Mesencephalic dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) constitute a neuromodulatory system that has been linked to error prediction and salience coding (Bromberg-Martin et al., 2010; Horvitz, 2000; Schultz et al., 1997). Prediction error signals drive the formation and the updating of stimulus-outcome associations by detection of mismatches between actual and expected experiences (Pearce and Hall, 1980; Rescorla and Wagner, 1972), which also operate when conditioned stimulus (CS)-unconditioned stimulus (US) and CS-no US associations need to be formed during fear conditioning and extinction learning, respectively (Bouton, 2004; McNally et al., 2011; Salinas-Hernández et al., 2018). More specifically, omission of an expected aversive stimulus during the early sessions of extinction training activates a subset of VTA dopaminergic neurons (Cai et al., 2020; Salinas-Hernández et al., 2018). Consequently, optogenetic inhibition of the VTA dopaminergic neurons during extinction training impairs, and their excitation enhances the extinction learning (Luo et al., 2018; Salinas-Hernández et al., 2018).

The amygdala is a key structure that plays a critical role in mediating fear- and anxiety-related behaviors, and is a primary site for acquisition and storage of fear memory (Davis, 2000; Duvarci and Pare, 2014; Luo et al., 2018; Salinas-Hernández et al., 2018). Dopamine (DA) is released in the amygdala during affective states, such as stress or fear (Inglis and Moghaddam, 1999; Yokoyama et al., 2005), and direct pharmacological intervention on dopaminergic receptors in the central amygdala (CeA) or basal amygdala (BA) affects the acquisition and storage of fear memories (Guarraci et al., 1999; Lee et al., 2017).

Interestingly, selective optogenetic stimulation of midbrain dopaminergic axons results in the release not only of the neuromodulator DA, but also of the fast-acting classical neurotransmitters GABA and/or glutamate in the dorsal striatum and nucleus accumbens (Granger et al., 2017; Tritsch et al., 2016). In the amygdala, glutamate was shown to be co-released together with DA in the CeA (Groessl et al., 2018; Mingote et al., 2015) and BA, in the latter, preferentially onto fast-spiking interneurons (Lutas et al., 2019). However, a co-release of GABA has not been reported so far.

Several lines of evidence suggest that within the amygdala, the intercalated cells (ITCs) could be a key target for dopaminergic regulation. ITCs constitute a specialized network of GABAergic cells and, in mice, are organized in several clusters around the basolateral complex of the amygdala (BLA) (Busti et al., 2011; Geracitano et al., 2007; Marowsky et al., 2005). Dopaminergic axons densely innervate the somata and dendrites of ITCs (Asan, 1997; Fuxe et al., 2003); however, the functional consequence of this innervation remained largely unexplored. Furthermore, ITCs show a high expression level of pre- and postsynaptic DA receptors (Fuxe et al., 2003; Pinto and Sesack, 2008; Wei et al., 2018). DA application in brain slices directly hyperpolarizes neurons in the medial and lateral ITC clusters via D1 receptors (DRD1) and thereby suppresses their output to CeA and BLA, respectively (Gregoriou et al., 2019; Mańko et al., 2011; Marowsky et al., 2005).

In that respect, ITC clusters are ideally positioned to integrate dopaminergic signals with the sensory information that is either conveyed directly (Asede et al., 2015; Barsy et al., 2020; Strobel et al., 2015) or that has been preprocessed in the BLA (Herry and Johansen, 2014; Kwon et al., 2015; Paré et al., 2004). Indeed, ITCs and their plasticity have been shown to play a significant role in extinction (Amano et al., 2010; Likhtik et al., 2008) and, more recently, also in fear learning and memory (Asede et al., 2015; Busti et al., 2011; Huang et al., 2014; Kwon et al., 2015). The classical view on ITC function within amygdala circuits posits an inhibitory action onto neighboring CeA and BLA nuclei to gate information flow (Ehrlich et al., 2009; Marowsky et al., 2005; Morozov et al., 2011; Paré et al., 2004). However, there is emerging evidence pointing toward a more complex picture that involves temporal separation in the activity of the individual clusters, i.e., dorsomedial (dm)- and ventromedial (vm)-ITC clusters, in fear recall and extinction (Busti et al., 2011). Considering the connections between the different clusters (Asede et al., 2015; Busti et al., 2011; Duvarci and Pare, 2014; Royer et al., 2000), it is plausible that ITCs’ inhibitory actions, not only onto CeA and BLA, but also onto other ITC clusters, could be modulated by DA.

