Pathway Specificity of Behavioral Timescale Synaptic Plasticity (BTSP) in the Prefrontal Cortex (PFC)

Modern theories of synaptic plasticity, central to understanding learning and memory, suggest that synapses undergo activity-dependent changes in strength. However, traditional models like spike-timing-dependent plasticity (STDP), with their reliance on nearly coincident and repetitive neural activity, fall short of capturing the extended temporal dynamics integral to behavioral learning. This discrepancy presents a notable challenge in synaptic plasticity research, often referred to as the "temporal credit assignment problem", which requires linking actions to outcomes that are temporally separated. Behavioral timescale synaptic plasticity (BTSP) was first discovered in the hippocampus and more recently in the prefrontal cortex of mice. Utilizing a combination of optogenetics and whole-cell electrophysiology experiments we sought to determine BTSP across pathway-specific inputs to layer 5 pyramidal neurons from key brain regions including the ventral hippocampus, basolateral amygdala, mediodorsal thalamus, and contralateral PFC. Our results reveal that BTSP can be selectively induced in the ventral hippocampus-PFC and mediodorsal thalamus-PFC pathways. Additionally, adjustments to ex vivo experimental conditions to mirror physiological calcium levels reveal the need for a Hebbian eligibility trace in order to induce plasticity. These findings pave the way for future research that bridges cellular mechanisms with behavioral outcomes, offering potential pathways for therapeutic interventions in conditions like Alzheimer's disease, where such synaptic mechanisms are disrupted.