Biology subjects

Ploski, J. E.

Publications and source records attributed to Ploski, J. E..

3 recordsLinked to original sources

bioRxiv2026

The cerebellum exploits a thalamic carrier frequency to refine motor behaviors

Despite enabling nearly all cerebellar-cortical communication, how the thalamus processes and interacts with cerebellar activity remains unclear. We found a pronounced 1-5 Hz (delta) rhythm in the thalamic membrane potential and cerebellothalamocortical local field potentials during nonmoving periods in behaving mice. We show, using photometry, multielectrode recordings, closed-loop stimulation, and dynamic clamp, that CaV3.1-dependent resonance of thalamic neurons facilitates transmission of delta-rhythm cerebellar activity to the cortex. Knockout of CaV3.1 in cerebellar-thalamic neurons diminishes the thalamocortical delta oscillation and specifically impairs motor learning while minimally affecting motor performance. These results ground population oscillations to features of ion channels, highlight the cerebellum and delta's utility in offline motor learning, and support a carrier frequency-like encoding mechanism that underlies cerebellothalamocortical communication.

neuroscience↗

bioRxiv2025

A Novel Mechanism for Tauopathy in Progressive Multiple Sclerosis: Excitotoxic Misplacement of a Mitochondrial Anchor into Dendrites Driven by Tau-hyperphosphorylation

On April 2nd, 2025, the FDA approved a Fast Track Designation for Biogen to use Antisense Oligonucleotides (ASO) to treat tauopathy in clinical trials for Alzheimers Disease (AD) to meet an unmet medical need [1]. For Multiple Sclerosis (MS), there is a similar unmet medical need regarding tauopathy when MS transitions into the late, or Progressive MS that is currently incurable. AD and MS share commonality: there is comorbidity between AD and MS [2], and the recent awareness that progressive MS may be considered a secondary tauopathy [3]. This study lays the basic science foundation for a future repurposing of ASO tauopathy therapy from AD to MS. The central hypothesis is that in Progressive MS, tauopathy is not a passive bystander but an active contributor to synaptic degeneration through a novel toxic target known as DSI (Dendritic Syntaphilin Intrusion) discovered in our laboratory. In this hypothesis, the excitotoxic N-methyl-D-aspartate receptor (NMDAR) GluN2B activates Tau hyperphosphorylation (p-Tau), leading to the mislocalization or intrusion of a mitochondrial anchor SNPH into neuronal dendrites (DSI). This causes mitochondrial damage and subsequent synapse/dendrite disintegration. In support of this hypothesis that tauopathy is a key driver of DSI, we demonstrated using primary neuronal cultures that inhibitors of p-Tau kinases and Tau-KO both completely abolish DSI. We propose that a therapy for Progressive MS is repurpose the existing FDA-approved ASO Tau knockdown therapy from AD to treat MS. FundingNIH R01 MSN233781 to SY Chiu

neuroscience↗

bioRxiv2019

Increasing Synaptic GluN2B levels within the Basal and Lateral Amygdala Enables the Modification of Strong Reconsolidation Resistant Fear Memories

Reconsolidation disruption has been proposed as a method to attenuate pathological memories in disorders such as PTSD. However, studies from our group and others indicate that strong memories are resistant to becoming destabilized following reactivation, rendering them impervious to agents that disrupt the re-stabilization phase of reconsolidation. Thus, therapies designed to attenuate maladaptive memories by disrupting reconsolidation updating have not been adequately developed. We previously determined that animals possessing strong auditory fear memories, compared to animals with weaker fear memories, are associated with an enduring increase in the synaptic GluN2A/GluN2B ratio in neurons of the mouse basal and lateral amygdala (BLA). In this study, we determined whether increasing GluN2B levels within BLA excitatory neuronal synapses is sufficient to enable modification of strong fear memories via reconsolidation. To accomplish this, we utilized a combinatorial genetic strategy to express GluN2B or GluN2B(E1479Q) in excitatory neurons of the mouse BLA before or after fear memory consolidation. GluN2B(E1479Q) contains a point mutation that increases synaptic expression of the subunit by interfering with phosphorylation-driven endocytosis. At the time of memory retrieval, increasing synaptic GluN2B levels by expression of GluN2B(E1479Q), but not GluN2B(WT), enhanced the induction of reconsolidation rendering the strong fear memory modifiable. GluN2B(WT) or GluN2B(E1479Q) expression did not influence fear memory maintenance or extinction. Fear memory consolidation, however, was enhanced when GluN2B(E1479Q) was expressed in the BLA at the time of training. These findings indicate that enhancing GluN2B synaptic trafficking may provide a novel therapeutic strategy to enhance modification of pathological memories.

neuroscience↗