In the Epistulae Morales ad Lucilium, Seneca wrote: “There are more things, Lucilius, likely to frighten us than there are to crush us; we suffer more often in imagination than in reality”. This sentence, from one of the key figures of the school of stoicism, describes inner fear within our imagination in the absence of a direct fear-provoking stimulus. Nowadays, even though anxiety and fear correspond to the same theoretical construct in some literature, anxiety differentiates from the latter based on the potential nature of the threat in the absence of an imminent harmful stimulus (Calhoon and Tye, 2015; Davis et al., 2010; Steimer, 2002). Anxiety disorders are becoming more commonly reported: 12-month prevalence estimates on mental disorders show that at least 14% of people in the European Union suffer from anxiety disorders (Wittchen et al., 2011), and around 31% of people in the United States have experienced some type of anxiety disorders in their lifetime (Kessler et al., 1994). Different brain areas play a role in the underlying circuitry of anxiety (Sandford et al., 2000). Stimulations in the brainstem, more precisely in the periaqueductal grey matter or the locus coerulus are specifically involved in the symptomatology of anxiety (Graeff et al., 1993; Redmond and Huang, 1979). Some studies have also shown how the amygdala plays a role in humans suffering from anxiety disorders (Birbaumer et al., 1998; Davidson et al., 1999) or in animal models with generalised fear responses associated with anxiety (Gründemann et al., 2019; Tovote et al., 2015; Wolff et al., 2014). Also, by using the elevated plus maze (EPM) as an anxiety task (Pellow et al., 1985), Tye and colleagues induced anxiolytic effects by targeting projections from the basolateral amygdala (BA) to the central nucleus of the amygdala (Tye et al., 2011). Additional structures are involved in anxiety and include the bed nucleus of the stria terminalis, whose subdivisions are differentially involved in anxiety responses (Duvarci et al., 2009; Kim et al., 2013), and the medial prefrontal cortex (mPFC), which has also been directly linked to anxiety processing in both humans (Rauch et al., 1997) and rodents (Park et al., 2016; Shah and Treit, 2003).

Last but not least, the ventral hippocampus (vH) plays a critical role in anxiety behaviour. Lesions in the vH induce anxiolysis during the exploration of elevated open arenas (e.g. EPM) (Jimenez et al., 2018; Kjelstrup et al., 2002; Padilla-Coreano et al., 2016), or generally in tasks associated with approach-avoidance conflicts (Schumacher et al., 2018). Neurons recorded in the vH showed increased firing in locations with elevated anxiety (Ciocchi et al., 2015; Jimenez et al., 2018). Likewise, projections neurons from and to the vH exhibit anxiety-related activity: amygdala projections to the vH are specifically shaping anxiety-related behaviour during the exploration of an EPM (Felix-Ortiz and Tye, 2014; Pi et al., 2020). Similarly, the reciprocal connection (from vH to BA) is involved in the expression of context-dependent fear memories (Kim and Cho, 2020). Furthermore, information related to anxiety in the vH is directly routed to the mPFC (Ciocchi et al., 2015), and synchronised activity in this monosynaptically connected long-range circuit (Adhikari et al., 2010; Adhikari et al., 2011) is essential for the expression of anxiety behaviour. Motivated by the critical role of the dorsal hippocampus (dH) region in the encoding of spatial information (O’Keefe, 1976; O’Keefe and Nadel, 2011), several studies focusing on the vH have described its involvement in spatial coding (Jung et al., 1994; Poucet et al., 1994). Yet, probably due to its anatomical location and the difficulties to record action potentials of single-unit activity in the vH, the individual neuronal dynamics associated with the changes between anxiogenic and non-anxiogenic states during spatial navigation remain poorly understood.

