Muscarinic signaling sustains delay-period selectivity in prefrontal cortex by preserving thalamic drive
- 1Korea Brain Research Institute
Abstract
Short-term memory (STM) requires the temporary maintenance of task-relevant information in prefrontal cortex (PFC). Reciprocal interactions between the mediodorsal thalamus (MD) and PFC have been implicated in sustaining this activity, but how thalamofrontal communication is maintained despite the biophysical constraints of repetitive synaptic transmission remains unclear. Here, we show that MD--PFC synapses exhibit profound frequency-dependent short-term depression, causing repetitive thalamic input to progressively lose its ability to drive PFC neurons. During STM performance, acetylcholine (ACh) levels in PFC rose rapidly following cue presentation and remained elevated throughout the delay period. Muscarinic ACh receptor (mAChR) activation did not alleviate synaptic depression, but instead increased the intrinsic excitability of PFC neurons, thereby preserving their responsiveness to weakened thalamic input. Conversely, mAChR blockade impaired STM performance and progressively disrupted delay-period directional representations at both the single-neuron and population levels, while largely sparing initial encoding. These findings identify muscarinic signaling as a postsynaptic gain mechanism that compensates for declining thalamofrontal efficacy and sustains task-relevant prefrontal representations during STM.
Related
- Striatal cholinergic interneuron pathology and muscarinic signaling independently shape motor dysfunction in a DYT-TOR1A dystonia model
- TGF-b/TIF1g signaling restrains CD8+ T cell expansion while preserving cytotoxic competence
- Anatomical mapping of dopamine D1 and muscarinic M4 receptor
- Broad Cognitive and Motivational Enhancement through M4-Selective Muscarinic Modulation
- The ssDNA-binding protein MEIOB sustains synaptonemal complex integrity by stabilizing recombination intermediates during male meiosis
BibTeX
@misc{kim2026muscarinic,
title = {{Muscarinic signaling sustains delay-period selectivity in prefrontal cortex by preserving thalamic drive}},
author = {Y. Kim and J. Kim and I. S. Choi and J. Lee and Y.-S. Yang and J. H. Choi and J.-W. Choi and J.-C. Rah},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.20.760355},
url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760355v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Muscarinic signaling sustains delay-period selectivity in prefrontal cortex by preserving thalamic drive
AU - Y. Kim
AU - J. Kim
AU - I. S. Choi
AU - J. Lee
AU - Y.-S. Yang
AU - J. H. Choi
AU - J.-W. Choi
AU - J.-C. Rah
PY - 2026
DA - 2026/10/20
PB - bioRxiv
DO - 10.64898/2026.10.20.760355
UR - https://www.biorxiv.org/content/10.64898/2026.10.20.760355v1
AB - Short-term memory (STM) requires the temporary maintenance of task-relevant information in prefrontal cortex (PFC). Reciprocal interactions between the mediodorsal thalamus (MD) and PFC have been implicated in sustaining this activity, but how thalamofrontal communication is maintained despite the biophysical constraints of repetitive synaptic transmission remains unclear. Here, we show that MD--PFC synapses exhibit profound frequency-dependent short-term depression, causing repetitive thalamic input to progressively lose its ability to drive PFC neurons. During STM performance, acetylcholine (ACh) levels in PFC rose rapidly following cue presentation and remained elevated throughout the delay period. Muscarinic ACh receptor (mAChR) activation did not alleviate synaptic depression, but instead increased the intrinsic excitability of PFC neurons, thereby preserving their responsiveness to weakened thalamic input. Conversely, mAChR blockade impaired STM performance and progressively disrupted delay-period directional representations at both the single-neuron and population levels, while largely sparing initial encoding. These findings identify muscarinic signaling as a postsynaptic gain mechanism that compensates for declining thalamofrontal efficacy and sustains task-relevant prefrontal representations during STM.
ER -