The hippocampus is key for episodic memory, learning and spatial navigation, as well as motivation, affect and anxiety (Gray and McNaughton, 2003; O’Keefe and Nadel, 1978; Strange et al., 2014; Wikenheiser and Schoenbaum, 2016). At almost every level of investigation – from gene expression, to afferent and efferent connectivity, and behavioural function – the hippocampus is organised as a gradient along the dorsal to ventral (posterior to anterior in humans) axis (Fanselow and Dong, 2010; Strange et al., 2014). Within this axis the most dorsal portion is proposed to be involved in learning and utilising fine-grained spatial and temporal structure, whereas the most ventral pole is thought to be involved in affect and motivation, and has a key role in value-based and reward-driven decision-making and anxiety-like calculations (Fanselow and Dong, 2010; Strange et al., 2014).

A distinguishing factor that separates the ventral from the dorsal hippocampus is dense input from the corticobasolateral nuclear complex of the amygdala (basal amygdala [BA]; McDonald and Mott, 2017; Strange et al., 2014). The BA comprises a diverse set of nuclei including the basolateral amygdala (BLA), the basomedial amygdala (BMA), the medial amygdala (MEA) and cortical amygdala, each of which sends projections to ventral hippocampus (vH) (McDonald and Mott, 2017; Petrovich et al., 2001; Strange et al., 2014). These nuclei, and their projections to vH, are thought to be crucial for the learning of reward- and threat-associated cues, and for the generation of appropriate goal-directed and anxiety-like behaviour (Beyeler et al., 2018; Beyeler et al., 2016; Felix-Ortiz et al., 2013; Felix-Ortiz and Tye, 2014; Hitchcott and Phillips, 1997; McHugh et al., 2004; Pi et al., 2020; Richardson et al., 2004; Selden et al., 1991; Sheth et al., 2008; Yang and Wang, 2017). Thus, it is commonly assumed that powerful and specific synaptic connectivity between these two structures is crucial for the maintenance of such behaviours. However, there is limited information describing the organisation of such functional connectivity between amygdala input and neurons in vH (Felix-Ortiz et al., 2013; Pi et al., 2020).

This lack of understanding is compounded by the fact that the vH, in particular its output structure the ventral CA1 and subiculum – where the majority of BA input is found – is organised as a parallel circuit, such that the majority of neurons project to only one downstream area (Gergues et al., 2020; Naber and Witter, 1998; Wee and MacAskill, 2020). Thus, while vH has powerful connections to the nucleus accumbens (NAc), the prefrontal cortex (PFC) and back to the BA, each of these projections arises from a distinct population of neurons. Importantly each of these projection populations is increasingly shown to underlie unique behavioural functions (Adhikari et al., 2010; Jimenez et al., 2018; LeGates et al., 2018; Sanchez-Bellot and MacAskill, 2021). For example, vH^NAc neuron activity is high during motivated behaviour and around rewarded locations (Ciocchi et al., 2015; Okuyama et al., 2016; Reed et al., 2018), is necessary for place-value associations (LeGates et al., 2018; Trouche et al., 2019) and can promote spatial and instrumental reinforcement (Britt et al., 2012; LeGates et al., 2018). In contrast, vH^PFC activity is proposed to support the resolution of approach avoidance conflict and contribute to spatial working memory (Padilla-Coreano et al., 2016; Sanchez-Bellot and MacAskill, 2021; Spellman et al., 2015), while vH^BA activity is proposed to support contextual learning (Jimenez et al., 2018). However, it remains unclear how the activity of these distinct populations in vH is differentially controlled to promote these functions. We reasoned that a means for this control would be projection-specific innervation from BA.

The circuit organisation of the nuclei in the BA is similar to classic cortical circuitry – with the majority of neurons classed as either excitatory pyramidal neurons or local inhibitory interneurons (McDonald and Mott, 2017). However, there is also evidence suggesting the presence of long-range inhibitory projection neurons throughout BA (Dedic et al., 2018; McDonald et al., 2012; McDonald and Zaric, 2015; Seo et al., 2016). Similar inhibitory projections from cortex are hypothesised to have a crucial regulatory role in modulating hippocampal circuit function (Basu et al., 2016; Melzer et al., 2012), but the connectivity and function of BA long-range inhibitory input in vH has never been directly investigated.