Thus, while mounting evidence supports that midbrain dopaminergic inputs play important roles in controlling amygdala function in fear learning as well as extinction (Abraham et al., 2014; Lee et al., 2017), the cellular impact onto specific amygdala microcircuits is incompletely understood (Grace et al., 2007; Lee et al., 2017). To address this knowledge gap, we used specific optogenetic stimulation of dopaminergic axons from VTA/SNC to explore the functional impact onto ITCs. We observed co-release of GABA from dopaminergic axons onto ITCs mediating fast inhibition. Phasic stimulation of dopaminergic fibers suppressed spontaneous inhibitory inputs onto dm-ITCs in a DA receptor-dependent manner. Consequently, when interrogating transmission between ITC clusters, we observed a presynaptic depression mediated by DRD1. Extinction learning promoted the co-release of GABA onto dm-ITCs and the DA-induced suppression of inhibition between dm- and vm-ITC clusters. Our results demonstrate a dual mechanism of action of dopaminergic inputs, with cooperative fast ionotropic and slower metabotropic components, which jointly regulate the inhibitory network formed between ITCs. We suggest that this can tip the activity balance between individual clusters to support fear suppression.

Here, we investigated the functional impact of midbrain dopaminergic inputs and dopaminergic modulation onto amygdala ITC clusters. Our key findings are that ITCs are controlled by several distinct mechanisms. These include fast inhibition resulting from a prominent co-release of GABA and slower mechanisms by a long-lasting DA-induced hyperpolarization, as well as a DRD1-mediated presynaptic suppression of inhibitory interactions between distinct ITC clusters (Figure 7A). Upon early extinction learning, fast inhibition onto dm-ITCs is increased, and DA more potently suppresses dm-ITC cluster-mediated inhibition of vm-ITCs. This may support a shift in the activity balance between these two distinct ITC clusters by inhibiting dm-ITCs and disinhibiting vm-ITCs to enable fear suppression during extinction learning (Figure 7B).

Figure 7

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Although it is well established that amygdala ITC clusters receive dense TH+ projections (Asan, 1997; Fuxe et al., 2003), here, we show that these are part of the mesolimbic and nigrostriatal pathways from VTA/SNC, also providing afferents to amygdalostriatal transition zone (Astria), BA, and CeA. The current knowledge about localization and molecular phenotype of amygdala-projecting midbrain neurons is still incomplete and, due to the lack of specific tools, has remained elusive for ITCs. Amygdala-projecting neurons are localized both in SNC and VTA, and a distinct population of DA neurons in DR/PAG targets CeA (Beier et al., 2015; Groessl et al., 2018; Poulin et al., 2018; Vogt Weisenhorn et al., 2016). A fraction of BLA-projecting neurons in VTA also expresses vGluT2 and/or is localized in medial VTA regions containing TH+/vGluT2+ neurons (Morales and Margolis, 2017; Poulin et al., 2018). The only evidence on the source of ITC inputs comes from a 6-OHDA lesion study (Ferrazzo et al., 2019) suggesting that ITCs are targeted by SNC/VTA regions that also target BLA. Our results are well in line with this and, additionally, suggest a differential targeting of dm- versus vm-ITC clusters by VTA and SNC. Consistent with previous ultrastructural investigations demonstrating that TH+ axons contact ITC somata, dendrites, and spines (Asan, 1997; Pinto and Sesack, 2008), we detected putative presynaptic terminals originating from VTA/SNC on the soma and along ITC dendrites, suggesting functional connectivity.

While co-release of glutamate and GABA from VTA/SNC dopaminergic neurons is well established in nucleus accumbens and dorsal striatum (Granger et al., 2017), glutamate co-release has only recently been demonstrated in CeA (Mingote et al., 2015). Here, we also find GABA co-release in CeA, although to a much lower extent than glutamate co-release. We did not observe glutamate co-release in the BLA, which is in line with a previous study (Mingote et al., 2015); however, see also Lutas et al., 2019.

Our study is the first to directly examine dopaminergic afferents onto amygdala ITCs via optogenetic stimulation. Combined qualitative anatomical and quantitative electrophysiological evidence strongly supports the notion that glutamate and GABA can be released from dopaminergic afferents onto ITCs, with a major contribution of GABA. GABA co-release is a prominent feature of midbrain dopaminergic neurons targeting dorsal striatum and nucleus accumbens, where it can rapidly inhibit medium spiny neurons of the direct and indirect pathways (Tritsch et al., 2012). The presence of vGluT1/2 and vGAT in dopaminergic fibers innervating medial ITC clusters is in accordance with canonical release mechanisms for glutamate and GABA, respectively. In dorsal striatum, however, GABA is transported into vesicles via the vesicular monoamine transporter VMAT2, suggesting a spatio-temporal synchronization of GABA and DA release from the same vesicles (Tritsch et al., 2012). Which of the two mechanisms is predominant in ITC afferents remains to be investigated. Furthermore, in dopaminergic striatal afferents, GABA is either synthesized in a non-canonical aldehyde-dehydrogenase1a1-dependent pathway and/or relies on GABA uptake from the extracellular milieu via GABA transporters (Kim et al., 2015; Tritsch et al., 2014). Although we did not determine the mechanism that provides GABA for inhibiting ITCs, regulation of GABA uptake could endow midbrain afferents with the flexibility to rapidly alter GABAergic co-transmission in a target-specific manner. It may, therefore, be a good candidate mechanism mediating changes in GABA co-release during early extinction learning.

