Medial prefrontal cortex receives input from dorsal raphe nucleus neurons targeted by Hypocretin1/OrexinA-containing axons

Cid-Pellitero, Esther Del; Garzón, Miguel

doi:10.1016/j.neuroscience.2010.10.058

Cited by 26 publications

(17 citation statements)

References 63 publications

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“…Our finding that 90% of the DR neurons projecting to mPFC are serotonergic aligns with several studies which reported percentages of 74–92% for this class of neurons (Fernandez et al, 2016; Lu et al, 2010; Meloni et al, 2008); however, there are two studies that found serotonergic proportions of 42% (Del Cid-Pellitero and Garzon, 2011) and 34% (Van Bockstaele et al, 1993). In the work by Del Cid-Pellitero et al, the tracer injections were directed at anterior cingulate cortex (ACC), medial orbital cortex, and prelimbic (PL) cortex, while ours were only directed at the PL and infralimbic (IL) cortices.…”

Section: Discussionsupporting

confidence: 91%

“…Serotonin-containing neurons that project from the DR to the mPFC have previously been identified using both retrograde (Del Cid-Pellitero and Garzon, 2011; Fernandez et al, 2016; Lu et al, 2010; Meloni et al, 2008; Van Bockstaele et al, 1993) and anterograde tracing approaches (Gagnon and Parent, 2014; Muzerelle et al, 2014; Vertes, 1991). Our finding that 90% of the DR neurons projecting to mPFC are serotonergic aligns with several studies which reported percentages of 74–92% for this class of neurons (Fernandez et al, 2016; Lu et al, 2010; Meloni et al, 2008); however, there are two studies that found serotonergic proportions of 42% (Del Cid-Pellitero and Garzon, 2011) and 34% (Van Bockstaele et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

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Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons

2017

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Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons

2017

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“…One of the targets within the forebrain is the mPFC (Wilson and Molliver, 1991; Verney et al, 2002; Del Cid-Pellitero and Garzon, 2011; Puig and Gulledge, 2011). The 5-HT projections are guided along the way to their target by various cues, either soluble or membrane-bound, as they develop (Petit et al, 2005; Anitha et al, 2008; Lee et al, 2010).…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, the 5-HT neurons located in the rostral raphe cluster extend profuse axon tracts into the fore- and midbrain (Gaspar et al, 2003; Bang et al, 2012). A distant target of the ascending 5-HT projection system within the forebrain is the medial prefrontal cortex (mPFC) (Del Cid-Pellitero and Garzon, 2011; Waselus et al, 2011). The mPFC is the seat of our highest cognitive abilities and known to be involved in attentional processes, working memory and behavioral flexibility (Miller and Cohen, 2001; Heidbreder and Groenewegen, 2003).…”

Section: Introductionmentioning

confidence: 99%

Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation

Witteveen¹,

Middelman²,

Hulten³

et al. 2013

Front. Cell. Neurosci.

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Besides its “classical” neurotransmitter function, serotonin (5-HT) has been found to also act as a neurodevelopmental signal. During development, the 5-HT projection system, besides an external placental source, represents one of the earliest neurotransmitter systems to innervate the brain. One of the targets of the 5-HT projection system, originating in the brainstem raphe nuclei, is the medial prefrontal cortex (mPFC), an area involved in higher cognitive functions and important in the etiology of many neurodevelopmental disorders. Little is known, however, about the exact role of 5-HT and its signaling molecules in the formation of the raphe-prefrontal network. Using explant essays, we here studied the role of the 5-HT transporter (5-HTT), an important modulator of the 5-HT signal, in rostral raphe-prefrontal network formation. We found that the chemotrophic nature of the interaction between the origin (rostral raphe cluster) and a target (mPFC) of the 5-HT projection system was affected in rats lacking the 5-HTT (5-HTT−/−). While 5-HTT deficiency did not affect the dorsal raphe 5-HT-positive outgrowing neurites, the median raphe 5-HT neurites switched from a strong repulsive to an attractive interaction when co-cultured with the mPFC. Furthermore, the fasciculation of the mPFC outgrowing neurites was dependent on the amount of 5-HTT. In the mPFC of 5-HTT−/− pups, we observed clear differences in 5-HT innervation and the identity of a class of projection neurons of the mPFC. In the absence of the 5-HTT, the 5-HT innervation in all subareas of the early postnatal mPFC increased dramatically and the number of Satb2-positive callosal projection neurons was decreased. Together, these results suggest a 5-HTT dependency during early development of these brain areas and in the formation of the raphe-prefrontal network. The tremendous complexity of the 5-HT projection system and its role in several neurodevelopmental disorders highlights the need for further research in this largely unexplored area.

