Thilo Womelsdorf
Vanderbilt University, TN·Neuroscience
Drugs that improve attention, memory and motivation in psychiatric illness often fail not because they do nothing, but because the dose needed for benefit also causes intolerable side effects. This work tests a chemical strategy meant to avoid that trade-off, and asks exactly which brain chemicals and cell types explain the benefit.
- Fields
Neuroscience
Pharmacology
Psychology
- Topics
muscarinic M1 receptor
positive allosteric modulator
acetylcholine
- Grants
- 1 known grant, through Jan 2027
What they work on
- Determine the dose-response efficacy of an M1 muscarinic receptor positive allosteric modulator on attention, working memory, effort control, cognitive flexibility and visuospatial problem solving in monkeys, using a multi-task touchscreen battery in home-cage kiosks.
- Benchmark the modulator against the agonist xanomeline and the non-selective cholinergic drug donepezil to identify which behavioral domains suffer dose-limiting side effects with conventional compounds.
- Measure drug-dose-dependent changes in extracellular acetylcholine, dopamine, serotonin, glutamate and GABA, plus the drug itself, simultaneously in dorsolateral prefrontal cortex, striatum and anterior cingulate cortex.
- Record neural spiking alongside the neurochemical measurements to test how the M1 modulator alters firing rates and synchronization of electrophysiologically distinguished interneuron types.
More about the research
The system is the nonhuman primate, whose brain organization and behavioral repertoire are close enough to ours to make the answers translatable.
Why it matters
People with schizophrenia frequently struggle with attention, memory and motivation, and existing cholinergic drugs are limited by side effects that reduce how well patients can tolerate them. By measuring precisely which cognitive and motivational domains an M1 positive allosteric modulator improves, at what dose, and through which neurotransmitter and interneuron changes, this work could inform how such compounds are dosed and targeted in treating schizophrenia and related disorders.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Jerri Rook
Vanderbilt University, TN·Pharmacology
Test whether positive allosteric modulators of the M1 muscarinic receptor induce long-term depression of excitatory synapses by acting on M1 in prefrontal cortex pyramidal cells, and whether this requires phospholipase D rather than M1 in inhibitory neurons.
Daniel Foster
University of South Carolina-Columbia, SC·Neuroscience
Test whether M4 PAMs, drugs that boost the M4 acetylcholine receptor, reduce repetitive over-grooming in SAPAP3 knockout mice and other mouse models of repetitive behavior.
Joshua I Gold
University of Pennsylvania, PA·Neuroscience
Develop and test a mathematical theory of adaptive decision bounds that update during deliberation, using behavioral experiments in humans and combined behavioral and neural studies in monkeys making decisions under changing conditions.
The school
Vanderbilt University: 22 labs on PI Pages, $1.3B a year on research, 494 research doctorates a year.
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