Elsevier

Neuroscience Letters

Volume 750, 17 April 2021, 135711
Neuroscience Letters

Effects of orbitofrontal cortex and ventral hippocampus disconnection on spatial reversal learning

https://doi.org/10.1016/j.neulet.2021.135711Get rights and content

Highlights

  • Behavioural flexibility is mediated by orbitofrontal-hippocampal interaction.

  • NMDA-induced orbitofrontal-hippocampal lesions affect early phase reversal learning.

  • Learning deficits can not be reduced to motor deficits or anxiety-related behavior.

Abstract

Behavioural flexibility is a cognition-related function that enables subjects to adapt to a changing environment. Orbitofrontal cortex (OFC) and hippocampus (HC) have been involved in cognitive flexibility, but the interaction between these structures might be of particular functional significance. We applied a disconnection model in C57BL/6JRj mice to investigate the importance of OFC and ventral HC (vHC) interaction. Spatial acquisition and reversal performance in the Morris water maze (MWM) was compared between animals with small contralateral excitotoxic lesions to OFC and vHC, ipsilateral lesions (i.e., OFC-vHC lesions in the same hemisphere), as well as small bilateral OFC or vHC lesions. Spatial learning and memory performance was mostly unimpaired or only slightly impaired in our brain-lesioned animals compared to sham-lesioned control mice. However, contralaterally lesioned mice were significantly impaired during the early phase of reversal learning, whereas the other lesion groups performed similar to controls. These mice might also have experienced some difficulties using cognitively advanced search strategies. Additional non-mnemonic tests indicated that none of the defects could be reduced to motor, motivational or anxiety-related changes. Our findings support the particular role of PFC−HC interaction in advanced cognitive processes and flexibility.

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.

References (63)

  • E. Piccart et al.

    Impaired appetitively as well as aversively motivated behaviors and learning in PDE10A-deficient mice suggest a role for striatal signaling in evaluative salience attribution

    Neurobiol. Learn. Mem.

    (2011)
  • A. Torres-Berrío et al.

    The ventral hippocampus is required for behavioral flexibility but not for allocentric/egocentric learning

    Brain Res. Bull.

    (2019)
  • R.S. Ross et al.

    The hippocampus is functionally connected to the striatum and orbitofrontal cortex during context dependent decision making

    Brain Res.

    (2011)
  • A. Adhikari et al.

    Synchronized activity between the ventral Hippocampus and the medial prefrontal cortex during anxiety

    Neuron

    (2010)
  • D.M. Bannerman et al.

    Regional dissociations within the hippocampus - Memory and anxiety

    Neurosci. Biobehav. Rev.

    (2004)
  • A.L. Tracy et al.

    The hippocampus and motivation revisited: appetite and activity

    Behav. Brain Res.

    (2001)
  • S. Ocklenburg et al.

    Hemispheric asymmetries and cognitive flexibility: an ERP and sLORETA study

    Brain Cogn.

    (2012)
  • H. Eichenbaum et al.

    Can we reconcile the declarative memory and spatial navigation views on hippocampal function?

    Neuron

    (2014)
  • R.C. Wilson et al.

    Orbitofrontal cortex as a cognitive map of task space

    Neuron

    (2014)
  • R. Cools et al.

    Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging

    J. Neurosci.

    (2002)
  • D.G. Ghahremani et al.

    Neural components underlying behavioral flexibility in human reversal learning

    Cereb. Cortex

    (2010)
  • L.K. Fellows et al.

    Ventromedial frontal cortex mediates affective shifting in humans: evidence from a reversal learning paradigm

    Brain

    (2003)
  • J. Hornak et al.

    Reward-related reversal learning after surgical excisions in orbito-frontal or dorsolateral prefrontal cortex in humans

    J. Cogn. Neurosci.

    (2004)
  • E.T. Rolls et al.

    Emotion-related learning in patients with social and emotional changes associated with frontal lobe damage

    J. Neurol. Neurosurg. Psychiatry

    (1994)
  • J.M. Birrell et al.

    Medial frontal cortex mediates perceptual attentional set shifting in the rat

    J. Neurosci.

    (2000)
  • G.B. Bissonette et al.

    Double dissociation of the effects of medial and orbital prefrontal cortical lesions on attentional and affective shifts in mice

    J. Neurosci.

    (2008)
  • D.A. Hamilton et al.

    Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions

    Genes Brain Behav.

    (2015)
  • G. Winocur et al.

    Effects of context manipulation on memory and reversal learning in rats with hippocampal lesions

    J. Comp. Physiol. Psychol.

    (1978)
  • A.R. Abela et al.

    Inhibitory control deficits in rats with ventral hippocampal lesions

    Cereb. Cortex

    (2013)
  • A. Vila-Ballo et al.

    Unraveling the role of the hippocampus in reversal learning

    J. Neurosci.

    (2017)
  • H. Malá et al.

    Prefrontal cortex and hippocampus in behavioural flexibility and posttraumatic functional recovery: reversal learning and set-shifting in rats

    Brain Res. Bull.

    (2015)
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