Biology subjects

Thakar, A.

Publications and source records attributed to Thakar, A..

3 recordsLinked to original sources

bioRxiv2026

Activity-based anorexia enhances glutamatergic synaptic transmission and neuronal excitability within the nucleus accumbens of female mice

Anorexia nervosa is a severe psychiatric disorder characterized by persistent food restriction and often excessive physical activity, implicating dysfunction in neural circuits governing motivation, reward, and behavioral persistence. The nucleus accumbens (NAc) is a central component of these circuits, yet synaptic and cellular adaptations within this region during anorexia-like states remain poorly defined. Using the activity-based anorexia (ABA) paradigm in adult female mice, we examined glutamatergic signaling and intrinsic neuronal properties in the NAc shell. ABA exposure produced rapid weight loss, reduced food intake, and progressively increased running-wheel activity. Biochemical analyses of NAc shell tissue revealed elevated membrane-associated GluA2 AMPA receptor protein. Consistent with this finding, whole-cell patch-clamp recordings from medium spiny neurons showed increased amplitude of spontaneous excitatory postsynaptic currents. ABA also enhanced intrinsic neuronal excitability, reflected by greater firing in response to depolarizing current injections. Together, these convergent biochemical and electrophysiological results demonstrate that ABA induces coordinated postsynaptic strengthening and increased intrinsic excitability in NAc shell medium spiny neurons. These adaptations suggest a sustained increase in accumbal output that may bias motivational circuit function and contribute to excessive activity and suppressed feeding during anorexia-like conditions, paralleling glutamatergic plasticity observed in other compulsive disorders, including substance use disorder.

neuroscience↗

bioRxiv2025

Kappa opioid receptors control a stress-sensitive brain circuit and drive cocaine seeking

Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. Kappa opioid receptors (kORs) play a critical role in mediating stress responses. Our previous studies in the ventral tegmental area (VTA) demonstrated that acute stress activates kORs to block long-term potentiation at GABAA synapses on dopamine neurons (LTPGABA) and triggers stress-induced reinstatement of cocaine seeking. Here we identify the specific GABAergic afferents affected by stress, the precise localization of kORs within the VTA, and show that VTA kOR activation is sufficient to drive reinstatement. We optogenetically activated specific GABAergic afferents and found that nucleus accumbens (NAc)-to-VTA, but not lateral hypothalamus (LH)-to-VTA projections, exhibit stress-sensitive LTPGABA. Using a conditional knock-out approach, we found that selectively deleting kORs from NAc neurons but not from dopamine cells prevents stress-induced block of LTPGABA. Selectively activating dynorphin-containing NAc neurons with an excitatory DREADD mimics acute stress, preventing LTPGABA at VTA synapses. We furthermore demonstrated that without acute stress, microinjection of a selective kOR agonist directly into the VTA facilitates cocaine reinstatement without similarly affecting sucrose-motivated responding, demonstrating the critical role of kORs in stress-induced cocaine reinstatement. Our results show that kORs on GABAergic NAc nerve terminals in the VTA underlie loss of LTPGABA that may drive stress-induced addiction-related behaviors. Our work highlights the importance of inhibitory inputs for controlling dopamine neuron excitability in the context of addiction and contributes to defining the circuit involved in stress-induced drug reinstatement.

neuroscience↗

bioRxiv2025

NF-κB mediates transactivation of HNRNPD, resulting in PTEN destabilization and constitutive activation of the PI3K-AKT pathway in oral cancer cells

Heterogeneous Ribonucleoprotein D (hnRNPD), an RNA binding protein transcriptionally upregulated by NF-{kappa}B transcription factor, is associated with poor outcome of Oral Squamous Cell Carcinoma (OSCC). However, the role of hnRNPD in OSCC remains elusive. This study reveals that hnRNPD positively affects the proliferation, migration, invasion, and survival of OSCC cells. Transcriptome profiling in hnRNPD knockout cells identified significant upregulation of PTEN and inhibition of the PI3K/AKT/mTOR axis. HnRNPD mediates the destabilization of PTEN mRNA by binding to the class II AU-Rich Element (ARE) in 3UTR of PTEN. The expression of hnRNPD and PTEN are strongly negatively correlated in OSCC tissue specimens, further corroborating hnRNPD-mediated PTEN destabilization. The hnRNPD knockout inhibited autophagy, evident by an accumulation of autophagic vesicles and decreased autophagic flux. Mechanistically, the hnRNPD knockout reduced the expression of NF-{kappa}B, eventually downregulating its transcriptional target LC3b, a key mediator of autophagy. SA-{beta}-Galactosidase staining in hnRNPD KO cells conclusively demonstrated the onset of cellular senescence. The present study demonstrates hnRNPD-driven positive modulation of autophagy via NF-{kappa}B, independent of the PI3K/AKT/mTOR axis, highlighting it as a novel therapeutic target for treating oral cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/631360v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@11f6844org.highwire.dtl.DTLVardef@f65124org.highwire.dtl.DTLVardef@1492571org.highwire.dtl.DTLVardef@13931dd_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHnRNPD mediates oral cancer cell proliferation, migration, invasion, and survival. C_LIO_LIHnRNPD acts as a novel regulator of the PI3K/AKT/mTOR axis by destabilization of PTEN. C_LIO_LINF-{kappa}B/RelA downregulated on knockout of HNRNPD, inhibiting autophagy through downregulating its transcriptional target LCB-II. C_LIO_LIHnRNPD mediates cellular senescence in oral cancer cells. C_LI

cancer biology↗