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“…The VTA is not the only gateway for Hcrt1/OxA neurons to gain acces to the mPFC. Significant Hcrt1/OxA targeting has also been described in some other brainstem nuclei projecting to mPFC, such as the locus coeruleus [49], dorsal raphe nucleus [50] and laterodorsal tegmental nucleus [51]. Conceivably, all these structures contribute to cortical-activating actions of Hcrt1/OxA.…”

Section: Discussionmentioning

confidence: 99%

Hypocretin1/orexinA-immunoreactive axons form few synaptic contacts on rat ventral tegmental area neurons that project to the medial prefrontal cortex

Cid-Pellitero

Garzón

2014

BMC Neurosci

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BackgroundHypocretins/orexins (Hcrt/Ox) are hypothalamic neuropeptides involved in sleep-wakefulness regulation. Deficiency in Hcrt/Ox neurotransmission results in the sleep disorder narcolepsy, which is characterized by an inability to maintain wakefulness. The Hcrt/Ox neurons are maximally active during wakefulness and project widely to the ventral tegmental area (VTA). A dopamine-containing nucleus projecting extensively to the cerebral cortex, the VTA enhances wakefulness. In the present study, we used retrograde tracing from the medial prefrontal cortex (mPFC) to examine whether Hcrt1/OxA neurons target VTA neurons that could sustain behavioral wakefulness through their projections to mPFC.ResultsThe retrograde tracer Fluorogold (FG) was injected into mPFC and, after an optimal survival period, sections through the VTA were processed for dual immunolabeling of anti-FG and either anti-Hcrt1/OxA or anti-TH antisera. Most VTA neurons projecting to the mPFC were located in the parabrachial nucleus of the ipsilateral VTA and were non-dopaminergic. Only axonal profiles showed Hcrt1/OxA-immunoreactivity in VTA. Hcrt1/OxA reactivity was observed in axonal boutons and many unmyelinated axons. The Hcrt1/OxA immunoreactivity was found filling axons but it was also observed in parts of the cytoplasm and dense-core vesicles. Hcrt1/OxA-labeled boutons frequently apposed FG-immunolabeled dendrites. However, Hcrt1/OxA-labeled boutons rarely established synapses, which, when they were established, were mainly asymmetric (excitatory-type), with either FG-labeled or unlabeled dendrites.ConclusionsOur results provide ultrastructural evidence that Hcrt1/OxA neurons may exert a direct synaptic influence on mesocortical neurons that would facilitate arousal and wakefulness. The paucity of synapses, however, suggest that the activity of VTA neurons with cortical projections might also be modulated by Hcrt1/OxA non-synaptic actions. In addition, Hcrt1/OxA could modulate the postsynaptic excitatory responses of VTA neurons with cortical projections to a co-released excitatory transmitter from Hcrt1/OxA axons. Our observation of Hcrt1/OxA targeting of mesocortical neurons supports Hcrt1/OxA wakefulness enhancement in the VTA and could help explain the characteristic hypersomnia present in narcoleptic patients.

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Medial prefrontal cortex receives input from dorsal raphe nucleus neurons targeted by Hypocretin1/OrexinA-containing axons

Cited by 26 publications

References 63 publications

Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons

Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons

Lack of serotonin reuptake during brain development alters rostral raphe-prefrontal network formation

Hypocretin1/orexinA-immunoreactive axons form few synaptic contacts on rat ventral tegmental area neurons that project to the medial prefrontal cortex

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