Secretin's role in the cerebellum: a larger biological context and implications for developmental disorders.

Evolutionarily conserved primitive learning andmemory networks including the cerebellum employclassical neurotransmitters and peptides sustainingtheir actions (1). Children learn to perform com-municative, affiliative adaptive acts that promote anoverall state of well-being and maintain homeostasis.The cerebellum is critical to learning and memory ofthese adaptive acts. Yung and colleagues’ review(this issue) of the role of secretin in the cerebellumdraws upon innovative studies conducted in bothbasic and clinical settings. Their main conclusionsare supportable and help advance translationalresearch on secretin and developmental disorders.The authors describe secretin as a retrogrademessenger and neuromodulator within the cerebel-lum and discuss its candidacy as a molecule in thetreatment of autism and related spectrum disorders.The contention that secretin’s role in developmentaldisorders should not be dismissed on the basis ofstudies published to date is a critical point that issupported by the experiments of Yung and col-leagues, by work in our laboratory (2–4) and by acareful reading of the literature. We would like toexpand upon the ideas presented in their article.Secretin’s role in regulation of stressYung and colleagues’ review is especially intriguingif placed in the context of the overall role thatneuropeptides such as secretin play in the modula-tion of stress across systems and their concomitanteffects on development and behavior. It is thoughtthat secretin is expressed at a relatively low level inthe CNS. Indeed our own studies show thatsecretin’s constitutive expression in the fore-brainis undetectable in a freely moving rat but robustlyup-regulated in response to an oxidative stressor,colchicine. Based on this finding, and in light ofreports by Yung and others, we hypothesize thatsecretin is a centrally acting stress-regulatory neuro-peptide synthesized and released in the brain, as it isin the gut, in response to homeostatic challenges (3).From this perspective, the actions and regulation ofsecretin in the cerebellum may well prove to be partof a unified and integrated stress-modulatory neu-ropeptide mechanism distributed throughout theCNS and periphery (4).The findings of Yung et al. on the cerebellumsupport the importance of secretin’s role in learningand memory networks and the conditioning ofadaptive behaviors. The midline cerebellum is partof an integrated network that regulates emotionalstates and behavioral expressions involving inter-connections of the cerebral and cerebellar corticesand their subcortical outlets including the amygdala,hypothalamus and periaqueductal gray (5). Learningand memory of fear responses, as reflected inchanges of somatic and autonomic response patternssuch as freezing, are altered by manipulating thecerebellar vermis (6). These response patterns arecritical to conditioning of cognition, emotionalcontrol, and execution of adaptive actions.Cerebral cortical thalamostriatal stress adaptationnetworks processing information from the midlinecerebellum are dysregulated in disorders of develop-ment, including autism.The cerebellum is part of an integrated networkregulating emotional behaviors that appears to beabnormal in autistic patients. Childhood cognitiveand emotional disorders associated with cerebellardamage include language difficulties, disinhibition,impulsivity and irritability, and failure to initiateand execute actions (7). Autistic patients exhibit