Adaptive decision making requires the evaluation of cost-benefit tradeoffs to guide action selection. Effort-based decision making involves weighing predicted gains against effort costs and is disrupted in several neuropsychiatric disorders. The ACC is postulated to control effort-base choice via its role in encoding the value of overcoming effort costs in rodent effort-based decision making assays. However, temporally precise methods of manipulating neural activity have rarely been applied to effort-based decision making. We developed and validated a mouse version of the barrier T-maze, and used optogenetics to inhibit ACC excitatory neurons at specific times during this task. Bilateral inhibition of ACC rapidly and reversibly impaired preference to exert greater effort for a larger reward when a less rewarded, low effort alternative was available. Equalizing effort for potential choice options led mice to choose the high reward arm of the maze regardless of whether the ACC was inhibited or not. The mechanics of choice behavior were altered during trials where the ACC was inhibited, but there were no effects on overall mobility or tendency to exert effort in an unrelated assay. These findings establish causality between ACC neural activity during a choice trial and effortful action selection during cost-benefit decision making.SIGNIFICANCE STATEMENTDisturbances in evaluating effort-based costs during decision making occur in depression, schizophrenia, addiction and Parkinson’s disease. Precisely resolving the function of prefrontal brain regions in mediating these processes will reveal key loci of dysfunction and potential therapeutic intervention in these disorders.

BackgroundAbnormal α‐synuclein (αS) plays an important role in the pathology of Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB). New evidence shows network hyperexcitability can accelerate synaptic and cognitive deficits in PDD and DLB. While 90% of epileptiform activity is detected during sleep in Alzheimer’s disease (AD), epileptiform activity during sleep in PDD or DLB is poorly understood. There are currently no known treatments to delay PDD or DLB progression. Although antiseizure drugs (ASDs) have been used to improve memory deficits in AD, this treatment approach has not been investigated in α‐synucleinopathies.MethodsTo explore the effect of ASDs in attenuating αS‐dependent seizure activity, we used transgenic mice expressing the A53T mutant human α‐synuclein (TgA53T) as a model of motor and cognitive decline in PDD and DLB. We have begun screening FDA‐approved ASDs using cortical electroencephalography with electromyography to examine epileptic events 24 hours before and after intraperitoneal injection. The two ASDs exhibiting the strongest efficacy in reducing epileptic activity across sleep‐wake states will be tested for effects on cognitive function and synaptic plasticity following chronic administration. We are also quantifying pathological high frequency network oscillations (HFOs), biomarkers of epileptogenesis.Results3‐4‐month‐old TgA53T mice experienced epileptiform events but had normal long‐term potentiation (LTP) and memory, indicating that epileptic activity onset precedes αS‐induced synaptic and cognitive deficits. Starting at 6 months of age, TgA53T hippocampal slices show the absence of LTP, with reduced c‐fos and calbindin and increased neuropeptide Y indicating alterations in hippocampal inhibitory circuitry. In behavioral testing, TgA53T mice exhibit impairment in fear conditioning, Y‐maze spatial recognition, and Barnes maze spatial learning and memory with age. Preliminary studies indicate lacosamide and brivaracetam as the most effective of ASDs tested in reducing epileptic myoclonus and interictal epileptiform events. We also found more HFOs in TgA53T mice and TgA53T mice with tau ablation.ConclusionSuppression of epileptic activity by ASDs would support ASDs as a novel treatment for reducing or preventing cognitive dysfunction in DLB and PDD. Furthermore, ASD‐induced reversal of synaptic and cognitive deficits would provide evidence that epileptic activity plays a causal role in αS‐dependent pathology.