The reduction of astrocytes and brain volume loss in anorexia nervosa—the impact of starvation and refeeding in a rodent model

Abstract

Anorexia nervosa (AN) is an often chronic, difficult to treat illness that leads to brain volume reductions in gray and white matter. The underlying pathophysiology is poorly understood, despite its potential importance in explaining the neuropsychological deficits and clinical symptoms associated with the illness. We used the activity-based anorexia model (ABA), which includes food reduction and running wheel access in female rats to study brain changes after starvation and refeeding. Longitudinal animal MRI and post-mortem brain sections confirmed a reduction in the mean brain volumes of ABA animals compared to controls. In addition, the mean number of astrocytes was reduced by over 50% in the cerebral cortex and corpus callosum, while the mean number of neurons was unchanged. Furthermore, mean astrocytic GFAP mRNA expression was similarly reduced in the ABA animals, as was the mean cell proliferation rate, whereas the mean apoptosis rate did not increase. After refeeding, the starvation-induced effects were almost completely reversed. The observation of the astrocyte reduction in our AN animal model is an important new finding that could help explain starvation-induced neuropsychological changes in patients with AN. Astrocyte-targeted research and interventions could become a new focus for both AN research and therapy.

Age influences structural brain restoration during weight gain therapy in anorexia nervosa

“…Several biological mechanisms have been discussed as explanations for the observed gray matter reduction and subsequent regeneration in AN patients, such as dehydration 7,17,51 or apoptosis (programmed cell death) of neurons or glia cells 52,53 . Recent reports on animal models of activity-based anorexia strongly support the hypothesis of glia cells playing a key role in AN 54,55 , suggesting that severe structural alterations in AN may be selectively linked to processes of astroglia and reduced glia cell proliferation 56 . While the number of glia cells seems to stay relatively stable during healthy ageing 57 , the notion of diminished astrocyte proliferation 56 offers an interesting explanation for the slower regeneration of cortical thickness in the older AN patients of the present study.…”

Thirty years after anorexia nervosa onset, serum neurofilament light chain protein concentration indicates neuronal injury

“…Other studies have reported neurohistological abnormalities in individuals with AN and in AN animal models indicating degeneration associated with "pseudoatrophia cerebri". A postmortem study showed quantitative and qualitative changes in neuronal dendritic spine morphology [37], and animal studies using dehydration-induced, forced food-restricted, or activity-based AN models have found reduced astrocytes in the hippocampus, corpus callosum, and cerebral cortex [9,[38][39][40]. Future studies need to collect biomarkers from cerebral spinal fluid to investigate possible degenerative processes caused by AN in greater detail.…”

Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency

“…5 a–f). Considering that many neurodegenerative diseases accompany reactive astrogliosis and that reduced astrocyte density was observed in major depressive disorder and starvation 27 , 31 , neurodegeneration accompanying astrocyte reduction in the hippocampus is a unique pathological change in aminopeptidase P1 deficiency. In addition, the morphology of astrocytes in the Xpnpep1 −/− CA3 subfields, determined by GFAP-immunoreactive signals distributed in the cellular processes, was similar to that of control astrocytes (Fig.…”

“…Moreover, phenylketonuria and homocystinuria, inborn errors of metabolism caused by the deficiency of phenylalanine hydroxylase and cystathionine β-synthase respectively, also exhibit gliosis in the brain 45 , 46 . Meanwhile, chronic unpredictable stress and starvation induced a reduction in astrocytes in the cerebral cortex 31 , 47 . A recent study showed that depletion of astrocytes by treatment with the gliotoxin L-α-aminoadipic acid (L-α-AAA) did not induce neuronal death in the hippocampal CA3 area without insults such as ischemia, but that the loss of astrocyte produced persistent Ca 2+ increase in the CA3 neurons after ischemia and reperfusion 48 .…”