In this study, we used a combination of retrograde tracing, electrophysiology and channelrhodopsin-2-assisted circuit mapping to show that BA provides both excitatory and direct inhibitory input to distinct projection populations within vH. We show that excitatory projections uniquely target vH neurons that project to NAc and back to the BA, and do not connect with neurons that project to PFC. In contrast, long-range inhibitory input preferentially targets BA-projecting vH neurons. Next, using a simple network model constrained by our electrophysiology recordings, we predicted that the ability of BA input to drive motivation- and value-promoting vH projections to NAc was dependent on the co-activation of both excitatory and inhibitory input from BA. Finally, we confirmed these predictions using in vivo optogenetics and genetically targeted pharmacology to show that long-range inhibition is required for the generation of spatial place preference. Together, our results outline a novel inhibitory projection from amygdala to vH that defines the activity of vH output neurons and is able to control hippocampal output to promote the formation of spatial place preference.

In this study, we have defined a novel long-range inhibitory projection from BA to vH. We show that this novel projection exists in concert with a parallel excitatory projection, and that the presence of its inhibitory influence can dramatically shift vH output in response to BA activity. While excitation alone preferentially drives a reciprocal projection back to BA, co-activation of both excitatory and inhibitory input preferentially drives a separate projection to NAc, which can support place-value associations.

We found that in addition to classically described excitatory input from BA to vH, there was also direct inhibitory projection (Figures 1 and 2). Excitatory input from BA to vH has been widely studied and is distributed across a large range of subnuclei, ranging from the MEA to the BLA, and well as cortical amygdala (McDonald and Mott, 2017). Each of the distinct nuclei of the amygdala are thought to control various aspects of cue-dependent learning and carry out unique roles during behaviour. Increasingly, function has been assigned to BA based on anatomical location. For example, anterior basolateral, basomedial and central amygdala have unique contributions to fear learning and extinction (Adhikari et al., 2015; Ciocchi et al., 2010; Kim et al., 2016; LeDoux, 2000), while more posterior and medial regions of BA are increasingly associated with reward learning, value calculations and prosocial behaviours (Chen et al., 2019; Kim et al., 2016; Lutas et al., 2019; Malvaez et al., 2019; Pi et al., 2020; Shemesh et al., 2016). However, the role within each of these nuclei is also diverse – with interspersed neurons involved in encoding behaviour across a wide range of different situations (Beyeler et al., 2016; Felix-Ortiz et al., 2013; Felix-Ortiz and Tye, 2014; Gründemann et al., 2019; Kim et al., 2016; Namburi et al., 2015b). We found that the BA inhibitory projection arose from GABAergic neurons interspersed between excitatory projection neurons throughout the entire extent of the BA (Figure 2—figure supplement 1). Thus, it will be important to systematically investigate the synaptic targeting and behavioural contribution of the input from different nuclei separately. However, in addition it will also be important to assess the differential contribution of excitatory and inhibitory drive, most likely through the use of intersectional genetic and anatomical approaches (Fenno et al., 2014; Kim et al., 2016).

Our results suggest that inhibitory input from BA to vH may be important for motivated behaviour, in particular we show that co-activation of both excitatory and inhibitory projections from BA, and not excitation alone, is essential for promoting place preference (Figures 7 and 8). Long-range inhibitory projections from classical excitatory projection areas have been increasingly identified as having a key role in shaping circuit output and for defining motivated behaviour. For example, functional inhibitory projections from PFC to NAc (Lee et al., 2014b), and BA to PFC (Seo et al., 2016) have both been shown to modulate value-based and reward behaviour, including the support of RTPP and aversion. The hippocampus also receives long-range inhibitory input from numerous regions including entorhinal (Basu et al., 2016; Melzer et al., 2012), septum (Schlesiger et al., 2021) and PFC (Malik et al., 2021). While these studies focussed on dorsal hippocampal circuitry and a role for these projections in memory and navigation, due to the known dichotomy between dorsal and ventral hippocampal function (Fanselow and Dong, 2010; Strange et al., 2014), it would be interesting to investigate the presence and function of such long-range inhibitory projections into vH. In particular, whether a role in motivated behaviour and place preference was specific to BA input or due to the dorsoventral location of this input in hippocampus. Interestingly, long-range inhibition from entorhinal cortex, septum and PFC all preferentially target interneurons and avoid pyramidal neurons (Basu et al., 2016; Melzer et al., 2012; Schlesiger et al., 2021). In contrast, our data show that BA long-range inhibition connects with both interneurons and pyramidal neurons (Figure 4), similar to that seen in long-range inhibitory projections from BA to PFC (Seo et al., 2016). This suggests that there may at least in part be interesting input-specific connectivity across the different long-range inhibitory inputs into hippocampus.

