Biology subjects

Yao, W.-D.

Publications and source records attributed to Yao, W.-D..

5 recordsLinked to original sources

bioRxiv2026

A choice disinhibition paradigm to reveal neural correlates of behavioral disinhibition in Frontotemporal dementia

Behavioral disinhibition is a hallmark symptom of behavioral variant frontotemporal dementia (bvFTD). There is no cure or strategy to slow progression, mainly due to little understanding of how disinhibition occurs and the mechanisms underlying self-control. To date, disinhibition has not been demonstrated in an FTD model. We designed a paradigm to assess disinhibition, separating general cognitive capacity, and found that aged mutant mice display increased impulsive choice but have intact cognition, suggestive of early-mid- stage bvFTD-associated symptoms. Further, the neural mechanisms underlying self-control are dissociable from impulsive choice; CaMKIIlower case Greek alpha- and somatostatin-expressing neurons in the medial prefrontal cortex, but not the classical anterior cingulate cortex, were activated during self-control. Together, we demonstrate behavioral disinhibition in mutant mice and identified specific regions and cell types that underlie self-control. This paradigm is viable for future work dissecting neural circuits underling impulsive choice and self-control behavior in bvFTD and other neurological conditions.

neuroscience↗

bioRxiv2026

Elevating Neuronal CYLD Causes Frontotemporal Dementia (FTD)-Relevant Behavioral and Physiological Deficits

Frontotemporal dementia (FTD), a leading form of presenile dementia disrupting behavior, language and/or movement, is linked to mutations of a number of genes, including CYLD that encodes a Lys63 (K63) deubiquitinating enzyme. Among several CYLD variants found in FTD patients, a gain-of-function missense mutant, M719V, has been proposed to be pathogenic, but its pathogenicity in vivo and the underlying mechanism remain unknown. Here, we have developed transgenic mice that express either wildtype (WT) or M719V-CYLD in neurons throughout the mouse brain using adeno-associated virus (AAV) mediated somatic brain transgenesis. We show that somatic M719V-CYLD transgenic mice display profound FTD-associated behavioral impairments, including risk-taking, reduced social interaction, and loss of empathy that emerge from early stages and worsen with aging. Furthermore, M719V-CYLD mice also show significant early neurophysiological impairments in the prefrontal cortex (PFC), including depolarized resting membrane potential, decreased synaptic transmission, and reduced neuronal excitability. Surprisingly, however, M719V-CYLD mouse brain exhibits elevated autophagy activity and decreased Akt-mTOR signaling without overt neuronal cell loss or microgliosis even at 12 months of age. Most M719V-CYLD-associated cellular and behavioral phenotypes are also recapitulated but to a lesser extent in WT-CYLD mice, suggesting CYLD activation is responsible for the observed neural circuit deficits and the M719V mutation is gain-of-function in nature. Our results uncover important roles of neuronal CYLD in PFC function and social behaviors and establish a unique animal model to investigate pathogenic mechanisms of FTD, in particular its social behavioral deficits, at molecular, cellular, synaptic and circuit levels.

neuroscience↗

bioRxiv2025

A Prefrontal Cortex-Nucleus Accumbens Circuit Attenuates Cocaine-conditioned Place Preference Memories

The infralimbic (IL) subregion of the prefrontal cortex (PFC), via its descending projection to the nucleus accumbens (NAc), inhibits cue-induced drug seeking and reinstatement, but the underlying mechanisms are not fully understood. Here we show that the intrinsic membrane excitability of IL layer 5 pyramidal neurons projecting to the NAc shell (IL-NAcSh neurons) suppresses cocaine-associated memories. Following repeated cocaine exposures in a conditioned place preference paradigm, IL-NAcSh neurons anatomically traced by fluorescent retrobeads undergo prolonged decrease of membrane excitability, lasting for at least 15 days after cocaine withdrawal. This persistent IL-NAcSh neuron hypoexcitability was accompanied by an increase in the rheobase, an increase in the afterhyperpolarization potential, and a decrease in the membrane input resistance. This cocaine induced neuroadapation in intrinsic excitability was not observed in prelimibic cortex neurons projecting to the NAc core (PL-NAcCo neurons), a separate descending circuit thought to promote cue-triggered drug seeking. Chemogenetic restoration of IL-NAcSh neuron activity extinguishes both the acquisition and retention of cocaine conditioned place preference memories. Our results provide direct support for the notion that the IL-NAcSh circuit serves to extinct drug associated memories and restoring the drug impaired excitability of IL-NAcSh neurons has the potential to mitigate drug-cue association memories and drug seeking.

neuroscience↗

bioRxiv2023

USP48/USP31 Is a Nuclear Deubiquitinase that Potently Regulates Synapse Remodeling

Deubiquitinases present locally at synapses regulate synaptic development, function, and plasticity. It remains largely unknown, however, whether deubiquitinases localized outside of the synapse control synapse remodeling. Here we identify ubiquitin specific protease 48 (USP48; formerly USP31) as a nuclear deubiquitinase mediating robust synapse removal. USP48 is expressed primarily during the first postnatal week in the rodent brain and is virtually restricted to nuclei, mediated by a conserved, 13-amino acid nuclear localization signal. When exogenously expressed, USP48, in a deubiquitinase and nuclear localization-dependent manner, induces striking filopodia elaboration, marked spine loss, and significantly reduced synaptic protein clustering in vitro, and erases [~]70% of functional synapses in vivo. USP48 interacts with the transcription factor NF-{kappa}B, deubiquitinates NF-{kappa}B subunit p65 and promotes its stability and activation, and up-regulates NF-{kappa}B target genes known to inhibit synaptogenesis. Depleting NF-{kappa}B prevents USP48-dependent spine pruning. These findings identify a novel nucleus-enriched deubiquitinase that plays critical roles in synapse remodeling.

neuroscience↗

bioRxiv2021

Cylindromatosis Drives Synapse Pruning and Weakening by Promoting Macroautophagy through Akt-mTOR Signaling

The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux and, conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.

neuroscience↗