Basal forebrain magnocellular cholinergic systems are damaged in mice following neonatal hypoxia-ischemia

Frances J. Northington, Panagiotis Kratimenos, Victoria Turnbill, Debra L. Flock, Daniella Asafu-Adjaye, Raul Chavez-Valdez, Lee J. Martin

Research output: Contribution to journalArticlepeer-review


Neonatal hypoxic-ischemic encephalopathy (HIE) causes lifelong neurologic disability. Despite the use of therapeutic hypothermia, memory deficits and executive functions remain severely affected. Cholinergic neurotransmission from the basal forebrain to neocortex and hippocampus is central to higher cortical functions. We examined the basal forebrain by light microscopy and reported loss of choline acetyltransferase-positive (ChAT)+ neurons, at postnatal day (P) 40, in the ipsilateral medial septal nucleus (MSN) after neonatal hypoxia-ischemia (HI) in mice. There was no loss of ChAT+ neurons in the ipsilateral nucleus basalis of Meynert (nbM) and striatum. Ipsilateral striatal and nbM ChAT+ neurons were abnormal with altered immunoreactivity for ChAT, shrunken and crenated somas, and dysmorphic appearing dendrites. Using confocal images with 3D reconstruction, nbM ChAT+ dendrites in HI mice were shorter than sham (p =.0001). Loss of ChAT+ neurons in the MSN directly correlated with loss of ipsilateral hippocampal area. In the nbM and striatum, percentage of abnormal ChAT+ neurons correlated with loss of ipsilateral cerebral cortical and striatal area, respectively. Acetylcholinesterase (AChE) activity increased in adjacent ipsilateral cerebral cortex and hippocampus and the increase was linearly related to loss of cortical and hippocampal area. Numbers and size of cathepsin D+ lysosomes increased in large neurons in the ipsilateral nbM. After neonatal HI, abnormalities were found throughout the major cholinergic systems in relationship to amount of forebrain area loss. There was also an upregulation of cathepsin D+ particles within the nbM. Cholinergic neuropathology may underlie the permanent dysfunction in learning, memory, and executive function after neonatal brain injury.

Original languageEnglish (US)
Pages (from-to)1148-1163
Number of pages16
JournalJournal of Comparative Neurology
Issue number8
StatePublished - Jun 2022


  • cathepsin D
  • choline acetyltransferase
  • executive function
  • learning
  • medial septal nucleus
  • memory
  • nucleus basalis of Meynert
  • somato-dendritic neuronal attrition
  • target deprivation

ASJC Scopus subject areas

  • General Neuroscience


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