We investigated the synaptic and circuit basis by which BA input could promote such motivated behaviour. The vH is increasingly viewed as being composed as a series of parallel output streams, where pyramidal neurons in the CA1/subiculum border are composed of multiple populations each projecting to a distinct downstream region including the NAc, the PFC and the BA. Each projection population in vH underlies a unique role during behaviour. In particular, vH^NAc neurons have been shown to be key for motivated behaviour, and the association of reward with a particular place or time (Britt et al., 2012; Ciocchi et al., 2015; LeGates et al., 2018; Okuyama et al., 2016; Trouche et al., 2019). We found that both excitatory and inhibitory input from BA made specific connections onto each of these projection populations (Figures 4—6), such that the balance of excitation and inhibition from BA into vH is well placed to determine their relative activity. Excitatory input alone preferentially activated vH^BA neurons, while excitatory and inhibitory input together preferentially activated vH^NAc neurons (Figure 6). Thus, BA input is well placed to define the activity of specific vH output pathways in response to a particular environment, state or task. More specifically, the level of inhibitory input form BA can control RTPP by defining the activity of vH^NAc neurons (Figures 7 and 8).

It is interesting to note, however, that there is overlap between different projection populations in vH. While roughly 80–90 % of neurons are thought to project to a single downstream region (Figure 3, Gergues et al., 2020; Naber and Witter, 1998; Wee and MacAskill, 2020), a proportion of vH neurons collateralise and project to two or more regions. In this study, we recorded from only single-labelled neurons after injection into two downstream regions (Figures 3—5), but as the efficiency of retrograde labelling is not 100% we cannot discount the fact that neurons in our dataset may project to more than one region not labelled by our injections. While the large differences in synaptic connectivity across projection populations (Figures 4 and 5) reinforce the idea of parallel projection populations in vH, due to their scarcity we did not explicitly address the connectivity of this small population of collateralising neurons. This is therefore an interesting future direction. Importantly, however, using our circuit model we found that the switch in activity from vH^BA to vH^NAc populations was robust despite large overlap of each projection population (Figure 6—figure supplement 2).

When considering the possibility of collateralising vH neurons, it is important to consider the distribution of projection neurons along the transverse (near CA2, to near subiculum) axis. Dual-projecting neurons are much more prominent in the proximal CA1 (at the CA1/CA2 border; Naber and Witter, 1998; Wee and MacAskill, 2020). This part of CA1 is preferentially associated with place coding and spatial navigation (Ciocchi et al., 2015; Henriksen et al., 2010). We focussed our investigations in distal CA1 (at the CA1/subiculum border) as this is where we found the most consistent excitatory and inhibitory input from BA (Figure 2—figure supplements 3 and 4; McDonald and Mott, 2017), and this is where the majority of long-range projection neurons are found (Figure 3; Naber and Witter, 1998; Wee and MacAskill, 2020). In this part of the hippocampus, dual-projection neurons are rarer (Naber and Witter, 1998), and this difference in cellular properties coincides with a preferential role of distal CA1 in non-spatial and object-place associations (Igarashi et al., 2014; Nakamura et al., 2013). Therefore, in the future it will be important to explicitly investigate the properties of these dual-projection neurons and also how their function and connectivity change along the transverse axis.

