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, 8 (4), e60678

Lesions of the Fasciculus Retroflexus Alter Footshock-Induced cFos Expression in the Mesopontine Rostromedial Tegmental Area of Rats

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Lesions of the Fasciculus Retroflexus Alter Footshock-Induced cFos Expression in the Mesopontine Rostromedial Tegmental Area of Rats

Paul Leon Brown et al. PLoS One.

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Representative photomicrographs illustrating the effects of low-intensity footshock on the expression of cFos in the RMTg, Hb and PVTp in a sham operated rat.
Cresyl violet stain of a section with an incomplete fr lesion (left) and acceptable lesion (right, *) from an excluded rat (A). cFos expression within the RMTg (B,C), habenula (D,E) and PVTp (F,G). Boxes within the low-magnification micrographs (left) approximate the area of the high-magnification illustrations (right), which show visible cFos positive objects. The RMTg core is the area within the circle (B; for a complete description of RMTg boundaries see [30], [31]). Dotted lines delineate the mHb, lHbm, and lHbl (D) and PVTp (F).Scale bar = 500 µm (A, B, D, F), 125 µm (C, E, G). D3V = dorsal third ventricle, xcsp = decussation of the superior cerebellar peduncle, IPN = interpeduncular nucleus, ml = medial lemniscus,
Figure 2
Figure 2. cFos positive objects in the RMTg of rats exposed to low-intensity footshock.
Exposure to shock elevated cFos expression in the RMTg. Lesions of the fr prevented the increase in shock-induced cFos expression in the RMTg core; shocked sham rats showed significantly elevated cFos expression (*, Tukey, p<0.05) relative to the other three conditions. In this and in all subsequent figures the number of subjects per group are indicated above each bar.
Figure 3
Figure 3. cFos positive objects in the Hb of rats exposed to low-intensity footshock.
Neither shock nor fr lesions altered cFos expression in the mHb. There was a significant effect of shock for the lHbm, lHbl, and PVTp. However, there was no significant effect of lesion or shock×lesion interaction for these three areas.
Figure 4
Figure 4. cFos positive objects in the RMTg of rats exposed to high-intensity footshock.
Exposure to shock elevated cFos expression in the RMTg. Lesions of the fr had no effect on shock-induced cFos expression. Elevated cell counts in no shock rats relative to the low-intensity experiment may be the result of a change in immunostaining procedures (see Methods).
Figure 5
Figure 5. cFos positive objects in the Hb of rats exposed to high-intensity footshock.
Neither shock nor fr lesion had an effect of cFos expression in the mHb. There was a significant effect of shock for the lHbm, lHbl, and PVTp. However, there was no significant effect of lesion or shock×lesion interaction for these three areas.

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