Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray (PAG)

Harvard University, Cambridge, Massachusetts, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2006; 26(1):193-202. DOI: 10.1523/JNEUROSCI.2244-05.2006
Source: PubMed


Recent evidence suggests that dopamine plays an important role in arousal, but the location of the dopaminergic neurons that may regulate arousal remains unclear. It is sometimes assumed that the dopaminergic neurons in the ventral tegmental area that project to the prefrontal cortex and striatum may regulate the state of arousal; however, the firing of these dopaminergic neurons does not correlate with overall levels of behavioral wakefulness. We identified wake-active dopaminergic neurons by combining immunohistochemical staining for Fos and tyrosine hydroxylase (TH) in awake and sleeping rats. Approximately 50% of the TH-immunoreactive (TH-ir) cells in the ventral periaqueductal gray matter (vPAG) expressed Fos protein during natural wakefulness or wakefulness induced by environmental stimulation, but none expressed Fos during sleep. Fos immunoreactivity was not seen in the substantia nigra TH-immunoreactive cells in either condition. Injections of 6-hydroxydopamine into the vPAG, which killed 55-65% of wake-active TH-ir cells but did not injure nearby serotoninergic cells, increased total daily sleep by approximately 20%. By combining retrograde and anterograde tracing, we showed that these wake-active dopaminergic cells have extensive reciprocal connections with the sleep-wake regulatory system. The vPAG dopaminergic cells may provide the long-sought ascending dopaminergic waking influence. In addition, their close relationship with the dorsal raphe nucleus will require reassessment of previous studies of the role of the dorsal raphe nucleus in sleep, because many of those experiments may have been confounded by the then-unrecognized presence of intermingled wake-active dopaminergic neurons.

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    • "Very little has been reported regarding changes to the vPAG during healthy aging, despite extensive attention paid to other dopaminergic systems such as SN and VTA. Based on its recently discovered role in sleep-wake cycle maintenance (Lu et al. 2006), future studies may address whether alterations to this region over aging occurs in association with sleep disturbances. There is also a paucity of data regarding effects of sleep disturbances on vPAG, although one study suggests that vPAG may be uniquely susceptible to intermittent hypoxia (Zhu et al. 2007). "
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    ABSTRACT: Sleep/wake disturbance is a feature of almost all common age-related neurodegenerative diseases. Although the reason for this is unknown, it is likely that this inability to maintain sleep and wake states is in large part due to declines in the number and function of wake-active neurons, populations of cells that fire only during waking and are silent during sleep. Consistent with this, many of the brain regions that are most susceptible to neurodegeneration are those that are necessary for wake maintenance and alertness. In the present review, these wake-active populations are systematically assessed in terms of their observed pathology across aging and several neurodegenerative diseases, with implications for future research relating sleep and wake disturbances to aging and age-related neurodegeneration.
    SpringerPlus 12/2015; 4(1):25. DOI:10.1186/s40064-014-0777-6
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    • "The neural circuit underlying the NAc control of sleep-wake behavior is not known, but it is clear that the GPe is not involved as the NAc has no connection with the GPe. Unlike the VTA and SNc, vPAG wake-active DA has strong projections to the basal forebrain, thalamus and hypothalamus, where DA and its receptors of D 1 and D 2 may directly promote arousal (Lu et al. 2006; Lazarus et al. 2012), which may underly the sleep increase in global D 2 knockout mice (Qu et al. 2010). Elucidation of these DA circuits will be critical for understanding complexity of DA in sleep control and the mechanisms of abnormal sleep seen in BG disorders such as Parkinson's disease, "
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    ABSTRACT: Lesions of the globus pallidus externa (GPe) produce a profound sleep loss (∼45%) in rats, suggesting that GPe neurons promote sleep. As GPe neuronal activity is enhanced by dopamine (DA) from the substantia nigra pars compacta (SNc), we hypothesized that SNc DA via the GPe promotes sleep. To test this hypothesis, we selectively destroyed the DA afferents to the caudoputamen (CPu) using 6-hydroxydopamine and examined changes in sleep-wake profiles in rats. Rats with 80–90% loss of SNc neurons displayed a significant 33.7% increase in wakefulness (or sleep reduction). This increase significantly correlated with the extent of SNc DA neuron loss. Furthermore, these animals exhibited sleep-wake fragmentation and reduced diurnal variability of sleep. We then optogenetic-stimulated SNc DA terminals in the CPu and found that 20-Hz stimulation from 9 to 10 PM increased total sleep by 69% with high electroencephalograph (EEG) delta power. We finally directly optogenetic-stimulated GPe neurons and found that 20-Hz stimulation of the GPe from 9 to 10 PM increased total sleep by 66% and significantly increased EEG delta power. These findings elucidate a novel circuit for DA control of sleep and the mechanisms of abnormal sleep in BG disorders such as Parkinson's disease and Huntington's disease.
    Cerebral Cortex 10/2014; DOI:10.1093/cercor/bhu241 · 8.67 Impact Factor
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    • "The rewarding properties of DRN stimulation were dependent on dopamine receptor activation. Although the DRN contains dopaminergic cell bodies (Dougalis et al., 2012; Lu et al., 2006), stimulation of these cells did not evoke reward-related behavior, suggesting action on mesolimbic dopamine circuitry. Accordingly, we found that nonserotonergic DRN neurons primarily project to the VTA, with comparatively sparse projections to the nucleus accumbens and other forebrain structures. "
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    ABSTRACT: The dorsal raphe nucleus (DRN) contains the largest group of serotonin-producing neurons in the brain and projects to regions controlling reward. Although pharmacological studies suggest that serotonin inhibits reward seeking, electrical stimulation of the DRN strongly reinforces instrumental behavior. Here, we provide a targeted assessment of the behavioral, anatomical, and electrophysiological contributions of serotonergic and nonserotonergic DRN neurons to reward processes. To explore DRN heterogeneity, we used a simultaneous two-vector knockout/optogenetic stimulation strategy, as well as cre-induced and cre-silenced vectors in several cre-expressing transgenic mouse lines. We found that the DRN is capable of reinforcing behavior primarily via nonserotonergic neurons, for which the main projection target is the ventral tegmental area (VTA). Furthermore, these nonserotonergic projections provide glutamatergic excitation of VTA dopamine neurons and account for a large majority of the DRN-VTA pathway. These findings help to resolve apparent discrepancies between the roles of serotonin versus the DRN in behavioral reinforcement.
    Cell Reports 09/2014; 8(6). DOI:10.1016/j.celrep.2014.08.037 · 8.36 Impact Factor
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