Lesions of the Basal Forebrain Cholinergic System in Mice Disrupt Idiothetic Navigation

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.

Neurotrophin regulation of Alzheimer's disease pathology

“…Lesioning of the basal forebrain in both wildtype and APP/PS1 mice resulted in slower escape latencies when platform location was changed on day 7. This deficit in memory updating is consistent with previous results (Hamlin et al, 2013), and is representative of cholinergic degeneration. Futhermore, in the probe trial we found that basal forebrain lesioned APP/PS1 spend significantly less time in the target quadrant, and make significantly fewer platform crossings compared to non-lesioned transgenic controls.…”

“…In a number of previous reports, a BFCN lesion was sufficient to induce specific cognitive deficits and accelerate Aβ pathology in AD model mice (Laursen et al, 2013, Hamlin et al, 2013 This indicates that our lesion size was sufficient to reduce cholinergic innervation to the hippocampus and induce flow-on effects.…”

“…It has been previously reported that, although BFCN lesioning in wildtype animals impairs uncued (idiothetic) maze tasks, it does not affect cued (allocentric) Morris water maze performance (Hamlin et al, 2013). Herein we hypothesized that a BFCN lesion would cause an impairment in hippocampal memory due to the reduction in neurotrophin levels in combination with tau dysfunction in the hippocampus.…”

“…Behavioral analysis performed on mice following infusion of p75-saporin indicates deficits in spatial learning in Morris water maze and place avoidance tasks (Berger-Sweeney et al, 2001, Hamlin et al, 2013. Moreover, no adverse effects such as abnormal loss of weight or disruption of sensorimotor coordination were reported following surgery and a 100% postsurgical survival rate was observed (Moreau et al, 2008).…”

Selective Manipulation of Neural Circuits

“…Saporin kills cells by inactivating ribosomes thereby inhibiting translation [169]. Targeting specific cell types and circuits has been accomplished with local injection of modified saporins that is conjugated with various proteins including cell type-specific antibodies and the neurotransmitter substance P [170][171][172][173][174][175][176][177]. Some neurotoxins, such as tetanus toxin and botulinum toxin are retrogradely transported by presynaptic neurons.…”