Biology subjects

Forcelli, P. A.

Publications and source records attributed to Forcelli, P. A..

4 recordsLinked to original sources

bioRxiv2026

Brainstem cholinergic cell loss causes slowly-developing motor impairments

Pedunculopontine nucleus (PPN) cholinergic degeneration is a feature of Parkinson's disease (PD), but it is difficult to isolate the symptoms and circuit alterations caused by cholinergic cell loss in PD, where multiple nuclei are simultaneously degenerating. Here we develop a novel mouse model of brainstem cholinergic cell loss to define the timeline of symptom development and map physiological adaptations within the brainstem. Mild motor symptoms, including balance and motor learning deficits reminiscent of early-stage PD, developed after cholinergic lesion with an unexpected long delay. Ex vivo whole-cell recordings showed that cholinergic cell loss increased excitatory synaptic drive onto glutamatergic PPN neurons and increased their intrinsic ability to generate sustained action potential output. In parallel, fiber photometry experiments revealed a slight increase in glutamatergic sensory responsiveness that closely tracked the delayed onset of behavioral symptoms. Together, these results reveal that brainstem cholinergic cell loss triggers the reorganization of motor-related brainstem circuits, providing critical insight into the consequences of non-dopaminergic degeneration in PD.

neuroscience↗

bioRxiv2024

Optogenetic stimulation of dorsal striatum bidirectionally controls seizures

Engagement of the striatum (caudate/putamen) and other basal ganglia nuclei during seizures was first observed over 75 years ago. Basal ganglia output nuclei, and the substantia nigra pars reticulata, in particular, have well-established anti-seizure effects across a large array of experimental models. However, striatal control of seizures is understudied. To address this gap, we used optogenetic approaches to activate and inactivate neurons in the dorsal striatum of Sprague-Dawley rats submitted to the gamma-butyrolactone (GBL) model of absence epilepsy, amygdala kindling model of temporal lobe epilepsy, and pilocarpine-induced Status Epilepticus (SE). All tests were performed on a within-subject basis. Animals were tested in two different light frequencies (5 Hz and 100 Hz). Open-loop (continuous light delivery) optogenetic activation of the dorsal striatal neurons robustly suppressed seizures in all models. On the other hand, optogenetic silencing of the dorsal striatal neurons increased absence seizure expression and facilitated SE onset but had no effect on kindled limbic seizures. In the GBL model, we also verified if the closed- loop strategy (light delivery in response to seizure detection) would be enough to induce antiseizure effects. On-demand light delivery in ChR2-expressing animals reduced SWD duration, while the same approach in ArchT-expressing animals increased SWD duration. These results demonstrated previously unrecognized anti-absence effects associated with striatal continuous and on-demand neuromodulation. Together, these findings document a robust, bidirectional role of the dorsal striatum in the control of seizure generation and propagation in a variety of seizure models, including focal seizure onset and generalized seizures.

neuroscience↗

bioRxiv2024

Senescent cell clearance ameliorates temporal lobe epilepsy and associated spatial memory deficits in mice

Current therapies for the epilepsies only treat the symptoms, but do not prevent epileptogenesis (the process in which epilepsy develops). Many cellular responses during epileptogenesis are also common hallmarks of cellular senescence, which halts proliferation of damaged cells. Clearing senescent cells (SCs) restores function in several age-associated and neurodegenerative disease models. It is unknown whether SC accumulation contributes to epileptogenesis and associated cognitive impairments. To address this question, we used a mouse model of temporal lobe epilepsy (TLE) and characterized the senescence phenotype throughout epileptogenesis. SCs accumulated 2 weeks after SE and were predominantly microglia. We ablated SCs and reduced (and in some cases prevented) the emergence of spontaneous seizures and normalized cognitive function in mice. Suggesting that this is a translationally-relevant target we also found SC accumulation in resected hippocampi from patients with TLE. These findings indicate that SC ablation after an epileptogenic insult is a potential anti-epileptogenic therapy.

neuroscience↗

bioRxiv2020

Inhibitory parvalbumin basket cells are selectively impaired during hippocampal sharp wave ripples in a mouse model of familial Alzheimer's disease

Memory disruption in mild cognitive impairment (MCI) and Alzheimers disease (AD) is poorly understood, particularly at early stages preceding neurodegeneration. In mouse models of AD, there are disruptions to sharp wave ripples (SWRs), hippocampal population events with a critical role in memory consolidation. However, the micro-circuitry underlying these disruptions is under-explored. We tested if a selective reduction in parvalbumin-expressing (PV) inhibitory interneuron activity underlies hyperactivity and SWR disruption. We employed the 5xFAD model of familial AD crossed with mouse lines labeling excitatory pyramidal cells (PCs) and inhibitory PV cells. We observed a 33% increase in frequency, 58% increase in amplitude, and 8% decrease in duration of SWRs in ex vivo slices from male and female 3-month 5xFAD mice versus littermate controls. 5xFAD mice of the same age were impaired in a hippocampal-dependent memory task. Concurrent with SWR recordings, we performed calcium imaging, cell-attached, and whole-cell recordings of PC and PV cells within the CA1 region. PCs in 5xFAD mice participated in enlarged ensembles, with superficial PCs having a higher probability of spiking during SWRs. Both deep and superficial PCs displayed an increased synaptic E/I ratio, suggesting a disinhibitory mechanism. In contrast, we observed a 46% spike rate reduction during SWRs in PV basket cells (PVBCs), while PV bistratified and axo-axonic cells were unimpaired. Excitatory synaptic drive to PVBCs was selectively reduced by 50%, resulting in decreased E/I ratio. Considering prior studies of intrinsic PV cell dysfunction in AD, these findings suggest alterations to the PC-PVBC micro-circuit also contribute to impairment. Significance StatementWe demonstrate that a specific sub-type of inhibitory neuron, parvalbumin-expressing basket cells, have selectively reduced activity in a model of Alzheimers disease during activity critical for the consolidation of memory. These results identify a potential cellular target for therapeutic intervention to restore aberrant network activity in early amyloid pathology. While parvalbumin cells have previously been identified as a potential therapeutic target, this study for the first time recognizes that other parvalbumin neuronal sub-types, including bistratified and axo-axonic cells, are spared. These experiments are the first to record synaptic and spiking activity during sharp wave ripple events in early amyloid pathology and reveal that a selective decrease in excitatory synaptic drive to parvalbumin basket cells likely underlies reduced function.

neuroscience↗