Kucinski, A. | bioRxiv Science

bioRxiv2026

Falls Induced by Optogenetic Inhibition of Basal Forebrain Cholinergic Projections after Dorsomedial Striatal Dopamine Depletion in a Dual Disruption Model of Falling Vulnerability in Parkinson Disease

Abstract/SummaryFalls are a common and debilitating feature of Parkinsons Disease (PD) patients. Prefrontal acetylcholine (ACh) deficits, as well as nigrostriatal dopamine deficits, are implicated in vulnerability to falls. PD patients with loss of cortical ACh and associated cognitive dysfunction experience a higher rate of falls than PD patients without cortical ACh loss. In addition, chemogenetic inhibition of basal forebrain (BF) neurons in rats increases the vulnerability to falls on a balance beam task. Here, the impact of transient optogenetic inhibition specifically of BF cholinergic neurons was assessed in rats with dorsomedial striatal dopamine lesions during traversal of straight or zig-zag balance beams using the Michigan Complex Movement Control Task (MCMCT). Adding transient optogenetic inhibition of BF cholinergic neurons with striatal dopamine lesions elevated falls above the level produced by striatal dopamine lesions or BF ACh inhibition alone, especially on the challenging zig-zag task. These results support the critical role of BF-cortical cholinergic circuits in alleviating vulnerability to falls in PD patients with striatal dopamine loss, suggesting that it is combined loss of BF cholinergic activity and striatal dopamine that leads to greatest vulnerability to falls and related complex movement impairments.

neuroscience↗

bioRxiv2019

Rescuing the attentional performance of rats with cholinergic losses by the M1 positive allosteric modulator TAK-071

Loss of basal forebrain cholinergic neurons contributes to the severity of the cognitive decline in age-related dementia and to impairments in gait and balance, and the resulting risks for falls, in patients with Parkinsons disease (PD). Contrasting with the extensive evidence indicating an essential role of cholinergic activity in mediating cognitive, specifically attentional abilities, treatment with conventional acetylcholinesterase inhibitors (AChEIs) has not fulfilled the promise of efficacy of pro-cholinergic treatments. Here we investigated the potential usefulness of a muscarinic M1 positive allosteric modulator (PAM) in an animal model of cholinergic loss-induced impairments in attentional performance. Given evidence indicating that fast, transient cholinergic signaling mediates the detection of cues in attentional contexts, we hypothesized that an M1 PAM amplifies such transient signaling, thereby enhancing and rescuing attentional performance. Rats performed an operant sustained attention task (SAT), including in the presence of a distractor (dSAT) and during a post-distractor (post-dSAT) period assessing their capacity for recovering performance. Basal forebrain infusions of the cholino-specific immunotoxin 192 IgG-saporin impaired SAT performance, and greater cholinergic losses predicted lower post-dSAT performance recovery. Administration of TAK-071 (0.1, 0.3 mg/kg, p.o., administered over 6-day blocks) improved the performance of all rats during the post-dSAT period (main effect of dose). Drug-induced improvement of post-dSAT performance was relatively greater in lesioned rats, irrespective of sex, and also manifested in female control rats. TAK-071 primarily improved perceptual sensitivity (d) in lesioned rats and facilitated the adoption of a more liberal response bias (B\"D) in all female rats. Collectively, these findings suggest that TAK-071 may benefit the attentional performance of patients with partial cholinergic losses and specifically in situations that tax top-down, or goal-driven, attentional control.

neuroscience↗