The cerebellum, located in the lower back of the skull, plays a key role in regulating voluntary movement like balance, motor learning and speech.
Recent evidence shows the cerebellum involved in higher-order brain functions, including visual response, emotion and motor planning.
And now, a team from Kyoto University has found another link: depressive behavior.
Writing in Cell Reports, the research team reports on a series of experiments with rats, finding that acute cerebellar inflammation puts the structure in an “overexcited” state, resulting in the animal developing a temporary decrease in motivation and sociability.
Team leader Gen Ohtsuki of Kyoto University’s Hakubi Center for Advanced Research explains that the investigation began in an effort to understand how the brain’s immune system can change its activity. I
n fact, literature has shown correlations between cerebellar dysfunction and certain pervasive developmental disorders such as autism and depression.
“Even though we now know more about the cerebellum’s role in higher-order brain functions, the detailed signal transduction machinery remains a mystery.
We know even less about what happens in the brain during excessive immune activity,” explains Ohtsuki.
“So we conducted series of experiments where we activated the immune cells in the cerebellum and observed the results.”
From supplementary video 1. Rats with acute cerebellar inflammation (middle) have reduced exploitative behavior compared to the control (left). When administered with anti-inflammatory cytokines or neuro-immunity suppressants their behavior is rescued (right). Credit: Kyoto University/Gen Ohtsuki
The brain’s immune cells are known as microglia, and they respond to bacteria and viruses to mitigate damage. That response results in inflammation. Utilizing electrophysiological techniques, the team found that microglia caused neurons to fire at an increased rate, a phenomenon known as intrinsic plasticity. This in turn caused the cerebellum to go into a hyperexcited state.
This immune-triggered response was shown to change behavior. When rats were induced with acute cerebellar inflammation, their sociability, free searching and motivation dramatically decreased.
“These behavioral modulations are signs of depression-like behavior. Once the inflammation subsided, they were back to normal,” Ohtsuki continues.
“Moreover, the phenotype can be rescued if the rats are treated with neuro-immunity suppressants and inflammatory cytokines.
We also investigated whether higher-order brain regions were affected.
fMRI studies on the rats show a clear increase in activity in the prefrontal cortex, highlighting the interconnectedness of the cerebellum to higher order brain regions.”
The team is encouraged by their results, but further investigation is needed.
“Excessive immune activity in the brain can induce behavioral pathology, and we expect it to be involved in other mental and cognitive disorders such as dementia.
But to understand anything about the pathological mechanisms we need to combine this with additional data such as genetic risk factors,” concludes Ohtsuki.
“In this study, we focused on inflammation.
In the future, we will begin firmly clarifying the physiological, molecular, and genetic aspects of these behavioral changes.”
The cerebellum is one of the first brain structures to emerge and one of the last to fully mature, at least in part because of its reciprocal closed-loop circuitry with multiple cortical regions1.
In adulthood, the cerebellum is characterized by its role in intrinsic motor learning2,3, but is gaining increasing appreciation for its role early in life to shape and refine neocortical circuits for affect and cognition4.
Children treated surgically for cerebellar tumors often experience symptoms of cerebellar cognitive syndrome, including poor decision making and planning, decreased working memory, poor speech generation, impaired visuospatial reasoning, and irritability compared to normative data5,6,7.
The constellation of effects depends on which hemisphere is involved, inclusion of the vermis, and the age of surgical resection.
Damage to the cerebellum in infancy is one risk factor among many contributing to whether a child is diagnosed with autism spectrum disorder (ASD), and is particularly associated with perseverative behaviors and inability to perceive or match another’s emotions8,9,10.
Pathologies of the cerebellum are also strongly associated with schizophrenia4,11, which is increasingly being viewed as a disorder with origins in development12,13,14,15,16.
Prostaglandin E2 (PGE2) is an eicosanoid that among its other physiological roles induces a fever17. PGE2 is produced from arachidonic acid (AA) by two enzymes acting sequentially. First, the cyclooxygenase enzymes COX-1 and COX-2 convert AA to prostaglandin H2. Then, prostaglandin E synthase (PGES) produces PGE2. In the rodent brain, most AA is synthesized from the endocannabinoid, 2-arachidonoylglycerol, by monoacylglycerol lipase (MAG lipase), but this has not been validated in the human18.
Estradiol is considered a sex steroid hormone made in the gonads, but there is an increasing appreciation for local synthesis in the brain, particularly in humans19,20.
Both isoforms of the estrogen receptor (ER) are expressed by cerebellar neurons, with ERα (Esr1) notable for much higher expression early in development and restriction to Purkinje cells compared to ERβ (estrogen receptor 2 (Esr2)).
The aromatase gene (Cyp19a) is also expressed by developing Purkinje cells, suggesting cell autonomous developmental regulation by estradiol21.
The laboratory rat provides a model for identifying previously unknown sensitive windows of vulnerability to acute events, such as infection, as well as sources of sensitivity to ongoing inflammation.
We have identified a neonatal sensitive period during which the cerebellum is susceptible to inflammation and mimetics of infection, resulting in impaired Purkinje neuron development. Either direct administration of the proinflammatory prostaglandin PGE2 into the cerebellum or peripheral administration of the inflammatory-inducing agent lipopolysaccharides stunts Purkinje neuron dendritic development22,23.
Remarkably, the deleterious effects of inflammation are only manifest if the exposure occurs during the second postnatal week of life.
The same treatments during the first or third week are completely without impact. The sensitive period is marked by the activation of the steroidogenic enzyme, aromatase (Cyp19a), which aromatizes androgen precursors into estrogens. Endogenous estradiol is elevated in the 2-week-old cerebellum, suggesting a normal role in maturation, but if increased in response to inflammation or direct administration, Purkinje neuron development is stunted.
The sensitive period is closed at the end of the 2nd week by a precipitous drop in the expression of the Cyp19a gene, as well as Esr1.
Thus, even though inflammation may induce the production of prostaglandin, without the increase in estradiol production and transduction, there are no deleterious consequences24.
As a first step in translating these findings to humans, we asked whether a similar coupling of inflammation to a cerebellar PGE2–estradiol pathway exists in the newborn and early childhood human cerebellum.
Toward that end, we obtained samples of post-mortem human cerebellum and quantified messenger RNA (mRNA) for the components of the PGE2–estradiol synthesis pathway as well as other markers of inflammation.
We predicted that:
(1) the enzymes producing PGE2 would be up-regulated in individuals whose medical records indicate signs of infection or inflammation at or near death,
(2) that the enzyme aromatase would also be up-regulated with infection or inflammation, and
(3) that expression of enzymes producing PGE2 and receptors signaling for PGE2 would correlate with aromatase expression during inflammation, but would not correlate in expression in individuals not experiencing inflammation.
Because the medical records associated with young children are limited, we also sought to confirm inflammatory status by measuring mRNA for Toll-like receptor 4 (TLR4) in the brain samples, a reliable indicator of inflammation25
More information: “Microglia-triggered plasticity of intrinsic excitability modulates psychomotor behaviors in acute cerebellar inflammation” Cell Reports (2019). DOI: 10.1016/j.celrep.2019.07.078
Journal information: Cell Reports
Provided by Kyoto University
