Dorsal Ventral Tegmental Area Research Articles

Early-life Stress Modifies the Reactivity of Neurons in the Ventral Tegmental Area and Lateral Hypothalamus to Acute Stress in Female Rats

Early-life stress (ELS) has long-term consequences, including an increased risk for drug abuse and psychiatric disorders later in life, which is higher in women than in men. The consequences of ELS include heightened sensitivity to stressful events. Here, we hypothesized that ELS changes the stress sensitivity of dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) and orexin (OXA) neurons in the lateral hypothalamus (LH), that are crucial for the control of motivated behaviors. We combined morphological and immunohistochemical approaches to investigate the effect of maternal separation (MS), a rodent model of the ELS, on the expression of c-Fos protein in putative DAergic and non-DAergic VTA and LH OXA neurons, as well as on dendritic spine density and morphology in the VTA of adult female rats. We showed that MS increased basal and acute restraint stress-induced c-Fos expression in putative DAergic neurons, specifically in the dorsomedial VTA, an area implicated in responsiveness to aversive stimuli. Conversely, restraint-induced increase in c-Fos expression in non-DAergic dorsolateral VTA neurons was dampened by MS. Furthermore, an increase in spine head diameter of VTA neurons and a concurrent decrease in dendritic spine density in dorsal VTA were observed. We also showed that MS changed the stress sensitivity of OXA neurons selectively in the dorsomedial hypothalamus (DMH), which is implicated in arousal and the stress response. These findings show the long-lasting consequences of ELS and indicate the selective, regional sensitivity of structures involved in the control of arousal, motivational behaviors and the stress response to ELS.

Dendritic Architecture Predicts in vivo Firing Pattern in Mouse Ventral Tegmental Area and Substantia Nigra Dopaminergic Neurons.

The firing activity of ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is an important factor in shaping DA release and its role in motivated behavior. Dendrites in DA neurons are the main postsynaptic compartment and, along with cell body and axon initial segment, contribute to action potential generation and firing pattern. In this study, the organization of the dendritic domain in individual VTA and SNc DA neurons of adult male mice, and their relationship to in vivo spontaneous firing, are described. In comparison with dorsal VTA DA neurons, ventrally located VTA neurons (as measured by cell body location) possess a shorter total dendritic length and simpler dendritic architecture, and exhibit the most irregular in vivo firing patterns among DA neurons. In contrast, for DA neurons in the SNc, the higher irregularity of firing was related to a smaller dendritic domain, as measured by convex hull volumes. However, firing properties were also related to the specific regional distribution of the dendritic tree. Thus, VTA DA neurons with a larger extension of their dendritic tree within the parabrachial pigmented (PBP) nucleus fired more regularly compared with those with relatively more dendrites extending outside the PBP. For DA neurons in the SNc, enhanced firing irregularity was associated with a smaller proportion of dendrites penetrating the substantia nigra pars reticulata. These results suggest that differences in dendritic morphology contribute to the in vivo firing properties of individual DA neurons, and that the existence of region-specific synaptic connectivity rules that shape firing diversity.

Sweet and bitter taste stimuli activate VTA projection neurons in the parabrachial nucleus

This study investigated neural projections from the parabrachial nucleus (PBN), a gustatory and visceral processing area in the brainstem, to the ventral tegmental area (VTA) in the midbrain. The VTA contains a large population of dopaminergic neurons that have been shown to play a role in reward processing. Anterograde neural tracing methods were first used to confirm that a robust projection from the caudal PBN terminates in the dorsal VTA; this projection was larger on the contralateral side. In the next experiment, we combined dual retrograde tracing from the VTA and the gustatory ventral posteromedial thalamus (VPMpc) with taste-evoked Fos protein expression, which labels activated neurons. Mice were stimulated through an intraoral cannula with sucrose, quinine, or water, and PBN sections were processed for immunofluorescent detection of Fos and retrograde tracers. The distribution of tracer-labeled PBN neurons demonstrated that the populations of cells projecting to the VTA or VPMpc are largely independent. Quantification of cells double labeled for Fos and either tracer demonstrated that sucrose and quinine were effective in activating both pathways. These results indicate that information about both appetitive and aversive tastes is delivered to a key midbrain reward interface via direct projections from the PBN.

