Negative Reward Signals from the Lateral Habenula to Dopamine Neurons Are Mediated by Rostromedial Tegmental Nucleus in Primates

Abstract

Lateral habenula (LHb) neurons signal negative ‘reward-prediction errors’ and inhibit midbrain dopamine (DA) neurons. Yet LHb neurons are largely glutamatergic, indicating that this inhibition may occur through an intermediate structure. Recent studies in rats have suggested a candidate for this role, the GABAergic rostromedial tegmental nucleus (RMTg), but this neural pathway has not yet been directly tested. We now show using electrophysiology and anatomic tracing that (1) the monkey has an inhibitory structure similar to the rat RMTg; (2) RMTg neurons receive excitatory input from the LHb, exhibit negative reward-prediction errors, and send axonal projections near DA soma; and (3) stimulating this structure inhibits DA neurons. Surprisingly, some RMTg neurons responded to reward cues earlier than the LHb, and carry "state value" signals not found in DA neurons. Thus, our data suggest that the RMTg translates LHb reward-prediction errors (negative) into DA reward-prediction errors (positive), while transmitting additional motivational signals to non-DA networks.

Modulation of Locomotor Activation by the Rostromedial Tegmental Nucleus

“…As the RMTg gained recognition as a distinct structure (Jhou, 2005;Jhou and Gallagher, 2007;Jhou et al 2009a, b;Perrotti et al, 2005;Kaufling et al, 2009Kaufling et al, , 2010, its capacity to control the activity of midbrain DA neurons (Hong et al, 2011;Matsui and Williams, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui et al, 2014) and the implications of this action in aversion (Jhou et al, 2009b), reward (Hong et al, 2011), and neurobiological responses to certain drugs of abuse (Matsui and Williams, 2011;Lecca et al, 2011Lecca et al, , 2012Jhou et al, 2013;Wasserman et al, 2013;Matsui et al, 2014) continue to concern investigators. Despite this wealth of interest, a fundamental behavior-locomotor activation-has been overlooked, yet we show here that modulation of RMTg activity has profound effects on locomotion.…”

“…Thus it should be no surprise that LPO-elicited locomotor activation is suppressed by bicuculline infusions into the RMTg, inasmuch as disinhibiting the RMTg enables it to more powerfully inhibit midbrain dopamine neurons (Jhou et al, 2009a(Jhou et al, , 2013Hong et al, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui and Williams, 2011;Wasserman et al, 2013). A more difficult issue to contemplate is how the LPO so efficiently elicits locomotion, presumably through the actions of direct projections to the VTA (Phillipson, 1979;Zahm et al, 2001;Zahm, 2005, 2006;Reynolds et al, 2006;Geisler et al, 2007), when LPO also projects strongly to the RMTg (Jhou et al, 2009b;Kaufling et al, 2009;Zahm et al, 2011), which, as we repeatedly emphasize, directly inhibits the VTA.…”

“…Indeed, lethargy and lack of motivation are core symptoms of major depressive disorder (American Psychiatric Association, 2013). The LHb, which activates and inactivates the RMTg and VTA, respectively (Hong et al, 2011), is overactive in rat models of depression (Caldecott-Hazard et al, 1988;Shumake et al, 2003;Li et al, 2013) and depressed human patients (Morris et al, 1999;Roiser et al, 2009). Inhibition of the LHb reverses depression-like behaviors in rats (Winter et al, 2011) and the LHb has been targeted with some success in deep brain stimulation to treat treatment-resistant depression in humans (Sartorius et al, 2010;Schneider et al, 2013).…”

“…The rostromedial tegmental nucleus (RMTg), a recently discovered structure located in the mesopontine tegmentum (Jhou, 2005;Jhou et al, 2009a, b;Kaufling et al, 2009), projects preferentially and strongly to (Jhou et al, 2009a, b, Balcita-Pedicino et al, 2011Bourdy et al, 2014) and thus is a strong inhibitor of (Hong et al, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui and Williams, 2011;Matsui et al, 2014) dopamine neurons in the VTA and substantia nigra compacta (SNc). RMTg is implicated together with the VTA in behavioral responding to reward omission, aversive stimuli, feareliciting stimuli, and certain drugs of abuse (Jhou et al, 2009a(Jhou et al, , 2013Hong et al, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui and Williams, 2011;Wasserman et al, 2013) and, more recently, with the SNc in motor skill and motor learning (Bourdy et al, 2014).…”

“…RMTg is implicated together with the VTA in behavioral responding to reward omission, aversive stimuli, feareliciting stimuli, and certain drugs of abuse (Jhou et al, 2009a(Jhou et al, , 2013Hong et al, 2011;Lecca et al, 2011Lecca et al, , 2012Matsui and Williams, 2011;Wasserman et al, 2013) and, more recently, with the SNc in motor skill and motor learning (Bourdy et al, 2014). Insofar as activation specifically of VTA dopamine neurons and accompanying release of dopamine in the Acb is the sine qua non of locomotor activation (references cited above), we hypothesized that the RMTg should also modulate locomotion.…”