To study the neuronal dynamics associated with anxiety behaviour in the vH, we simultaneously recorded the activity of individual neurons during the exploration of the EPM, as well as during the exploration of a novel behavioural paradigm, the elevated linear maze (ELM). During the same recording session, we modified the ELM from a non-anxiogenic to an anxiogenic configuration, while recording the activity of the same individual vH neurons. This enabled the investigation of the neuronal dynamics within the vH underlying different anxiety states. We specifically examined the remapping of neuronal activity at the single neuron and population level as animals transitioned from a non-anxiogenic configuration to an anxiogenic one. Collectively, the results of this study show that the neuronal activity in the vH does not simply reflect anxiogenic locations but that it is dynamically modulated by the experience and expectation of anxiety during spatial navigation.

To investigate the neuronal dynamics governing anxiety behaviour in the vH, we recorded the activity of individual neurons while rats explored anxiogenic locations. In addition to the classical EPM, we used a novel ELM, which allowed us to rapidly change the anxiety content of the maze to expose rats to non-anxiogenic or anxiogenic configurations. We found that the neuronal activity of the vH exhibited a uniform spatial representation in the non-anxiogenic configuration of the ELM and that vH neurons displayed direction-dependent spatial firing when shuttling from one end of the ELM to another. When the anxiogenic location was introduced by removing the protective sidewalls from half of the track, the peak firing activity remapped towards the newly introduced anxiogenic location, the spatial properties of the neuronal activity diminished, and direction-dependent firing was homogenised. Of important note, neuronal activity in the closed arm of the ELM predicted the extent of the upcoming exploration in the open arm even before rats entered into the open anxiogenic location.

Much of the anxiety research in freely moving rodents has been relying on the EPM. Using the EPM, it has been shown that: amygdala projections to the vH control the expression of anxiety (Felix-Ortiz and Tye, 2014; Pi et al., 2020); there is an anxiety-associated neuronal activity in the vH routed to the mPFC Ciocchi et al., 2015; and that the vH-prefrontal pathway is critical for anxiety behaviour (Adhikari et al., 2010; Adhikari et al., 2011; Ciocchi et al., 2015). The first part of this manuscript focuses on the activity of neurons recorded in the vH during the exploration of an EPM. We divided the exploration of the EPM into different trajectories. We observed a localised increase in the density of peak firing activity when rats crossed the centre in all the different C-C or C-O trajectories (Figure 1E). This might be explained by the fact that not only the open arms of an EPM are anxiogenic, but also the centre zone (Mendes-Gomes et al., 2011). Unfortunately, it proved difficult to analyse these effects quantitatively, because rats explored the open arms only minimally and sporadically, consistent with the anxiogenic nature of the EPM paradigm.

