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Early life stress (ELS) is a risk factor for developing functional gastrointestinal disorders, and has been proposed to be related to a central amplification of sensory input and resultant visceral hyperalgesia. We sought to characterize ELS-related changes in functional brain responses during acute noxious visceral stimulation. Neonatal rats (males/females) were exposed to limited bedding (ELS) or standard bedding (controls) on postnatal days 2–9. Age 10–11 weeks, animals were implanted with venous cannulas and transmitters for abdominal electromyography (EMG). Cerebral blood flow (rCBF) was mapped during colorectal distension (CRD) using [14C]-iodoantipyrine autoradiography, and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping and functional connectivity. EMG responses to CRD were increased after ELS, with no evidence of a sex difference. ELS rats compared to controls showed a greater significant positive correlation of EMG with amygdalar rCBF. Factorial analysis revealed a significant main effect of ‘ELS’ on functional activation of nodes within the pain pathway (somatosensory, insular, cingulate and prefrontal cortices, locus coeruleus/lateral parabrachial n. [LC/LPB], periaqueductal gray, sensory thalamus), as well as in the amygdala, hippocampus and hypothalamus. In addition, ELS resulted in an increase in the number of significant functional connections (i.e. degree centrality) between regions within the pain circuit, including the amygdala, LC/LPB, insula, anterior ventral cingulate, posterior cingulate (retrosplenium), and stria terminalis, with decreases noted in the sensory thalamus and the hippocampus. Sex differences in rCBF were less broadly expressed, with significant differences noted at the level of the cortex, amygdala, dorsal hippocampus, raphe, sensory thalamus, and caudate-putamen. ELS showed a sexually dimorphic effect (‘Sex x ELS’ interaction) at the LC/LPB complex, globus pallidus, hypothalamus, raphe, septum, caudate-putamen and cerebellum. Our results suggest that ELS alters functional activation of the thalamo-cortico-amydala pathway, as well as the emotional-arousal network (amygdala, locus coeruleus), with evidence that ELS may additionally show sexually dimorphic effects on brain function., Highlights • Early life stress (ELS) elicits visceral hyperalgesia in adult offspring. • ELS alters functional activation of the thalamo-cortico-amydala pathway. • ELS shows a sexually dimorphic effects on brain function. • Functional imaging-based endpoints promise improved animal-to-human translation.

Highlights • Thalamocortical projections from ATN are ipsilateral with the exception of a restricted bilateral AV projection to RSC. • Corticothalamic projections to the ATN are bilateral with the exception of an ipsilateral Cg projection to the AV nucleus. • The subiculum receives ipsilateral ATN efferents and provides the ATN with bilateral afferents. • The LD nucleus has exclusively ipsilateral, bidirectional connections with investigated cortical and hippocampal targets. • The postsubiculum has exclusively ipsilateral, bidirectional connections with the ATN, as well as the LD nucleus., Dense reciprocal connections link the rat anterior thalamic nuclei with the prelimbic, anterior cingulate and retrosplenial cortices, as well as with the subiculum and postsubiculum. The present study compared the ipsilateral thalamic-cortical connections with the corresponding crossed, contralateral connections between these same sets of regions. All efferents from the anteromedial thalamic nucleus to the cortex, as well as those to the subiculum, remained ipsilateral. In contrast, all of these target sites provided reciprocal, bilateral projections to the anteromedial nucleus. While the anteroventral thalamic nucleus often shared this same asymmetric pattern of cortical connections, it received relatively fewer crossed inputs than the anteromedial nucleus. This difference was most marked for the anterior cingulate projections, as those to the anteroventral nucleus remained almost entirely ipsilateral. Unlike the anteromedial nucleus, the anteroventral nucleus also appeared to provide a restricted, crossed projection to the contralateral retrosplenial cortex. Meanwhile, the closely related laterodorsal thalamic nucleus had almost exclusively ipsilateral efferent and afferent cortical connections. Likewise, within the hippocampus, the postsubiculum seemingly had only ipsilateral efferent and afferent connections with the anterior thalamic and laterodorsal nuclei. While the bilateral cortical projections to the anterior thalamic nuclei originated predominantly from layer VI, the accompanying sparse projections from layer V largely gave rise to ipsilateral thalamic inputs. In testing a potentially unifying principle of anterior thalamic – cortical interactions, a slightly more individual pattern emerged that reinforces other evidence of functional differences within the anterior thalamic and also helps to explain the consequences of unilateral interventions involving these nuclei.