Lesioning Thalamic Reticular Cholinergic Neurons

My name is Emily Masi and I am a rising sophomore studying neuroscience and public health here at the College. I have been working in Dr. Burk’s lab since the beginning of this semester, and its focus has been the role of orexin projections to the basal forebrain in attention, the effects of reward delay discounting on impulsivity and the role of the cholinergic system in this pathway, and the actions of acetylcholine at muscarinic and nicotinic receptors under cognitively challenging conditions.

This summer I will examine whether the novel immunotoxin anti-ChAT-saporin selectively damages cholinergic neurons in rats, while sparing parvalbumin-positive neurons in the thalamic reticular nucleus (TRN). Choline acetyltransferase (ChAT) is an enzyme that catalyzes the synthesis of the neurotransmitter acetylcholine (ACh) from choline and acetyl-CoA in cholinergic neurons. ChAT serves as a specific marker for cholinergic neurons, the atrophy and loss of which are found in aging, Alzheimer’s disease, Down and Rett syndromes. Anti-ChAT-saporin should selectively destroy cholinergic neurons, but not noncholinergic neurons, and it is expected to cross-react with rat, mouse, and human ChAT.

It is known that there is a loss of ACh projections to the cortex and hippocampus in Alzheimer’s disease patients, which might exacerbate the functional impairment and neurodegeneration associated with the disease, but their role in other regions such as the TRN is unknown. Cholinergic neurons originating in the basal forebrain of rats are known to facilitate attention processing, but the exact neural circuitry mediating the effects of acetylcholine on attention is unknown. However, the TRN is hypothesized to engage in a number of diverse processes, such as sensory information processing, attention, and the generation of synchronous activity in the thalamocortical system.

The ability to study the effects of damaging this pathway will be an important step in further understanding neural pathways involved in attention. If the toxin is effective in lesioning cholinergic TRN and not GABAergic TRN neurons, we expect to conduct another experiment next fall assessing the effects of these lesions on attentional performance in rats.  A final outcome for research on the TRN’s role in attention is the attempted mediation of the effects of cholinergic neuron atrophy in aging and Alzheimer’s disease.