To overcome this problem, we introduced a novel ELM on which rats were motivated to shuttle from one extremity to the other to receive rewards. The ELM had three different configurations: non-anxiogenic (CC configuration); anxiogenic (CO configuration); and a configuration with new texture and visual cues (CT). Configurations could be quickly switched within a session. At the behavioural level, we observed anxiety-related behaviour during ELM exploration comparable to the ones during EPM exploration (Figure 2D and E). However, the main advantage of the ELM was the possibility to record the neuronal activity of the same vH neurons while rapidly modifying ELM configurations and motivating rats to spend more time in the anxiogenic location. After animals transited from a non-anxiogenic to an anxiogenic configuration, we observed a significant increment in peak firing activities predominately located in the open area. We attributed this recruitment or remapping of the neuronal activity to the anxiogenic location. The neuronal mechanisms during spatial remapping remain largely elusive. Global remapping is a phenomenon observed in the dH when animals move from one environment to a different one (Leutgeb et al., 2005). One could argue that the simple removal of the walls is changing the environment of the ELM and therefore animals could perceive the open arm as a completely novel environment, inducing global remapping. Nevertheless, remapping of neuronal activity in a new environment is expected to be random and independent of a previously explored environment (Gauthier and Tank, 2018; Leutgeb et al., 2005; Schlesiger et al., 2018), even when emotional contexts are introduced (Moita et al., 2004). However, the remapping of neuronal activity observed in vH neurons is not arbitrary as it is most prominent in the anxiogenic location, contrary to a uniformly distributed peak activity in case of a random remapping (Figure 3B). Nonetheless, the opening of walls per se, independent of the anxiogenic experience, could cause changes in vH neuronal activity. Previous work has shown that novel environments elicit the activation of vH neurons to a similar extent as an aversive stimulus (Graham et al., 2021). To show that the remapping of neuronal activity relies on anxiety, we changed the ELM from a CC to CT configuration during the same recording session. In the CT configuration, the previously open location changed to a novel one with a different floor texture and visual patterns in the inner part of the walls, but with protective sidewalls kept all along the track (Figure 2B). As anticipated, these changes equally induced a remapping of neuronal activity in the vH. Yet, in this case, the remapping was distributed over the length of the maze and the novel area did not show an increased number of peak firing activity (Figure 3C). Overrepresentation of behaviourally relevant locations or episodes is not novel in the hippocampal research field. It has been previously demonstrated that hippocampal place cells fire preferentially at reward locations during goal-directed tasks (Dupret et al., 2010; Hok et al., 2007; Hollup et al., 2001; Jin and Lee, 2021) and global remapping is observed in the intermediate hippocampus due to motivational changes (Jin and Lee, 2021). Several experiments have tackled the role of dH neurons in fear conditioning and other aversive tasks, resulting in similar activity patterns to the ones found in this research. Dorsal hippocampal place cells were shown to remap or partially remap in the presence of an aversive stimulus (Kong et al., 2021; Moita et al., 2004; Wu et al., 2017), or remap towards areas of aversive stimuli or threats (Schuette et al., 2020; Wang et al., 2012; Wang et al., 2015), by increasing their activation (Wu et al., 2017) or by synchrony with or reactivation of a subset of basal and BA neurons (Girardeau et al., 2017; Kong et al., 2021). Interestingly, the non-aversive stimulus, presented in the same context as the aversive ones, did not induce remapping in dorsal hippocampal neurons (Moita et al., 2004; Wang et al., 2015), a similar effect to our observations in vH neurons.

Furthermore, the vH is strongly associated with anxiety, and the anxiogenic location represents a highly salient environment for vH-dependent computations (Bannerman et al., 2014). This is supported by our finding that neurons of the vH overrepresent the anxiogenic area. Interestingly, in addition to the global remapping, we also found differences in the rate remapping between the CC-CO and the CC2-CT conformation changes. Rate remapping was significantly more robust in the novel context than in the anxiogenic one, in line with the literature suggesting that novelty induces rate remapping in hippocampal neurons (Kaefer et al., 2019; Leutgeb et al., 2005; Rennó-Costa et al., 2010). Regarding spatial properties of the hippocampal neurons, conflicting effects have been observed with aversive stimuli in the dH. In some cases, spatial information was not significantly different between non-aversive and aversive conditions, but the variance was significantly greater Wu et al., 2017; in other cases, spatial information was higher in non-aversive compared to aversive contexts Wang et al., 2015; while others report either an increase in place field size (Moita et al., 2004) or a decrease (Schuette et al., 2020). One paper reports various changes in the activity of vH neurons when mice are confronted with an aversive odour stimulus. They report a decrease in place field size, remapping of the activity and increase of the firing rate in the presence of the aversive odour (Keinath et al., 2014). Similarly, we also observe remapping of neuronal activity in aversive conditions and, in fact, a tendency, yet no significance, of the neurons to increase their firing rate in the CO configuration compared to the CC (Figure 4—figure supplement 1C). However, in our study, the activity of the neurons in vH increases its coverage, while in Keinath et al., it is reduced (smaller place fields). In the Keinath et al. study, the aversive stimulus was presented on a small area while in our case the source of the anxiogenic stimulus cannot be pinpoint to a specific part of the open arm, which might have contributed to the different observations. In our experiments, the spatial properties of the neurons in the anxiogenic area of the CO configuration are reduced (lower spatial information and higher sparsity) compared to the CC configuration (Figure 4). Overall, all these elements further strengthen the role of vH in the emotional processing of information.

