The mesopontine rostromedial tegmental nucleus: A structure targeted by the lateral habenula that projects to the ventral tegmental area of Tsai and substantia nigra compacta

Abstract

Prior studies revealed that aversive stimuli and psychostimulant drugs elicit Fos expression in neurons clustered above and behind the interpeduncular nucleus that project strongly to the ventral tegmental area (VTA) and substantia nigra (SN) compacta (C). Other reports suggest that these neurons modulate responding to aversive stimuli. We now designate the region containing them as the mesopontine rostromedial tegmental nucleus (RMTg) and report herein on its neuroanatomy. Dense mu opioid receptor and somatostatin immunoreactivity characterize the RMTg, as do neurons projecting to the VTA/SNC that are enriched in GAD 67 mRNA. Strong inputs to the RMTg arise in the lateral habenula (LHb) and, to a lesser extent, the SN. Other inputs come from the frontal cortex, ventral striatopallidum, extended amygdala, septum, preoptic region, lateral, paraventricular and posterior hypothalamus, zona incerta, periaqueductal gray, intermediate layers of the contralateral superior colliculus, dorsal raphe, mesencephalic, pontine and medullary reticular formation, and the following nuclei: parafascicular, supramammillary, mammillary, ventral lateral geniculate, deep mesencephalic, red, pedunculopontine and laterodorsal tegmental, cuneiform, parabrachial and deep cerebellar. The RMTg has meager outputs to the forebrain, mainly to the ventral pallidum, preoptic-lateral hypothalamic continuum and midline-intralaminar thalamus, but much heavier outputs to the brainstem, including, most prominently, the VTA/SNC, as noted above, and to medial tegmentum, pedunculopontine and laterodorsal tegmental nuclei, dorsal raphe and the locus ceruleus and subceruleus. The RMTg may integrate multiple forebrain and brainstem inputs in relation to a dominant LHb input. Its outputs to neuromodulatory projection systems likely converge with direct LHb projections to those structures.

Effects of Drugs of Abuse on Putative Rostromedial Tegmental Neurons, Inhibitory Afferents to Midbrain Dopamine Cells

“…Jhou et al (2009a) recently showed that aversive stimuli induce Fos expression in VTA-projecting RMTg neurons, and phasically stimulate their electrical activity in behaving rats. Notably, a substantial number of VTA-projecting RMTg cells receive a major afferent from the LHb (Jhou et al, 2009b), thus corroborating the idea that RMTg might signal aversive events and inhibit midbrain DA neurons. Hence, in vivo we first tested the responses of putative RMTg neurons to a standard aversive somatosensory stimulus (hindpaw mechanical stimulation), which is known to exceed the threshold of pain in freely moving animals (Cahusac et al, 1990).…”

“…The i.p. injection of ( + ) methamphetamine hydrochloride (10 mg/kg in 0.9% saline; 1 ml/kg) given 2 h prior killing was used to produce Fos expression in the RMTg, as previously described by Jhou et al (2009b). See Supplementary Materials and Methods for detailed information.…”

“…This inhibition unlikely is monosynaptic, being relayed by GABA neurons in the RMTg, which receive a major LHb input, and heavily project to midbrain DA neurons (see Jhou et al, 2009b). To investigate this possibility, in a separate series of experiments, the effect of RMTg stimulation on the spontaneous firing rate of DA neurons in the VTA was examined.…”

“…Figure 3 shows that these sites were localized within the RMTg region as recently defined (Jhou et al, 2009a, b;Kaufling et al, 2009) (Figure 3a and b). In addition, the RMTg is reliably identified by accumulation of Fosimmunoreactive (Fos-IR) neurons following pharmacological stimuli, such as an acute methamphetamine administration (Jhou et al, 2009b). To verify that the recording sites (marked with Pontamine sky blue) were located in the RMTg, we carried out electrophysiological experiments as described above and thereafter induced Fos expression by injecting methamphetamine (10 mg/kg, i.p., 2 h before killing).…”

“…Recent studies indicate that drugs of abuse affect GABA neurons in the RMTg: these neurons, and notably those projecting to the VTA, express DFosB (Kaufling et al, 2009;Perrotti et al, 2005) and c-Fos following repeated cocaine exposure (Geisler et al, 2008). In addition, RMTg neurons are immunoreactive against m-opioid receptors (Jhou et al, 2009b) and supposedly respond to opioid administration (Jhou et al, 2009c).…”