Functional Dissection of a Parabrachial-Thalamic Circuit Mediating Cold Allodynia in a CIPN Model

Mishra, Ankita (2025) Functional Dissection of a Parabrachial-Thalamic Circuit Mediating Cold Allodynia in a CIPN Model. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS Dissertation of Ankita Mishra (20MS180)) 20MS180_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (4MB)

Abstract

Chemotherapy-induced peripheral Neuropathy (CIPN) remains a significant dose-limiting side effect of commonly used chemotherapeutic agents like oxaliplatin, characterized by chronic cold allodynia. Despite its prevalence, the underlying neural mechanisms remain incompletely understood. In this study, we investigate the role of a parabrachial-thalamic circuit in mediating cold hypersensitivity in a murine model of CIPN. Using a combination of circuit-specific viral strategies, DREADDs (Designer Receptors Exclusively Activated by Designer Drugs), and in vivo fiber photometry with GCaMP6s, we map and functionally manipulate the projections from lateral parabrachial nucleus (LPBN) neurons to the parafascicular thalamic nucleus (PFT). Our results demonstrate that chemogenetic activation of PFT neurons receiving LPBN input enhances nocifensive responses to cold stimuli, while silencing this circuit using Kir2.1-mediated hyperpolarization attenuates these responses significantly. We further show that NMDAR-dependent synaptic activity and CaMKII-driven plasticity within this LPBN-PFT pathway are critical for developing and maintaining cold allodynia. Disruption of either GluN1 expression or CaMKII signaling in PFT neurons significantly reduces hypersensitivity, suggesting a key role for synaptic plasticity in chronic pain sensitization and neural encoding of aversive cold stimuli. Our findings delineate a functionally significant LPBN-PFT circuit underlying cold allodynia in CIPN and highlight the importance of thalamic synaptic plasticity in nociplastic pain. These insights offer potential targets for therapeutic intervention in chemotherapy-induced neuropathic pain. 7

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