Origin of the serotonergic innervation to the rat dorsolateral hypothalamus: Retrograde transport of cholera toxin and upregulation of tryptophan hydroxylase mRNA expression following selective nerve terminals lesion

Abstract

The regulation of serotonin synthesis was investigated in the serotonergic neurons, which provide afferents to the dorsolateral hypothalamus (DLH). The origin of the DLH projection neurons within the raphe nucleus was identified by retrograde transport of Cholera toxin (CTb) and their serotonergic nature confirmed by tryptophan hydroxylase (TPH) immunocytochemistry. Disruption of serotonin synthesis steady-state was induced unilaterally by a selective and local destruction of serotonergic nerve terminals with 5,7-dihydroxytryptamine (5,7-DHT), stereotaxically injected in the right DLH. The results show that most of the serotonergic dorsal raphe neurons projecting to the DLH have an ipsilateral localization within the lateral aspects of the nucleus. In rats with unilateral DLH lesion, a population of serotonergic cells within the raphe nucleus exhibited a clear increase in TPH mRNA. These cells were about five times more numerous in the ipsilateral as compared to the contralateral dorsal raphe nucleus and they had, for the most part, a lateral localization within the raphe nucleus. Sham-operated rats did not exhibit any upregulation of TPH mRNA. Together, the present results provide the first demonstration that a discreet and selective destruction of serotonergic terminals induces a circumscribed and striking increase in TPH mRNA expression in a subset of brainstem serotonergic neurons projecting to and/or passing through the DLH. On the basis of these results and previous in vivo measurements of TPH activity (e.g., 5-HT synthesis), we suggest that this upregulation in TPH mRNA expression results from the loss of pre-synaptic and/or post-synaptic regulation of serotonin synthesis. These new findings raise important issues related to the repercussions of a local disruption in serotonergic neurotransmission on brain areas remote from the site of injury.

Adverse experience during early life and adulthood interact to elevate tph2 mRNA expression in serotonergic neurons within the dorsal raphe nucleus

“…Azmitia proposed that these serotonergic circuits involving the ventrolateral geniculate and suprachiasmatic nucleus may be involved in modulation of diurnal rhythms of corticosterone secretion and sleep-wake cycles (Azmitia, 1978). More recent studies provide evidence for serotonergic projections from the DRVL/VLPAG region to components of a central autonomic control system, including the lateral hypothalamus (Ljubic-Thibal et al, 1999) and rostroventrolateral medulla (Bago et al, 2002; Underwood et al, 1999a). Consistent with these findings, anatomical and functional studies suggest that DRVL/VLPAG serotonergic neurons may be part of a sympatho-motor command center controlling sympathetic and motor components of the fight-or-flight response (Johnson et al, 2004; Johnson et al, 2005; Johnson et al, 2008; Kerman et al, 2006; Lowry et al, 2008a).…”

Corticotropin-releasing factor-related peptides, serotonergic systems, and emotional behavior

“…The DRVL/VLPAG gives rise to projections involved in visual function including the superior colliculus and lateral geniculate nucleus (O'Hearn and Molliver, 1984; Waterhouse et al, 1993). Further, the DRVL/VLPAG also projects to the hypothalamus, medulla, PAG, and subcortical somatosensory regions, and data also suggest that DRVL/VLPAG serotonergic neurons control, via multisynaptic connections, presympathomotor neurons in the spinal cord (Beitz, 1982; Stezhka and Lovick, 1997; Ljubic-Thibal et al, 1999; Underwood et al, 1999; Kirifides et al, 2001; Bago et al, 2002; Kerman et al, 2006). The DRVL/VLPAG connections suggest that this region is important in control over panic-like and fight-or-flight behaviors.…”

Functional topography of midbrain and pontine serotonergic systems: implications for synaptic regulation of serotonergic circuits

“…Thus, based on their afferent and efferent connections, DRVL/VLPAG serotonergic neurons are ideally situated to regulate the fight-or-flight response or other emotional behaviors that involve changes in muscle tone, e.g., freezing. The DRVL/VLPAG region gives rise to reciprocal connections to a number of subcortical structures involved in central autonomic control, including the lateral hypothalamus (Ljubic-Thibal et al 1999), rostroventrolateral medulla (Bago et al 2002Underwood et al 1999a), and dorsolateral periaqueductal gray (Beitz 1982;Stezhka and Lovick 1997). In addition, the DRVL/VLPAG gives rise to projections to subcortical structures involved in visual processing, including the dorsal and ventral parts of the lateral geniculate body, lateral posterior nucleus of the thalamus, superior colliculus, and the retina (Janusonis et al 1999;Villar et al 1987Villar et al , 1988Waterhouse et al 1993), as well as subcortical somatosensory areas including the principle nucleus of the trigeminal nerve, ventral posterior medial thalamus (Kirifides et al 2001), and parafascicular thalamic nucleus (Chen et al 1992;Kirifides et al 2001).…”