Another relevant observation relates to the directional firing of vH neurons. In the non-anxiogenic configuration of the ELM, the spatial activity of single vH neurons varied depending on the direction of exploration. Similar observations have been made in both the dH (McNaughton et al., 1983) and vH (Royer et al., 2010) for linear mazes, suggesting of a common principle underlying spatial information along the dorso-ventral axis of the hippocampus. With respect to the vH, Royer et al. hypothesised that the differential activity between inbound and outbound trajectories might be caused by the reward delivered at the end of the arm implying some reward-associated value coding. In contrast to Royer et al., we placed rewards at both extremities of the ELM. Although this does not invalidate the view of Royer et al., in our study, the direction-dependent firing was homogenised in the anxiogenic configuration of the ELM, with vH neurons exhibiting similar firing independently of the direction of exploration in the open arm (Figure 5). We attribute the homogenisation of the direction-dependent firing in single vH neurons to the relevance of the anxiogenic location for vH-dependent computations. One cannot rule out that the homogenisation is also a product of the noticeable change in the maze configuration, implying that the closed and open arm are easier to discern for the animal. Therefore, in both directions, the animal receives similar visual inputs and, therefore, activity homogenises. However, our control experiments, in which we introduced a new, but non-anxiogenic environment to the ELM (Figure 5C), also resulted in a clear differentiation of both parts of the ELM in both directions of travel. Still, we failed to observe a homogenisation of the activities.

Furthermore, the modulation of the neuronal activity in the anxiogenic location was not exclusively observed while the rats explored the open area. The CO configuration of the ELM contained protective walls in half of the maze, while the other half was entirely open. The neuronal population activity was a good predictor of the extent of the exploration of the open location, even when rats explored the closed arm before entering to the open location. Indeed, the neuronal activity in the closed arm, of neuronal pairs, was sufficient to infer whether rats would perform proximal or distal explorations of the open arm (Figure 6). Anxiety-related modulation of vH neuronal activity in both the closed and the open locations implies that not only a direct experience of anxiety enhances neuronal activity in the vH, but also its anticipation without a direct confrontation to an anxiety-inducing situation.

Overall, we provided evidence that the neuronal dynamics within the vH are subjected to the experience of anxiety. When an anxiogenic situation was encountered, vH neurons, first, over-represented this location (Figure 3). Second, spatial properties of the neurons, with their main activity in the anxiogenic area, were reduced (Figure 4). Third, vH neuronal activity was tuned to the anxiogenic environment, impairing previous direction-dependent neuronal activity manifesting in the absence of anxiety (Figure 5). Fourth, the neuronal activity of vH neurons reflected and predicted the exploration of an anxiogenic location (Figure 6). Collectively, these results expand our view of vH function by highlighting dynamic and predictive computations during anxiety.

Data is available in Github (https://github.com/Klausberger-Laboratory/Malagon-Vina-Anxiety2022; copy archived at Malagon-Vina, 2023).

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Author details

1. Hugo Malagon-Vina

   Division of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   hugo.malagonvina@meduniwien.ac.at

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5029-8464

2. Stéphane Ciocchi

   1. Division of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
   2. Laboratory of Systems Neuroscience, Department of Physiology, University of Bern, Bern, Switzerland

   Contribution

   Conceptualization, Resources, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing – original draft, Project administration, Writing – review and editing

   Contributed equally with

   Thomas Klausberger

   For correspondence

   stephane.ciocchi@unibe.ch

   Competing interests

   No competing interests declared

3. Thomas Klausberger

   Division of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing – original draft, Project administration, Writing – review and editing

   Contributed equally with

   Stéphane Ciocchi

   For correspondence

   thomas.klausberger@meduniwien.ac.at

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7269-3158

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