Roles of the ventral hippocampus and medial prefrontal cortex in spatial reversal learning and attentional set-shifting

https://doi.org/10.1016/j.nlm.2021.107477Get rights and content

Highlights

  • The ventral hippocampus is critical for behavioral adaptation in spatial reversal learning but not in set-shifting.

  • The rats with inactivated ventral hippocampus might still be able to process new spatial information.

  • The medial prefrontal cortex is not involved in flexible spatial processing on the rotating arena.

Abstract

Neural components enabling flexible cognition and behavior are well-established, and depend mostly on proper intercommunication within the prefrontal cortex (PFC) and striatum. However, dense projections from the ventral hippocampus (vHPC) alter the functioning of the medial PFC (mPFC). Dysfunctional hippocampo-prefrontal connectivity negatively affects the integrity of flexible cognition, especially in patients with schizophrenia. In this study, we aimed to test the role of the vHPC and mPFC in a place avoidance task on a rotating arena using two spatial flexibility task variants – reversal learning and set-shifting. To achieve this, we inactivated each of these structures in adult male Long-Evans rats by performing bilateral local muscimol (a GABAA receptor agonist) injections. A significantly disrupted performance was observed in reversal learning in the vHPC-inactivated, but not in the mPFC-inactivated rats. These results confirm the notion that the vHPC participates in some forms of behavioral flexibility, especially when spatial cues are needed. It seems, rather unexpectedly, that the mPFC is not taxed in these flexibility tasks on a rotating arena.

Introduction

Flexible cognition allows for the shaping of our behavior or intentions in dynamically changing circumstances, and is an essential component of executive functioning. The term “behavioral flexibility” encompasses the ability to shift attention between different features of stimuli, task sets, or strategies, and adjust behavioral responses (Brown & Tait, 2015). These changes in behavior can be divided into several types, depending on the character of the task. Two basic forms of flexibility are reversal learning and attentional or strategy set-shifting. Reversal learning involves a shift of relevance within one defined set of cues (Brady & Floresco, 2015). The cue that was initially reinforced with simple discrimination now becomes irrelevant, and vice versa, previously a non-reinforced cue is newly of high value (Brady & Floresco, 2015). This type of flexibility requires the extinction of a previously learned stimulus–response association and the reinforcement of a new one (Floresco, Zhang, & Enomoto, 2009). If an animal initially needs to go right to obtain a reward, in the new set, it must start going left. In both examples, the task rule or the cue type remains in the same dimension, and switching attention between multiple dimensions is not required. Therefore, it is a relatively simple form of flexibility (Brown & Tait, 2015).

In contrast, set-shifting is cognitively more complex, as it requires a combination of sensory perception, working memory and sustained attention (Bissonette, Powell, & Roesch, 2013). A change can be performed within a whole cue set (one dimension) or between different cue features, tasks, or mental sets (multiple different dimensions), in which the subject must redirect its attention. Based on this information, we define two subcategories of set-shifting. Firstly, an intradimensional set-shift (IDS) involves replacing a whole set of both relevant and irrelevant cues for new ones within one dimension (e.g., if one dimension is odor, the change is made, e.g., by substituting lavender and mint scents for jasmine and rosemary), while an extradimensional set-shift (EDS) refers to an alternation among different cues, rules or strategies, depending on currently relevant contingencies (e.g., a switch of relevance from substrate shape to odor) (Bissonette et al., 2013). The different features of presented cues can be olfactory, visual, tactile or spatial, and can be variously combined, especially in challenging spatial tasks. This is one of the main reasons why set-shifting is a powerful tool in animal research – such an experimental setup reliably mimics the complex situations that emerge in everyday human life (Popik & Nikiforuk, 2015).

Another form of flexible behavior is extinction. This phenomenon happens unconsciously if a conditioned behavior is no longer reinforced with a reward or punishment. A common use of testing this ability is with fear conditioning, when an aversive stimulus, e.g. a mild electric shock, is paired with a neutral context, e.g. wall color in the room, or some stimulus, e.g. tone (Milad & Quirk, 2002). If the aversive stimulus is not present anymore, the fear response slowly fades until it disappears entirely. Extinction-like processes are a component of complex behaviors observed in both reversals and set-shifting tasks.

