733: Whole-Brain Mapping Reveals Altered Pain Representations Following Early Life Adversity

Topic: Basic Science
Subtopic: Pain category (ICD-11), Neuropathic pain , , , , , , , , , , Neuroanatomical circuit analysis

Background and Aims: Chronic pain is a multifaceted condition shaped by numerous biological, psychological, and environmental factors. Among these, adverse childhood experiences (ACEs) have been consistently linked to increased susceptibility to chronic pain through long-lasting alterations in stress- and pain-processing circuits, including regions such as the insula, anterior cingulate cortex, and amygdala. Here, we investigate how an animal model of early life adversity (ELA) alters nociceptive processing and susceptibility towards developing neuropathic chronic pain following injury. Using behavioral assays, whole-brain activity mapping, and computational analyses in TRAP2 reporter mice before and after spared nerve injury (SNI), we aim to identify neural circuits through which ELA influences baseline nociception and chronic pain development.

Methods: Early life adversity (ELA) was modeled in mice using the limited bedding and nesting (LBN) paradigm, which induces fragmented maternal care and produces long-term behavioral alterations. To identify neural circuits underlying altered nociceptive processing, we used TRAP2 × Ai75 tdTomato reporter mice to permanently label neurons activated by painful stimuli prior to chronic pain induction. Neuropathic pain was induced using the spared nerve injury (SNI) model. Mechanical and thermal sensitivity were assessed in both LBN and control-reared animals before and after injury. Four weeks post-SNI, mice underwent a light-touch stimulation protocol to evoke allodynia and were sacrificed one hour later for cFos-based whole-brain activity mapping. Behavioral assays, whole-brain imaging, and computational analyses were used to identify brain regions and neural activity patterns associated with ELA-mediated alterations in baseline nociception and chronic pain susceptibility.

Results: LBN mice exhibited increased baseline mechanical and thermal sensitivity, demonstrated by lower von Frey withdrawal thresholds and shorter Hargreaves latencies relative to controls. Following SNI, however, LBN animals displayed reduced nocifensive responses to cold stimulation and trends toward reduced thermal hypersensitivity, suggesting a potential protective effect after injury. Whole-brain TRAP analysis revealed decreased baseline activity in somatosensory-related regions, including primary somatosensory cortex and trigeminal nuclei, alongside altered activity in pain-associated thalamic regions. In contrast, post-SNI cFos mapping demonstrated increased activity within cortical and extended amygdalar regions, including the BST, medial amygdala, retrosplenial cortex, anterior cingulate cortex, and claustrum. UMAP and functional correlation analyses further showed that LBN animals exhibited more tightly clustered and less modular brain-wide pain activity patterns, suggesting increased functional correlation and altered large-scale organization of nociceptive networks following ELA.

Conclusions: Our findings demonstrate that early life adversity produces long-lasting alterations in nociceptive processing and brain-wide pain circuitry. LBN mice exhibited heightened baseline pain sensitivity alongside widespread changes in neural activity within somatosensory, thalamic, cortical, and extended amygdalar regions. Following neuropathic injury, pain-related activity shifted from predominantly thalamic alterations to increased engagement of higher-order emotional and associative regions, including the amygdala and retrosplenial cortex, suggesting altered cognitive and affective processing of pain. Computational analyses further revealed tighter clustering and reduced modularity of pain-related brain activity in LBN animals, indicating disrupted large-scale network organization. Together, these findings suggest that early life stress reshapes neural pain circuits in ways that alter both baseline nociception and chronic pain responses, providing insight into how adverse childhood experiences may increase vulnerability to chronic pain disorders.

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Presenting Author: May Hui
Submitting Author: May Hui

Senior Author: Kevin Beier

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Pieter Derdeyn: PhD - UC Irvine