Lesions of the basal forebrain cholinergic system in mice disrupt idiothetic navigation

PLoS One. 2013;8(1):e53472. doi: 10.1371/journal.pone.0053472. Epub 2013 Jan 8.

Abstract

Loss of integrity of the basal forebrain cholinergic neurons is a consistent feature of Alzheimer's disease, and measurement of basal forebrain degeneration by magnetic resonance imaging is emerging as a sensitive diagnostic marker for prodromal disease. It is also known that Alzheimer's disease patients perform poorly on both real space and computerized cued (allothetic) or uncued (idiothetic) recall navigation tasks. Although the hippocampus is required for allothetic navigation, lesions of this region only mildly affect idiothetic navigation. Here we tested the hypothesis that the cholinergic medial septo-hippocampal circuit is important for idiothetic navigation. Basal forebrain cholinergic neurons were selectively lesioned in mice using the toxin saporin conjugated to a basal forebrain cholinergic neuronal marker, the p75 neurotrophin receptor. Control animals were able to learn and remember spatial information when tested on a modified version of the passive place avoidance test where all extramaze cues were removed, and animals had to rely on idiothetic signals. However, the exploratory behaviour of mice with cholinergic basal forebrain lesions was highly disorganized during this test. By contrast, the lesioned animals performed no differently from controls in tasks involving contextual fear conditioning and spatial working memory (Y maze), and displayed no deficits in potentially confounding behaviours such as motor performance, anxiety, or disturbed sleep/wake cycles. These data suggest that the basal forebrain cholinergic system plays a specific role in idiothetic navigation, a modality that is impaired early in Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / physiopathology
  • Alzheimer Disease / psychology
  • Animals
  • Cholinergic Neurons / drug effects
  • Cholinergic Neurons / physiology*
  • Conditioning, Psychological / physiology
  • Cues*
  • Fear / physiology
  • Humans
  • Locomotion / physiology
  • Male
  • Maze Learning / physiology*
  • Memory, Short-Term / physiology
  • Mental Recall / physiology
  • Mice
  • Mice, Inbred C57BL
  • Prosencephalon / drug effects
  • Prosencephalon / injuries
  • Prosencephalon / physiopathology*
  • Ribosome Inactivating Proteins, Type 1 / toxicity
  • Saporins

Substances

  • Ribosome Inactivating Proteins, Type 1
  • Saporins

Grants and funding

This work was supported by the National Health and Medical Research Council of Australia (Project Grant 569507; Postdoctoral Fellowship 569886 to A.S.H.; Career Development Fellowship 569601 to E.J.C.) and a Mason Foundation grant [http://www.nhmrc.gov.au/, http://www.anz.com/personal/private-bank-trustees/trustees/granting/granting-programs/health-medical/#NMP] The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.