High-resolution mapping of neuronal activity using the lipophilic thallium chelate complex TlDDC: Protocol and validation of the method

• Published in: NeuroImage (Orlando, Fla.) Fla.), 2010-01, Vol.49 (1), p.303-315
• Main Authors: Goldschmidt, Jürgen, Wanger, Tim, Engelhorn, Achim, Friedrich, Hergen, Happel, Max, Ilango, Anton, Engelmann, Mario, Stuermer, Ingo W., Ohl, Frank W., Scheich, Henning
• Format: Article
• Language: English
• Subjects: Acoustic Stimulation; Animals; Aqueous solutions; Autoradiography; Behavior, Animal - drug effects; Blood-brain barrier; Brain - cytology; Brain Mapping - methods; Cerebral Cortex - physiology; Chelating Agents - administration & dosage; Diethyldithiocarbamate; Ditiocarb - administration & dosage; Female; Formaldehyde; GABA Agonists; Gene expression; Gerbillinae; Imaging; Injections, Intraperitoneal; Injections, Intravenous; Jugular Veins - physiology; Laboratory animals; Male; Methods; Muscimol; Nanocrystals; Neurons - physiology; Pain Measurement - drug effects; Permeability; Potassium; Radiopharmaceuticals - administration & dosage; Rats; Rats, Wistar; Reproducibility of Results; Rodents; Thallium; Veins & arteries
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2009.08.012

In neurons the rate of K+-uptake increases with increasing activity. K+-analogues like the heavy metal ion thallium (Tl+) can be used, therefore, as tracers for imaging neuronal activity. However, when water-soluble Tl+-salts are injected systemically only minute amounts of the tracer enter the brain and the Tl+-uptake patterns are influenced by regional differences in blood–brain barrier (BBB) K+-permeability. We here show that the BBB-related limitations in using Tl+ for imaging neuronal activity are no longer present when the lipophilic Tl+ chelate complex thallium diethyldithiocarbamate (TlDDC) is applied. We systemically injected rodents with TlDDC and mapped the Tl+-distribution in the brain using an autometallographic (AMG) technique, a histochemical method for detecting heavy metals. We find that Tl+-doses for optimum AMG staining could be substantially reduced, and regional differences attributable to differences in BBB K+-permeability were no longer detectable, indicating that TlDDC crosses the BBB. At the cellular level, however, the Tl+-distribution was essentially the same as after injection of water-soluble Tl+-salts, indicating Tl+-release from TlDDC prior to neuronal or glial uptake. Upon sensory stimulation or intracortical microstimulation neuronal Tl+-uptake increased after TlDDC injection, upon muscimol treatment neuronal Tl+-uptake decreased. We present a protocol for mapping neuronal activity with cellular resolution, which is based on intravenous TlDDC injections during ongoing activity in unrestrained behaving animals and short stimulation times of 5 min.