In addition to the role of BA and vH in value-based and motivated behaviour, multiple studies have examined the role of excitatory BLA input into vH in the generation of anxiety-like behaviour (Felix-Ortiz et al., 2013; Pi et al., 2020). The vH has a key role in the generation of appropriate behaviour in anxiogenic environments (Gray and McNaughton, 2003; Kjelstrup et al., 2002; McHugh et al., 2004). This is thought to be achieved both by resolving approach-avoidance conflict during decision-making via vH^PFC projection neurons (Padilla-Coreano et al., 2016; Sanchez-Bellot and MacAskill, 2021), but recently also via generation of a specific anxiogenic state defined via projections to the lateral hypothalamus (LH; Jimenez et al., 2018). In our study, we detected only minimal excitatory or inhibitory BA input onto vH^PFC neurons (Figure 4), suggesting that innervation from other local or long-range afferent regions may be key for this behavioural role (Sanchez-Bellot and MacAskill, 2021). However, BA input does innervate vH^LH neurons (Gergues et al., 2020; Wee and MacAskill, 2020), and thus it is interesting to note the possibility that the anxiogenic influence of excitatory, anterior BLA input (Felix-Ortiz et al., 2013; Pi et al., 2020) may be via this distinct circuit. vH^LH neurons are present in more distal areas of ventral subiculum, with only a minority present in the CA1/proximal subiculum border region considered in this study (Wee and MacAskill, 2020). However, how BA input interacts with distal subicular circuits that project to distinct downstream regions including hypothalamus and retrosplenial cortex (Cembrowski et al., 2018; Kim and Spruston, 2012), and how inhibitory and excitatory input interact with this circuit is an interesting future direction.

Our study focussed on the postsynaptic influence of BA inhibitory projections, and the cellular properties of these projection neurons remain unknown. Anatomical studies have suggested that BA inhibitory projections are preferentially observed in somatostatin (SOM)- and neuropeptide Y (NPY)-expressing neurons (McDonald et al., 2012; McDonald and Zaric, 2015), and almost completely absent in parvalbumin (PV)- and vasoactive intestinal peptide (VIP)-expressing neurons. Consistent with this, we found a proportion of SOM-positive neurons in BA that project to vH (Figure 2—figure supplement 2). Thus, there is the potential for inhibitory input to be from both specific nuclei in BA (Figure 1, Figure 2—figure supplement 1), but also different genetically defined populations of inhibitory neurons, as is seen for excitatory amygdala projections (Kim et al., 2016). Similarly, in our study we did not differentiate BA input onto different types of inhibitory interneuron in vH. There is enormous diversity of interneuron types throughout the hippocampus (Group et al., 2008), each of which is involved in distinct parts of the circuit calculation – such as dendritic-targeting SOM- and VIP-expressing neurons, perisomatic PV-expressing interneurons and cholecystokinin (CCK)-expressing interneurons. Inhibitory input from entorhinal cortex preferentially innervates CCK interneurons (Basu et al., 2016), while input from PFC specifically innervates VIP interneurons (Malik et al., 2021). Thus, how BA input differentially innervates these populations is an important and interesting future question.

Finally, it is important to note that we investigated the connectivity of this circuit at a steady state, and all of our slice physiology was performed in animals that had only experienced their home cage environment. Therefore, it is unknown how this circuit may be updated by experience and new learning, and the plasticity mechanisms that might underlie this updating. The reciprocal connection from vH to BA has been shown to undergo robust plasticity (Bazelot et al., 2015), and BA circuitry rapidly updates in response to learning cue associations (Beyeler et al., 2016; Namburi et al., 2015b; Namburi et al., 2015a). Therefore, an important future direction will be to understand how the BA-vH circuit is altered by learning and novel experience, and how this plasticity influences the relative targeting of excitatory and inhibitory connections onto each of the vH projection populations.

All main figures are supplied with source data used to generate the figures.

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Author details

1. Rawan AlSubaie

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Conceptualization, Formal analysis, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0721-4744

2. Ryan WS Wee

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0273-5521

3. Anne Ritoux

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5760-6172

4. Karyna Mishchanchuk

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0996-790X

5. Jessica Passlack

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1043-3980

6. Daniel Regester

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5372-7479

7. Andrew F MacAskill

   Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

   Contribution

   Conceptualization, Formal analysis, Funding acquisition, Investigation, Resources, Supervision, Writing – original draft, Writing – review and editing

   For correspondence

   a.macaskill@ucl.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0196-3779

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