Biology subjects

Thiagarajan, N.

Publications and source records attributed to Thiagarajan, N..

2 recordsLinked to original sources

bioRxiv2026

Disrupted neuropeptide-signaling drives enduring reward deficits after early-life stress

Whereas brain systems mediating acute stress are essential for survival, chronic early-life stress (ELA) may lead to poor ability to experience pleasure (anhedonia), a core feature of depression. For decades, the stress neuropeptide corticotropin-releasing hormone (CRH) has been a target for treating depression. However the failure of several clinical trials blocking CRH receptor1 (CRHR1) has left the therapeutic role of CRH signaling a major unresolved mystery. Here, we uncover the signaling plasticity behind this enigma with the use of in vivo G protein-coupled activation-based (GRAB) imaging and viral-genetic and pharmacological mechanistic manipulations. We find that CRH signaling via CRHR1 indeed disrupts reward behaviors in control mice, but is disrupted in anhedonic mice with a history of ELA. Instead, activation of CRH receptor 2 (CRHR2) reverses anhedonia-like behaviors in adult ELA mice. These findings redefine our understanding of stress-mediated anhedonia and provide a precise, novel therapeutic target for stress-related mental illness.

neuroscience↗

bioRxiv2024

Paraventricular Thalamus Neuronal Ensembles Encode Early-life Adversity and Mediate the Consequent Sex-dependent Disruptions of Adult Reward Behaviors

While links between early-life adversity (ELA) and mental illnesses characterized by dysregulated reward behaviors are well-established, the underlying mechanisms remain unclear. In mice, ELA reduces hedonic consumption and interest in sex reward in adult males and, in contrast, augments reward consumption in females. Here, using genetic tagging (TRAPing) we found robust, sex-specific activation of thalamic paraventricular nucleus (PVT) neurons during ELA. Manipulating these neurons in adults normalized reward behaviors: Blocking TRAPed anterior PVT neurons restored hedonic consumption in ELA males and augmented hedonic consumption in control females. In contrast, activation of these neurons reduced consumption in control males and ELA females. For posterior PVT, blocking TRAPed cells attenuated excessive reward consumption in ELA females and reduced it in control males. Thus, PVT is key for adaptive brain plasticity; anterior and posterior PVT carry different functions and contribute to the effects of ELA on adult reward behaviors in a sex-dependent manner.

neuroscience↗