Frontal cortex stroke-induced impairment in spatial working memory on the trial-unique nonmatching-to-location task in mice

Josh Houlton; Deanna Barwick; Andrew N Clarkson

doi:10.1016/j.nlm.2020.107355

Frontal cortex stroke-induced impairment in spatial working memory on the trial-unique nonmatching-to-location task in mice

Neurobiol Learn Mem. 2021 Jan:177:107355. doi: 10.1016/j.nlm.2020.107355. Epub 2020 Dec 1.

Authors

Josh Houlton¹, Deanna Barwick¹, Andrew N Clarkson²

Affiliations

¹ Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin 9054, New Zealand.
² Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin 9054, New Zealand. Electronic address: andrew.clarkson@otago.ac.nz.

PMID: 33276070
DOI: 10.1016/j.nlm.2020.107355

Abstract

Stroke-induced cognitive impairments are of significant concern, however mechanisms that underpin these impairments remain poorly understood and researched. To further characterise cognitive impairments in our frontal cortex stroke model, and to align our assessments with what is used clinically, we tested young C57BL/6J mice trained in operant touchscreen chambers to complete the trial-unique nonmatched-to-location (TUNL) task. Based on baseline performance, animals were given either stroke (n = 12) or sham (n = 12) surgery using a photothrombosis model, bilaterally targeting the frontal cortex. Upon recovery, post-stroke spatial working memory was assessed by varying the degree of separation and delay within TUNL trials. Seven weeks after surgery, animals received a prelimbic injection of the retrograde tracer cholera toxin B (CTB) to access thalamo-PFC connectivity. Tissue was then processed histologically and immunohistochemically to assess infarct volume, astrogliosis and thalamocortical connectivity. Assessment of TUNL probes revealed sensitivity to a frontal cortex stroke (separation: p = 0.0003, delay: p < 0.0001), with stroke animals taking significantly longer (p = 0.0170) during reacquisition of the TUNL task, relative to shams. CTB-positive cell counts revealed a stroke-induced loss of thalamo-PFC connectivity. In addition, quantification of reactive astrogliosis revealed a positive correlation between the degree of astrogliosis expanding into white matter tracts and the development of cognitive impairments. This study reveals a stroke-induced impairment in mice completing the TUNL task. Our findings also demonstrate a significant loss of thalamo-PFC connections and a correlation between white matter reactive astrogliosis and cognitive impairment. Future experiments will investigate therapeutic interventions in the hope of promoting functional improvement in cognition.

Keywords: Cognition; Cognitive impairment; Photothrombotic stroke; Prefrontal cortex; Spatial working memory; Touchscreens.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Fluorescent Antibody Technique
Frontal Lobe / pathology*
Male
Memory Disorders / etiology*
Memory Disorders / pathology
Memory, Short-Term*
Mice
Mice, Inbred C57BL
Spatial Memory
Stroke / complications
Stroke / pathology*