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1 Neuroscience Discovery, Eli Lilly & Co., Indianapolis, IN, USA
2 Neuroscience Discovery, Eli Lilly & Co., Indianapolis, IN, USA; Dept of Anatomy & Cell Biology, Indiana University, Indianapolis, IN, USA
* To whom correspondence should be addressed. E-mail: cyang{at}lilly.com.
The medial septum / vertical limb of diagonal band complex (MS/vDB) consist of cholinergic, GABAergic and glutamatergic neurons that project to the hippocampus and functionally regulate attention, memory and cognitive processes. Using tyrosine hydroxlase (TH) immunocytochemistry and dark-field light microscopy, we found that the MS/vDB is innervated by a sparse network of TH-immunoreactive (putative catecholaminergic) terminals. MS/vDB neurons are known to fire in rhythmic theta burst frequency of 3-7 Hz to pace hippocampal theta rhythm. Extracellular single-unit recording in theta and non-theta firing MS/vDB neurons and antidromically-identified MS/vDB-hippocampal neurons were made in urethane-anesthetized rats. Tail-pinch noxious stimuli and VTA stimulation (20 Hz) evoked spontaneous theta burst firing in MS/vDB neurons. Systemic D1/5 antagonists SCH23390 or SCH39166 (0.1 mg/kg,i.v.) alone suppressed the spontaneous theta bursts, suggesting a tonic facilitatory endogenous dopamine D1 tone that modulates theta bursts in vivo. Activation of D1/5 receptor by dihydrexidine (10 mg/kg, i.v.) led to an increase in mean firing rate in 60 % of all theta and non-theta MS/vDB neurons; with an increase in the number of theta bursts and spikes/burst in theta cells. In strong theta firing MS/vDB neurons, D1/5 receptor stimulation suppressed the occurrence of theta burst firing while the overall increase in spontaneous mean firing rate remained. In low baseline theta MS/vDB neurons D1/5 receptor stimulation increases the occurrence of theta bursts, along with a net increase in mean firing rate. Atropine injection consistently disrupts theta burst pattern and reduced the time spent in theta firing. Collectively, these data suggest that dopamine D1/5 stimulation enhances the mean firing rate of most MS/vDB neurons and also provides a state-dependent bi-directional modulation of theta burst occurrence. Some of these MS/vDB neurons may be cholinergic or GABAergic that may indirectly regulate theta rhythm in the hippocampus.
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