ITCs receive a number of well-characterized excitatory inputs from BLA, thalamus, prefrontal and sensory cortex that drive their activity (Amir et al., 2011; Asede et al., 2015; Cho et al., 2013; Paré et al., 2003; Strobel et al., 2015). Apart from local inhibitory interactions between ITCs, which were proposed to stabilize overall spike output (Geracitano et al., 2007; Mańko et al., 2011; Royer et al., 2000), it remained unclear which extrinsic inputs inhibit ITCs. Co-release of GABA from dopaminergic midbrain could provide a rapid and temporally precise signal to inhibit ITC spike activity in response to salient stimuli and/or during learning. Furthermore, spatially targeted inhibition onto ITC dendrites or spines may shunt glutamatergic inputs to enable local control of synaptic plasticity (Tritsch et al., 2016).

Phasic activity of midbrain dopaminergic neurons may signal unexpected rewards or aversive events such as noxious stimuli, and these activity patterns shape DA release in target structures (Brischoux et al., 2009; Bromberg-Martin et al., 2010). Phasic stimulation (>20 Hz) of VTA neurons increases DA release in forebrain structures, including amygdala, and affects behavior (Holloway et al., 2019; Tsai et al., 2009). In our hands, phasic stimulation of midbrain dopaminergic inputs hyperpolarized dm-ITCs similarly to direct DA application, and depressed sIPSCs in a DA-R-dependent manner, strongly suggesting that physiologically released DA modulates ITC function. Our finding that a fraction of ITCs is directly DA-responsive may help to resolve discrepancies from earlier work demonstrating hyperpolarization of dm- and vm-ITCs in young (Mańko et al., 2011; Marowsky et al., 2005) versus no detectable effect in dm-ITCs in adult animals (Kwon et al., 2015). A reduction of sIPSC amplitude may suggest a postsynaptic mechanism, whereby DA could directly modulate GABA_A-Rs to decrease GABA_A currents, similarly to what was observed in striatum (Flores-Hernandez et al., 2000; Hoerbelt et al., 2015; Tritsch and Sabatini, 2012). Given that sIPSCs include action potential-driven events, and considering that release can be multivesicular (Rudolph et al., 2015), a reduction in presynaptic input activity or release probability could contribute to a decreased sIPSC amplitude. The novel aspect of our work is that DA also modulates ITC interactions via presynaptic DRD1. Thus, activity of dm-ITCs is shaped by DA modulation of their input from l-ITCs and output to vm-ITCs, as well as direct DA-induced hyperpolarization, indicating that several distinct dopaminergic mechanisms act in concert to gate ITC activity.

While ITCs form local inhibitory networks not only within but also between medially located neighboring clusters (Amir et al., 2011; Busti et al., 2011; Geracitano et al., 2007; Morozov et al., 2011; Royer et al., 2000), our novel finding that l-ITCs provide input to dm-ITCs suggests further complexity of inhibitory and disinhibitory interactions between ITC clusters that can provide a substrate for integration of information from distinct afferents (Asede et al., 2015; Morozov et al., 2011; Strobel et al., 2015). DA also modulated the interactions between ITC clusters. Its disinhibitory effect via presynaptic DRD1 in the target cluster resembles the situation in the nucleus accumbens, where presynaptic DRD1 attenuates IPSCs and consequently, lateral inhibition between medium spiny neurons, a mechanism proposed to diminish competitive interactions between single projection neurons or ensembles (Nicola and Malenka, 1997; Pennartz et al., 1992; Taverna et al., 2005). In analogy, the same mechanism may enable selection of specific ITC clusters or ensembles within clusters during distinct behavioral states. Modulation of the l-ITC→dm-ITC pathway could thus function to select and/or amplify the output of dm-ITCs with distinct projection patterns (Asede et al., 2015; Busti et al., 2011; Duvarci and Pare, 2014). While postsynaptic inhibition of ITCs would decrease overall inhibitory output onto diverse downstream regions, target-specific presynaptic disinhibition can promote inhibition from distinct ITC clusters or ensembles onto defined downstream regions. These mechanisms may help to sharpen competitive interactions between clusters and to select a defined ITC network output.

