Abstract
Midbrain dopamine neurons are an essential part of the circuitry underlying motivation and reinforcement. They are activated by rewards or reward-predicting cues and inhibited by reward omission. The lateral habenula (lHb), an epithalamic structure that forms reciprocal connections with midbrain dopamine neurons, shows the opposite response being activated by reward omission or aversive stimuli and inhibited by reward-predicting cues. It has been hypothesized that habenular input to midbrain dopamine neurons is conveyed via a feedforward inhibitory pathway involving the GABAergic mesopontine rostromedial tegmental area. Here, we show that exposing rats to low-intensity footshock (four, 0.5 mA shocks over 20 min) induces cFos expression in the rostromedial tegmental area and that this effect is prevented by lesions of the fasciculus retroflexus, the principal output pathway of the habenula. cFos expression is also observed in the medial portion of the lateral habenula, an area that receives dense DA innervation via the fr and the paraventricular nucleus of the thalamus, a stress sensitive area that also receives dopaminergic input. High-intensity footshock (120, 0.8 mA shocks over 40 min) also elevates cFos expression in the rostromedial tegmental area, medial and lateral aspects of the lateral habenula and the paraventricular thalamus. In contrast to low-intensity footshock, increases in cFos expression within the rostromedial tegmental area are not altered by fr lesions suggesting a role for non-habenular inputs during exposure to highly aversive stimuli. These data confirm the involvement of the lateral habenula in modulating the activity of rostromedial tegmental area neurons in response to mild aversive stimuli and suggest that dopamine input may contribute to footshock- induced activation of cFos expression in the lateral habenula.
Highlights
Transient changes in midbrain dopamine (DA) neuron activity appear to encode a signal that optimizes action selection by promoting rewarding actions and suppressing non-optimal behaviors [1,2,3]
The habenula (Hb), a phylogenetically conserved epithalamic structure [11,12], is functionally and anatomically well positioned for encoding, in concert with midbrain DA neurons, the motivational value of aversive stimuli [13,14,15]
Representative examples of cFos expression following exposure to low-intensity footshock in a sham rat are shown in Figure 1 for the RMTg (1B and 1C), Hb (1D and 1E) and PVTp (1F and 1G; see Figure S1 for representative photomicrographs from a footshocked, fr lesioned rat). cFos expression in the Hb following lowintensity footshock appeared to be limited to TH positive areas of the lHbm
Summary
Transient changes in midbrain dopamine (DA) neuron activity appear to encode a signal that optimizes action selection by promoting rewarding actions and suppressing non-optimal behaviors [1,2,3]. While midbrain DA neurons receive extensive glutamatergic input [4,5] that drives reward-induced neuronal activation [6], knowledge of the inhibitory inputs responsible for transient decreases in DA neuron activity following aversive stimuli [7,8,9,10] remains limited. Lesions of the lHb in rats increase impulsivity [21], and sucrose- and cocaine-seeking [22,23], behaviors normally associated with elevations in DA activity. This suggests that habenular activation acts as a ‘brake’ on midbrain DA neuronal firing
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