Effects of orbitofrontal cortex and ventral hippocampus disconnection on spatial reversal learning
Introduction
Cognitive flexibility includes set-shifting responses from one stimulus dimension to another, and reversal learning to shift within the same dimension [1]. Human neuroimaging demonstrated increased activity in orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) during such flexibility-based tasks [[2], [3], [4]]. Patients with lesions in prefrontal (PFC) areas correspondingly displayed impaired flexibility [[5], [6], [7]]. Notably in rodents, lesions to mPFC and OFC impaired set-shifting and reversal learning, respectively [[8], [9], [10]]. Cognitive flexibility thus clearly depends on these PFC regions (see [11,12]), but older studies had also described affected reversal learning in hippocampus-lesioned rats [13,14]. Others reported that lesions in the ventral, but not dorsal, hippocampus (HC) impaired inhibitory control [15]. It was therefore proposed that HC, by creating a flexible representation of the environment, is likely to play a crucial role in adaptive behaviour and reversal learning as well [16].
Notably, Malá and colleagues reported that combined lesions of PFC and fimbria-fornix affected set-shifting and reversal learning [17]. These findings suggest that the interaction between HC and PFC is of particular importance in cognitive flexibility. One might even wonder whether the interaction between these regions could be of higher functional importance than their separate contribution. This interdependent functionality hypothesis is definitely supported by the anatomical connectivity between PFC and HC regions. More specifically, tracing studies revealed strong pathways between ventral HC (vHC) and PFC areas (including OFC and infralimbic/prelimbic mPFC areas), whereas projections between dorsal HC and PFC seemed significantly weaker [[18], [19], [20], [21]].
To evaluate the putative importance of HC-PFC connectivity in reversal learning, we set out to examine the effects of OFC and vHC disconnection on reversal learning. Disconnection models are considered essential tools to study interdependent functionality between brain regions [22]. In our present approach, we therefore compared the effect of contralateral disconnection lesions (i.e., lesion to OFC in one hemisphere combined with lesion to vHC in the contralateral hemisphere), with that of ipsilateral lesions. We hypothesized that performance during reversal learning would be impaired in the disconnection model, whereas this would not be the case (or to a lesser extent) in the ipsilateral model (i.e., functional vHC-OFC interaction still intact in one hemisphere) or in mice with bilateral lesions of only OFC or vHC (i.e., one of the regions still completely bilaterally intact).
Section snippets
Animals
10−12-week-old C57BL/6JRj female mice were obtained from Janvier Labs (Le Genest-Saint-Isle, FR). We included only female animals to reduce variability due to male territorial fighting. Territorial fighting and differences in social hierarchy in socially housed males have been shown to affect behavioural readouts before [23], whereas it is much easier to house female mice socially [24]. Animals (n = 75) were group-housed (5–8 per cage) in temperature-controlled rooms (22 ± 1 °C) with a 12 -h
Lesions
Stereotaxically defined OFC and vHC regions [25] were lesioned with NMDA micro-injections. Corresponding areas in control animals and non-targeted regions in experimental groups (e.g., ventral HC in the bilateral OFC group) were injected with vehicle (saline). After histological verification, 14 animals were excluded from further analyses for the absence of lesions and/or incorrect lesion position. This resulted in a final n of 16 for the control group, 13 for contralaterally lesioned group, 15
Discussion
In this report, we studied the effect of HC-OFC disconnection lesions on spatial learning and reversal. Contralateral and ipsilateral excitotoxic lesions were applied to OFC and vHC, as well as bilateral OFC or vHC lesions. MWM performance was similar between groups during the initial learning phase (acquisition), but the contralaterally lesioned group performed worse on the first day of reversal learning. This confirms the particular importance of vHC-OFC interaction in MWM reversal learning –
CRediT authorship contribution statement
David Thonnard: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Writing - original draft, Writing - review & editing. Zsuzsanna Callaerts-Vegh: Conceptualization, Supervision, Validation, Writing - original draft, Writing - review & editing. Rudi D’Hooge: Conceptualization, Funding acquisition, Project administration, Resources, Writing - original draft, Writing - review & editing.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
DT is a doctoral student of the Flemish science and technological development fund Agentschap Innoveren & Ondernemen. This study was also financed by a C1 grant of the University Research Council to RDH.
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