Cholinergic modulation of thalamocortical projections to prefrontal cortex in cognition - cognitive flexibility is required to adjust behavior to changes in the environment

The National Institute of Mental Health awarded The Trustees of Columbia University in the City of New York $244,428 on August 20, 2026, under the Mental Health Research Grants program (CFDA 93.242) to conduct research on cholinergic modulation of thalamocortical projections to prefrontal cortex in cognitive flexibility.

The research will determine whether acute adult cholinergic modulation in the prefrontal cortex modulates attentional set-shifting performance and whether enhancing acetylcholine in the adult prefrontal cortex rescues cognitive deficits in a developmental model with decreased thalamo-prefrontal projections. The work addresses cognitive impairments in schizophrenia and other psychiatric conditions that remain intractable with current antipsychotic medications, exploring whether cholinergic enhancement can reopen plasticity windows to remediate neural circuit-level deficits.

Work is performed in New York, with a period of performance from August 20, 2026, through August 19, 2029. The award is classified as a Project Grant, the standard assistance type under NIMH's Mental Health Research Grants program, which supports basic and clinical research to transform understanding and treatment of mental illnesses.

Decades of work have highlighted the role of the prefrontal cortex (PFC), which integrates subcortical and cortical inputs, including from the mediodorsal nucleus of the thalamus (MD) in enabling cognitive flexibility. The proper wiring of these inputs during development is required for optimal prefrontal cortex maturation and miswiring is thought to lead to psychopathology. For instance, studies tracking adolescents with high clinical risk for schizophrenia show hypoconnectivity between MD-PFC, predicting disease onset later in life. Despite advances in antipsychotic medications, the vast majority of schizophrenia patients develop deficits in cognition and working memory that remain largely intractable with limited therapeutic options. Neuromodulation by so-called cognitive enhancers is an emerging field in neuroscience. Over the last decade one promising neuromodulator class is acetylcholine, whose phasic release in PFC has been linked to cognitive performance and attentional selectivity. In fact, cholinergics have become a mainstay treatment for alleviating the cognitive symptoms of mild-to-moderate alzheimer's dementia, and in late 2024 the first cholinergic drug was approved for treating various schizophrenia symptoms. More recently, cholinergics have been used to reverse aberrant thalamocortical connections in the visual system even when administered in adulthood, raising the possibility of "reopening" plasticity windows and potentially remediating psychiatric deficits at the neural circuit level. Here, I will determine whether acute adult cholinergic modulation in the PFC modulates attentional set shifting performance and whether enhancing acetylcholine in the adult PFC rescues cognitive deficits in an established developmental model with decreased thalamo-prefrontal projections. I will then attempt to reopen cortical plasticity via sub-chronic cholinergic augmentation in our developmental model. To this end I will use a combination of a transgenic mouse model, viral circuit-restricted expression of dreadd inhibition, fiber photometry, a fluorescent acetylcholine biosensor, optogenetics, and behavioral tests. Aim 1 will measure real-time acetylcholine dynamics during attentional set-shifting behavior and determine through optogenetic modulation whether acetylcholine supports working memory and attentional set shifting behavior. Aim 2 will use parallel optogenetic and pharmacological means to determine whether acute or sub chronic enhancement of acetylcholine reopens cortical plasticity in our published MD-PFC impaired mouse model. These studies will determine how acetylcholine interacts with thalamocortical projections in PFC during cognitively-demanding behavior, and may also be instructive in addressing whether cholinergic modulation in adulthood can restore a developmental imbalance in activity that increases risk for developing a psychiatric disorder.