptoms are observed. Our central hypothesis is that manipulating the firing activity within selected microcircuits before the onset of symptoms by chemogenetic inhibition and/or excitation of key target populations will slow HD disease progression. A crucial early event in HD is the pathological increase in the overall excitatory output from cortex onto striatum. The enhanced excitability of cortical pyramidal neurons (CPNs) in pre-symptomatic HD is one key target for correctional intervention. The window before the onset of symptoms presents an opportunity to inhibit the firing rate of CPNs projecting to the striatum with the prospect of preventing or slowing disease progression. For manipulation of neuronal activity, we utilized bioluminescent optogenetics (BL-OG) that employs light-emitting luciferases to activate light-sensing opsins. We are testing the effects of circuit manipulation on preventing or delaying behavioral deficits in the R6/2 transgenic mouse model of HD. To selectively target CPNs projecting to the striatum, an AAV vector carrying a Cre-inducible inhibitory LMO (AAV-CamKIIa-DIO-NCS3-hGtACR1) was injected into the cortex of 3-week-old mice, while a retrogradely transported Cre-recombinase (AAVrg-hSyn-Cre-P2A-dTomato) was injected into the striatum. Two weeks later, luciferin or vehicle were administered once every other day for 2 weeks to decrease CPN firing. Rotarod, open field, and CatWalk were used to assess motor coordination, exploratory behavior, and gait function. We assessed cognitive behavior through water T-maze, novel object recognition test, and passive avoidance test. Our studies will contribute to understanding how microcircuit manipulation influences motor and cognitive behavior in HD and will drive translational progress toward novel therapeutic purposes.
- Name
- Name Part
- Ikefuama, Ebenezer C.
- Role
- Role Term (marcrelator)
(authorityURI="http://id.loc.gov/vocabulary/relators", valueURI="http://id.loc.gov/vocabulary/relators/cre")
- Creator
- Name
- Name Part
- Schalau, R.C.
- Role
- Role Term (marcrelator)
(authorityURI="http://id.loc.gov/vocabulary/relators", valueURI="http://id.loc.gov/vocabulary/relators/cre")
- Creator
- Name
- Name Part
- Uprety, Anusha M.
- Role
- Role Term (marcrelator)
(authorityURI="http://id.loc.gov/vocabulary/relators", valueURI="http://id.loc.gov/vocabulary/relators/cre")
- Creator
- Name
- Name Part
- Tree, Maya O.
- Role
- Role Term (marcrelator)
(authorityURI="http://id.loc.gov/vocabulary/relators", valueURI="http://id.loc.gov/vocabulary/relators/cre")
- Creator
- Name
- Name Part
- Dunbar, G. L.
- Role
- Role Term (marcrelator)
(authorityURI="http://id.loc.gov/vocabulary/relators", valueURI="http://id.loc.gov/vocabulary/relators/cre")
- Creator
- Name
- Name Part
- Rossignol, J.
- Role
- Role Term (marcrelator)
(authorityURI="http://id.loc.gov/vocabulary/relators", valueURI="http://id.loc.gov/vocabulary/relators/cre")
- Creator
- Name
- Name Part
- Hochgeschwender, Ute
- Role
- Role Term (marcrelator)
(authorityURI="http://id.loc.gov/vocabulary/relators", valueURI="http://id.loc.gov/vocabulary/relators/cre")
- Creator
- Origin Information
- Date Created
- 2023-04-25
- Subject (Local)
- Topic
- Bioluminescence
- Subject (Local)
- Topic
- Optogenetics
- Subject (Local)
- Topic
- pyramidal neurons
- Subject (Local)
- Topic
- Huntington's Disease
- Subject (Local)
- Topic
- circuit manipulation
- Genre
- posters
- Note:
funding
- This research was supported by the the National Science Foundation (NSF) and its Division of Biological Infrastructure under Award No. 1707352 and CBET-1464686; Central Michigan University Spring 2023 Student Performance, Exhibition, Competition, or Presentation (PECP) Grant to ECI
- Access Condition:
use and reproduction
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- Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
- Access Condition:
logo
(href="https://licensebuttons.net/l/by-nc-nd/4.0/88x31.png")
- Access Condition:
rights statement
(href="http://rightsstatements.org/vocab/InC/1.0/")
- In Copyright
- Identifier:
DOI
- 10.26300/a52r-v486