NMDA alters rotenone toxicity in rat substantia nigra zona compacta and ventral tegmental area dopamine neurons

Previous patch-clamp studies by our laboratory showed that acute exposure to the pesticide rotenone augments inward currents evoked by N-methyl-d-aspartate (NMDA) in substantia nigra zona compacta (SNC) dopamine neurons in slices of rat brain. The present experiments were done to search for histological evidence of increased neurotoxicity produced by combined rotenone and NMDA treatments. In horizontal slices of rat midbrain, we found that a 30min superfusion with 100nM rotenone caused significant injury to tyrosine hydroxylase (TH)-positive proximal dendrites in dorsal and ventral regions of the SNC and ventral tegmental area (VTA). Moreover, treatment with 100μM NMDA potentiated rotenone toxicity. In contrast, treatment with 30μM NMDA protected against rotenone-induced injury to dendrites in the ventral SNC and ventral VTA. Interestingly, treatment with 30μM NMDA-alone produced an apparent increase in proximal dendrite scores in ventral SNC and dorsal VTA. We conclude that NMDA has concentration-dependent actions on rotenone toxicity that differ according to regional subtype of dopamine neuron.

Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli

Midbrain dopamine neurons play central roles in reward processing. It is widely assumed that all dopamine neurons encode the same information. Some evidence, however, suggests functional differences between subgroups of dopamine neurons, particularly with respect to processing nonrewarding, aversive stimuli. To directly test this possibility, we recorded from and juxtacellularly labeled individual ventral tegmental area (VTA) dopamine neurons in anesthetized rats so that we could link precise anatomical position and neurochemical identity with coding for noxious stimuli. Here, we show that dopamine neurons in the dorsal VTA are inhibited by noxious footshocks, consistent with their role in reward processing. In contrast, we find that dopamine neurons in the ventral VTA are phasically excited by footshocks. This observation can explain a number of previously confusing findings that suggested a role for dopamine in processing both rewarding and aversive events. Taken together, our results indicate that there are 2 functionally and anatomically distinct VTA dopamine systems.

Electrical stimulation of the ventral tegmental area exerts opposite effects on male rat sexual behaviour expression depending on the stimulated sub region

The effects of electrical stimulation of the ventral tegmental area (VTA) on male rat sexual behaviour were studied. Stimulation of dorsal VTA facilitated copulation of sexually experienced animals; while ventral VTA stimulation inhibited sexual behaviour. In sexually exhausted rats, stimulation at either region lacked of an effect. It is concluded that different loci within the VTA exert opposite influences on male sexual behaviour expression and that copulation to satiation modifies this VTA control.

Estrogen receptor-beta immunoreactivity in the midbrain of adult rats: regional, subregional, and cellular localization in the A10, A9, and A8 dopamine cell groups.

Estrogen modulates dopamine synthesis, release, and metabolism in corticolimbic and striatal targets of midbrain dopamine neurons. The relevant sites of receptor-mediated action, however, had been elusive, because all available evidence suggested a paucity of intracellular estrogen receptors in the A8, A9, and A10 dopamine regions and their afferent targets. More recent evidence of a relative abundance of the beta isoform of the estrogen receptor (ER) in the substantia nigra and ventral tegmental area (VTA), however, suggests that this newly described receptor may be important in estrogen's stimulation of midbrain DA systems. It is unknown, however, precisely how ERbeta is distributed with respect to the functionally and neurochemically diverse cell populations of the ventral midbrain. To address these issues, this study used single- and double-label immunocytochemistry to detail the regional, subregional, and cellular distributions of ERbeta immunoreactivity in and around midbrain dopamine-containing cell groups in hormonally intact adult male and female rats. These analyses revealed that ERbeta-immunoreactive nuclei were found only in neurons, more specifically, within subsets of both dopaminergic and nondopaminergic neurons in the dorsal VTA, the parabrachial pigmented nucleus, the substantia nigra pars lateralis, the retrorubral fields, and to a lesser extent the linear midline nuclei. These regional and cellular receptor distributions thus place the ERbeta isoform in anatomical register with midbrain dopamine systems known to participate in a spectrum of motor, cognitive, and affective functions.

Intraventricular administration of D-Ala 2-Met 5-enkephalinamide induces rapid recovery of responding for electrical brain stimulation from the ventral tegmental area following uncontrollable footshock

The effects of uncontrollable footshock were assessed in CD-1 mice responding for electrical brain stimulation (ICSS) from the dorsal aspects of the ventral tegmental area (VTA). Uncontrollable footshock provoked a marked reduction of responding for ICSS immediately, 24 h and 168 h following initial stresser exposure. Intraventricular administration of the neuropeptide, D-Ala 2-Met 5-enkephalinamide (DALA) (1 μg/μl delivered in a 1-μl volume) following induction of reward alterations from the dorsal VTA provoked a rapid recovery of responding for ICSS in the immediate poststressor interval. This ameliorative effect of the neuropeptide deteriorated 24 h after initial exposure to uncontrollable footshock and was absent 1 week later. These data are discussed with respect to stressor-induced anhedonia in the mesocorticolimbic system.