Successful adaptation to changing contingencies depends on overlapping circuitries connecting the prefrontal cortex (PFC) with other subcortical structures (Floresco et al., 2009, Ragozzino, 2007). Many cognitive functions are dissociated in different regions of the PFC, which together select relevant stimuli, integrate them with experience and emotions, and modify the resultant behavior. In humans, the dorsolateral PFC is associated with executive functions, like attention, planning, working memory, or problem-solving, whereas ventral parts of the PFC allow for motor inhibition and verbal communication (Szczepanski & Knight, 2014). The anterior cingulate cortex (ACC) modulates emotional regulation and monitors error and conflict responses, while the orbitofrontal cortex (OFC) mostly mediates motivational processes, and both contribute to decision-making (Carter et al., 1998, Khani, 2014, Szczepanski and Knight, 2014). The PFC as a whole is the key structure involved in cognitive control, that is, the ability to actively use relevant information and guide behavior while ignoring irrelevant stimuli in the presented task, because it functions as the main information processing center, receiving inputs from many subcortical and sensory systems and transferring processed information to other, especially motor behavior driving structures.

The well-established thalamo-fronto-striatal loop plays the most important role in this process, forming an interconnected network subserving the cognitive flexibility (Cummings, 1995, Tekin and Cummings, 2002). However, a recent study by Park, O’Reilly, et al. (2019) did not observe any impairment in either learning or memory in an active place avoidance task on the rotating arena, suggesting that the rodent medial PFC (mPFC) is not necessarily critical for cognitive control, despite the prevailing opinion that the mPFC significantly contributes to information processing and related cognitive functions. Thus, spatial representation might be more dependent on other structures, possibly the hippocampus (Kelemen and Fenton, 2010, Lee et al., 2012). Various studies have shown impairments in either attentional set-shifting or spatial strategy set-shifting in animals with a dysfunctional ventral hippocampus (vHPC) (Brady, 2009, Brooks et al., 2012, Torres-Berrío, Vargas-López, & López-Canul, 2019). These impairments were manifested mainly by perseverative errors, indicating problems with abandoning previous strategies and holding on to learned rules, habits, and behavior. Anatomical alterations supporting the vHPC-mPFC deficits in rats with neonatal lesions of the vHPC (NVHL rats) have also been found – PFC pyramidal neurons have much shorter dendrites and reduced arborization, and the density of dendritic spines is much lower in the PFC, but also in the nucleus accumbens (NAc), compared to healthy rats (Flores et al., 2005, Marquis et al., 2008). Adult NVHL rats show many behavioral and neurobiological aberrations that are also seen in schizophrenia patients, therefore, it is a valid and often used animal model in research of this illness (O’Donnell, 2012).

In the present study we tested the hypothesis that transient functional inactivation of the vHPC and mPFC in Long-Evans rats would affect behavioral flexibility in active place avoidance tasks, with modifications taxing reversal learning and attentional set-shifting (Svoboda, Stankova, Entlerova, & Stuchlik, 2015). We further hypothesized that the inactivation of both structures would exert a similar effect, according to the well-established role of frontotemporal crosstalk in behavioral flexibility in the healthy brain (Bähner & Meyer-Lindenberg, 2017, Floresco et al., 1997, Laroche et al., 2000, Siapas, Lubenov, & Wilson, 2005) and schizophrenia (John, 2009, Kolb and Whishaw, 1983, Meyer-Lindenberg et al., 2005).

Section snippets

Animals

Forty-three male Long-Evans rats (3–4 months old) from the breeding colony of the Institute of Physiology, ASCR, were included in the statistical analysis. Rats were housed in pairs and kept at a 12/12 h light/dark cycle. The animals were food-restricted and maintained at 85–90% of their ad libitum body weight. A day before the first behavioral training, a needle was pierced through a skin fold on their back and bent at the tip to prevent slipping out, allowing for the delivery of a shock

Results

Nine rats (three from the mPFC group, six from the vHPC group) that were unable to learn the initial place avoidance task were excluded from the analysis and further training. One rat from the vHPC group was excluded due to locomotor issues after muscimol injection, and one additional rat from the vHPC group was excluded because of an inaccurate cannula placement. In total, forty-three rats were included in the statistical analysis.

