Intravenous delivery of Viral Vectors to Mouse Brain
1 Purpose: The mammalian brain is arguably the most complex structure on Earth, with billions of intricately interconnected neurons comprising the circuitry underlying our behavior. This anatomical complexity greatly complicates the search for effective treatments of neurological and neuropsychiatric disorders because they often have to do with problems in particular neural circuits rather than the brain as a whole. This makes systemic application of drugs problematic: while they may do the right thing in the right circuit, they also do the wrong thing in wrong circuits, leading to serious side effects. My lab is recently developed a bioinformatically-based approach to making molecular genetic tools for manipulating specific parts of neural circuits we call Enhancer-Driven Gene Expression (EDGE). While it has generated many useful research tools, it also has the potential to lead to a new generation of neuronal celltype-specific vectors capable of both more effectively modeling and, ultimately, treating diseases of the human brain. We therefore need to screen large numbers of EDGE-AAVs, so in this proposal we will optimize the noninvasive delivery of viral vectors targeting specific neuronal cell types by comparing the efficacy of the two major IV administration techniques, retro-orbital (RO) versus tailvein (TV) administration.
2 Distress: Both RO and TV are minimally invasive, mild procedures. The animal is lightly anesthetized and vector is delivered intravenously.
3 Expected benefit: Given that we have been screening these vectors via intracranial stereotactic injections (i.e. brain surgery) to date , switching to IV will lead to both a significant reduction of number of animals used (one can see the whole brain at once, rather than having to do multiple injections) and also reduce the level of distress relative to our current protocol to screen AAV vectors via stereotactic surgery.
4 Number of animals: 72 Mus musculus
5 This pilot is for a Reduction and Refinement of our current protocol, so we hope once we know which method works best, we can immediately add it to our main protocol.
2 Distress: Both RO and TV are minimally invasive, mild procedures. The animal is lightly anesthetized and vector is delivered intravenously.
3 Expected benefit: Given that we have been screening these vectors via intracranial stereotactic injections (i.e. brain surgery) to date , switching to IV will lead to both a significant reduction of number of animals used (one can see the whole brain at once, rather than having to do multiple injections) and also reduce the level of distress relative to our current protocol to screen AAV vectors via stereotactic surgery.
4 Number of animals: 72 Mus musculus
5 This pilot is for a Reduction and Refinement of our current protocol, so we hope once we know which method works best, we can immediately add it to our main protocol.