Stressor-induced behavioral alterations in intracranial self-stimulation from the ventral tegmental area: Evidence for regional variations

Exposure to uncontrollable footshock reduced responding for electrical brain stimulation (ICSS) from the ventral tegmental area (VTA) of the CD-1 mouse. Such an effect, however, varied with electrode position in the tegmental field. In both a rate-dependent and a current intensity paradigm, ICSS from the dorsal VTA was reduced immediately, 24 hr and 168 hr following exposure to acute uncontrollable footshock. In contrast, ICSS from the ventral VTA was unaffected by the Stressor regimen. These data are consistent with the suggestion that a Stressor may reduce the rewarding value ordinarily derived from ICSS. Inasmuch as the Stressor differentially affected ICSS from the dorsal and ventral tegmentum, these data provide evidence for a functional differentiation within the midbrain tegmental area.

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on catecholamines and metabolites in primate brain and CSF

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration is able to produce nigrostriatal damage and motor disabilities in primates similar to those seen in Parkinson's disease. Two months after MPTP treatment in African Green monkeys, significant depletions of dopamine (DA) and/or homovanillic acid (HVA) were found in the dorsal ventral tegmental area, and septum, but not in the ventral part of the ventral tegmental area or nucleus accumbens. However, DA losses were greater at all examined sites in the striatum. In putamen and caudate nucleus the decreases in DA and HVA appeared more marked dorsolaterally than ventromedially. After MPTP treatment the ratio HVA/DA was elevated in the septum and all striatal regions; in the striatum the increases in ratio were greater in the dorsolateral than in the ventromedial samples. NE concentration was not significantly altered by MPTP in the mesolimbic system. In control animals the HVA concentration and the ratio HVA/DA were higher in the putamen than in the caudate nucleus. A longitudinal study showed that CSF HVA and 3-methoxy-4-hydroxyphenylglycol were reduced by MPTP and remained below baseline level for 12 months after MPTP treatment. This biochemical study indicates that in the monkey MPTP is able to induce selective damage within both the nigrostriatal and mesolimbic DA systems.

Calcitonin gene-related peptide in the ventral tegmental area: selective modulation of prefrontal cortical dopamine metabolism.

The distribution of calcitonin gene-related peptide (CGRP) in the A10 dopamine (DA) cell group region of the ventral tegmental area (VTA) of the rat was examined using immunohistochemical techniques. CGRP-like immunoreactivity was localized to axons innervating the rostral and dorsal VTA. Direct administration of CGRP to the VTA of the rat resulted in a dose-related increase in DA utilization in the medial prefrontal cortex, but not other mesocortical, mesolimbic, or striatal DA terminal field regions. These data suggest that CGRP may function to selectively modulate the activity of VTA dopaminergic neurons which innervate the prefrontal cortex.

Locomotor stepping elicited by electrical stimulation of the lateral hypothalamus requires an ipsilateral descending pathway

The effects of unilateral midbrain lesions on stepping produced by ipsilateral medial forebrain bundle (mfb) stimulation was determined in acute experiments. Rats were anesthetized with nembutal, mounted in a stereotaxic apparatus and suspended over a wheel which rotated when the rat stepped. Stimulation consisted of 10-sec trains of 50 Hz cathodal pulses (0.5 msec) at currents up to 200 μA delivered through monopolar electrodes. The stimulation sites were in the mfb at the level of the subthalamic nucleus. One side of the midbrain was randomly selected to receive a radio-frequency lesion. Certain midbrain lesions (N=11) abolished or severely reduced stepping elicited from ipsilateral mfb stimulation but produced no effect on contralaterally elicited stepping. Areas of common damage in these lesions included the medial half of the medial lemniscus and the ventral tegmental area (VTA). Lesions that were without effect (N=18) generally spared the dorsal VTA but damaged extensively either the ventrolateral VTA, medial lemniscus, substantia nigra, red nucleus, or central gray. A supplemental experiment further implicated a critical descending system since neither unilateral nor bilateral mfb lesions blocked stepping elicited by VTA stimulation. Together these results suggest that a descending path through the ipsilateral dorsal VTA mediates stepping elicited by mfb stimulation in the anesthetized rat.