Discussion

Expanding our knowledge about the participation of the mPFC or vHPC in behavioral flexibility seems quite necessary, as evidence has accumulated that frontotemporal crosstalk contributes to flexibility in the healthy human brain (Bähner & Meyer-Lindenberg, 2017) while its aberrant function is a hallmark of schizophrenia (Meyer-Lindenberg et al., 2005). In this study, we sought to examine the effects of bilateral mPFC or vHPC muscimol inactivations on behavioral flexibility in active place

Conclusions

In conclusion, our study clearly shows the importance of the vHPC rather than frontotemporal connections for flexible behavior, specifically in reversal on a rotating arena, while the mPFC was not found to contribute to any kind of flexibility tested on the arena. These findings suggest that the neural substrates of behavioral flexibility might be more widely distributed and more closely related to specific demands of a task than previously expected. If this is true, not all set-shifting

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The study was supported mainly by the Czech Health Research Council (AZV) grant 17-30833A awarded to AS. It was also supported by the Czech Science Foundation (GACR) grant 20-00939S awarded to AS and the Ministry of Education Youth and Sports (MEYS CZ) bilateral INTER-ACTION project LTAUSA19135 awarded to JS. Partial support also came from the Academic Mobility project PAN-20-08. We thank Michaela Radostna and Jindrich Kalvoda for technical assistance and David W. Hardekopf for proofreading.

CRediT authorship contribution statement

D. Cernotova: Investigation, Data curation, Writing - original draft, Writing - review & editing. A. Stuchlik: Conceptualization, Writing - original draft, Funding acquisition, Supervision. J. Svoboda: Conceptualization, Investigation, Data curation, Writing - original draft, Writing - review & editing, Funding acquisition, Supervision.

References (44)

  • E.H. Park et al.

    How the Internally Organized Direction Sense Is Used to Navigate

    Neuron

    (2019)
  • K. Placek et al.

    Impairments in set-shifting but not reversal learning in the neonatal ventral hippocampal lesion model of schizophrenia: Further evidence for medial prefrontal deficits

    Behavioural Brain Research

    (2013)
  • B. Poucet et al.

    Effects of short-lasting inactivations of the ventral hippocampus and medial septum on long-term and short-term acquisition of spatial information in rats

    Behavioural Brain Research

    (1991)
  • A.G. Siapas et al.

    Prefrontal phase locking to hippocampal theta oscillations

    Neuron

    (2005)
  • S.M. Szczepanski et al.

    Insights into Human Behavior from Lesions to the Prefrontal Cortex

    Neuron

    (2014)
  • S. Tekin et al.

    Frontal-subcortical neuronal circuits and clinical neuropsychiatry: An update

    Journal of Psychosomatic Research

    (2002)
  • A. Torres-Berrío et al.

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

    Brain Research Bulletin

    (2019)
  • A.R. Abela et al.

    Inhibitory control deficits in rats with ventral hippocampal lesions

    Cerebral Cortex

    (2013)
  • P.D. Avigan et al.

    Flexible spatial learning requires both the dorsal and ventral hippocampus and their functional interactions with the prefrontal cortex

    Hippocampus

    (2020)
  • Bahník, Š. (2014). Carousel Maze Manager (Version 0.4.0) Software. Available at:...
  • A.M. Brady et al.

    Operant procedures for assessing behavioral flexibility in rats

    Journal of Visualized Experiments

    (2015)
  • J.M. Brooks et al.

    Transient inactivation of the neonatal ventral hippocampus impairs attentional set-shifting behavior: Reversal with an α7 nicotinic agonist

    Neuropsychopharmacology

    (2012)
  • Cited by (0)

    View full text