In the context of behavior, in vivo pharmacological studies in amygdala pointed to a role of DRD1 in the acquisition of cued fear memory (Guarraci et al., 1999; Lamont and Kokkinidis, 1998; Nader and LeDoux, 1999) as well as in the acquisition of extinction (Hikind and Maroun, 2008). Cellular effects of DRD1 include altered excitability of BLA projection and local interneurons, as well as DRD1-dependent long-term potentiation in the BLA-CeA pathway that has been discussed in the context of fear acquisition (Groessl et al., 2018; Lee et al., 2017). However, DRD1-dependent ITC network modulation could provide the required flexibility to support behavioral transitions during acquisition of extinction memory. Circuit and immediate early gene mapping studies converged on a model where dm-ITCs become engaged and undergo plasticity during fear learning, keeping vm-ITC activity in check. During extinction learning, this balance tips toward recruitment of vm-ITCs, which are required for extinction retrieval (Busti et al., 2011; Duvarci and Pare, 2014; Likhtik et al., 2008). Our data suggest that dopaminergic afferent control over ITCs could play a critical role in these transitions. Consistent with the above model, enhanced GABA co-release onto dm-ITCs during early extinction could rapidly decrease their activity and, together with enhanced DRD1-mediated disinhibition of vm-ITCs, allow for activation of the latter.

DA neurons in the VTA are activated by unexpected omission of the US, implying that they provide a prediction error-like signal to downstream targets, including ITCs (Luo et al., 2018; Salinas-Hernández et al., 2018). A recent study indicates that medial versus lateral VTA activity provides a reward-prediction error-like signal and a salience signal, respectively, during extinction learning (Cai et al., 2020). Furthermore, emerging evidence starts to point to a role for the nigrostriatal pathway in emotional regulation. Activation of the SNC, for example, enhances extinction memory retrieval and renders it more resistant to renewal (Bouchet et al., 2018). Therefore, a differential innervation from dopaminergic VTA/SNC regarding strength and input origin could provide a more prominent modulation of dm- versus vm-ITC activity. This could enable both extinction learning and retrieval by dampening dm-ITC activity more strongly to enable vm-ITC disinhibition.

Downstream dm- and vm-ITCs most likely exert behavioral output by differentially inhibiting specific fear- and extinction-related subpopulations of BLA and CeL, or centro-medial (CeM) neurons (Figure 7B; Asede et al., 2015; Duvarci and Pare, 2014; Gregoriou et al., 2019). Concurring or subsequent synaptic plasticity at BLA and other afferents onto dm- and vm-ITCs could help maintain this activation pattern during extinction retrieval (Amano et al., 2010; Asede et al., 2015; Huang et al., 2014; Kwon et al., 2015).

While our study delineates several novel cellular mechanisms by which mesolimbic and nigrostriatal dopaminergic afferents control amygdala ITC networks, the observed ex vivo alterations are still correlative. Further studies are warranted to understand how these cellular mechanisms impact fear and extinction learning and memory. Beyond fear memories, DA is critical for processes related to incentive salience, motivation, and cue-reward learning (Abraham et al., 2014; Bromberg-Martin et al., 2010). For example, VTA dopaminergic inputs to BLA are activated by motivationally salient appetitive and aversive outcomes and acquire responses to predictive cues during learning (Lutas et al., 2019). DA is also released in the amygdala during affective states such as stress (Belujon and Grace, 2015; Yokoyama et al., 2005). Therefore, it is intriguing to speculate that dopaminergic modulation of distinct ITC clusters may also play a role in other processes such as reward learning and addiction, as well as in the control of mood-related behaviors, such as anxiety- and depression-like behavior (Ferrazzo et al., 2019; Kuerbitz et al., 2018).

Data deposited in Dryad Digital Repository (https://doi.org/10.5061/dryad.jh9w0vt9b).

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Author details

1. Ayla Aksoy-Aksel

   1. Hertie Institute for Clinical Brain Research, Tübingen, Germany
   2. Centre for Integrative Neuroscience, Tübingen, Germany
   3. Department of Neurobiology, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, Germany

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0418-6466

2. Andrea Gall

   1. Hertie Institute for Clinical Brain Research, Tübingen, Germany
   2. Centre for Integrative Neuroscience, Tübingen, Germany
   3. Department of Neurobiology, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, Germany

   Contribution

   Formal analysis, Investigation, Visualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

3. Anna Seewald

   Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria

   Contribution

   Investigation, Visualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

4. Francesco Ferraguti

   Department of Pharmacology, Medical University of Innsbruck, Innsbruck, Austria

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3843-5857

5. Ingrid Ehrlich

   1. Hertie Institute for Clinical Brain Research, Tübingen, Germany
   2. Centre for Integrative Neuroscience, Tübingen, Germany
   3. Department of Neurobiology, Institute of Biomaterials and Biomolecular Systems, University of Stuttgart, Stuttgart, Germany

   Contribution

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

   For correspondence

   ingrid.ehrlich@bio.uni-stuttgart.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9078-2429

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