Neural Circuits and Brainstem Control of Lower Urinary Tract Function
PROJECT — MAPPING BRAINSTEM CONTROL OF BLADDER FILLING AND VOIDING
Neurons in Barrington’s nucleus (Bar) in the brainstem are both sufficient and necessary for regulating detrusor activity and voiding contractions. This project aims to define the anatomical and functional interfaces between these neurons and neurons that connect to them.
Our goal is to develop a comprehensive map of the brain’s anatomy and functional circuits that regulate bladder filling and voiding.
We use retrograde tracing, including modified rabies virus labeling (1), CTb, and (trans-synaptic) anterograde (2-5) tracing techniques, to identify the neurons that innervate critical neuronal subpopulations and to map the central nervous system (CNS) circuits for maintaining continence. We also perform Channelrhodopsin-Assisted-Circuit-Mapping (CRACM) (6) followed by optogenetic activation or inhibition of neurons. This allows us to detect and manipulate the neuronal activity of specific, monosynaptically connected populations.
>> For these studies we use state-of-the-art neural mapping methods, coupled with measurements of bladder function in awake and anesthetized states. This project investigates how the brain integrates signals from the bladder and the external environment to control bladder filling and voiding <<
- Funding and collaboration on the project: NIH-NIDDK, R01 DK125708 (Verstegen), 2020-2025, and R01 DK113030 (Zeidel - PI), 2017-2022.
Useful references:
1) Callaway and Luo., 2021 - Monosynaptic Circuit Tracing with Glycoprotein-Deleted Rabies Viruses. PMCID: PMC4469731
2) Zingg et al., 2017 - AAV-Mediated Anterograde Transsynaptic Tagging: Mapping Corticocollicular Input-Defined Neural Pathways for Defense Behaviors. PMCID: PMC5538794
3) Zingg et al., 2020 - Synaptic Specificity and Application of Anterograde Transsynaptic AAV for Probing Neural Circuitry. PMCID: PMC7159884
4) Tsai et al., 2022 - Trans-Seq maps a selective mammalian retinotectal synapse instructed by Nephronectin. PMCID: PMC9172271
5) Verstegen et al., (2019) Current Biology 29, 2775-2789. PMCID: PMC6736713
6) Petreanu et al., 2009- The subcellular organization of neocortical excitatory connections. PMCID: PMC2745650
Read more:
Barrington’s nucleus contains predominantly glutamatergic neurons, as shown by the presence of a GFP reporter for the type 2 vesicular glutamate transporter (Vglut2) and absence of a reporter for the vesicular GABA/glycine transporter (Vgat). Panels (a) and (b) compare the distributions of Vglut2 (glutamatergic) and Vgat (GABAergic/ glycinergic) neurons, respectively.
Injecting CTb into the lumbosacral spinal cord retrogradely labels neurons in Barrington’s nucleus and the Locus Coeruleus (LC).