Abstract
Emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling with studies on stress-induced endocannabinoid dysregulation focusing on cerebral changes that are temporally proximal to stressors. Little is known about temporally distal and sex-specific effects, especially in cerebellum, which is vulnerable to early developmental stress and is dense with cannabinoid receptors. Following limited bedding at postnatal days 2–9, adult (postnatal day 70) cerebellar and hippocampal endocannabinoids, related lipids, and mRNA were assessed, and behavioral performance evaluated. Regional and sex-specific effects were present at baseline and following early-life stress. Limited bedding impaired peripherally-measured basal corticosterone in adult males only. In the CNS, early-life stress (1) decreased 2-arachidonoyl glycerol and arachidonic acid in the cerebellar interpositus nucleus in males only; (2) decreased 2-arachidonoyl glycerol in females only in cerebellar Crus I; and (3) increased dorsal hippocampus prostaglandins in males only. Cerebellar interpositus transcriptomics revealed substantial sex effects, with minimal stress effects. Stress did impair novel object recognition in both sexes and social preference in females. Accordingly, the cerebellar endocannabinoid system exhibits robust sex-specific differences, malleable through early-life stress, suggesting the role of endocannabinoids and stress to sexual differentiation of the brain and cerebellar-related dysfunctions.
Highlights
In humans, poor prenatal and early postnatal care is a major developmental stressor commonly found in low socioeconomic groups[1,2]
Stress typically results in hypothalamic release of corticotropin releasing hormone (CRH), which stimulates the pituitary gland to secrete adrenocorticotropic hormone (ACTH) and, in turn, prompts the adrenal cortex to release cortisol
Early-life stress affects the endocannabinoid system by (a) decreasing CB1Rs in adulthood in males[27] across cerebral regions such as striatum, prefrontal cortex, and amygdala as concluded through [3H]CP55,940 binding and mRNA expression, though findings in females have been mixed[28], and (b) increasing gene expression for endocannabinoid degradation enzymes in frontal cortex, striatum, hippocampus, and amygdala[29], though surprisingly these effects have not been studied in the cerebellum
Summary
Poor prenatal and early postnatal care is a major developmental stressor commonly found in low socioeconomic groups[1,2]. In the hippocampus, there appears to be more CB1R protein in males than females, though females tend to show higher CB1R G-protein activation from endocannabinoids, suggesting more efficient coupling of CB1Rs in females[25] These sex differences in the cannabinoid system may be important for key sex differences observed in behavior following stressors. Early-life stress affects the endocannabinoid system by (a) decreasing CB1Rs in adulthood in males[27] across cerebral regions such as striatum, prefrontal cortex, and amygdala as concluded through [3H]CP55,940 binding and mRNA expression, though findings in females have been mixed[28], and (b) increasing gene expression for endocannabinoid degradation enzymes in frontal cortex, striatum, hippocampus, and amygdala[29], though surprisingly these effects have not been studied in the cerebellum. The hippocampus’s role in memory formation and linkage with the HPA axis may explain the array of impairments common to early-life stress and the development of psychopathology[39]
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