Inhibition of VTA neurons activates the centrally projecting Edinger–Westphal nucleus: Evidence of a stress–reward link?

Abstract

The primary site of urocortin 1 (Ucn1) expression in the brain is the centrally projecting Edinger-Westphal nucleus. The EWcp is innervated by dopaminergic neurons of the ventral tegmental area (VTA). To investigate whether activity of EWcp is regulated by the VTA, we investigated the effects of local pharmacological inhibition of VTA activity on the induction of Fos immunoreactivity in the EWcp of male C57BL/6J mice. A unilateral intracranial administration of the GABA agonist muscimol aimed at the VTA resulted in increased number of Fos-positive cells in the EWcp. This induction was lower than that produced by an intraperitoneal injection of 2.5 g/kg of ethanol. To investigate whether inhibition of dopaminergic neurons was responsible for induction of Fos, a second experiment was performed where the dopamine agonist quinpirole was unilaterally injected targeting the VTA. Injections of quinpirole also significantly induced Fos in EWcp neurons. The induction occurred only on the side of EWcp ipsilateral to the VTA injection. These results indicate that activity of EWcp is inhibited by tonic activity of dopaminergic VTA neurons, and that unilateral projections of VTA onto Ucn1-containing EWcp neurons provide a link between systems regulating approach and avoidance behaviors.

Edinger-Westphal peptidergic neurons enable maternal preparatory nesting

“…It also suggests that the long nesting bouts necessary for preparatory nesting occur at the expense of sleep. This is reminiscent of a role recently described for VTA dopaminergic neurons in regular nesting ( Eban-Rothschild et al., 2016 ), which have been suggested to interact with EWcp neurons functionally ( Ryabinin et al., 2013 ). Intriguingly, loss-of-function or silencing experiments show that EWcp CART+ neurons have a more significant impact on the nesting sequence in pregnant mice than in virgins by increasing the time allotted to nesting during pregnancy.…”

Control of chronic excessive alcohol drinking by genetic manipulation of the Edinger–Westphal nucleus urocortin-1 neuropeptide system

“…Recent investigations of CRF system contributions to binge alcohol drinking focused on the ventral tegmental area and dorsal raphe nucleus. 14 , 16 These regions (as well as the lateral septum) are likely relevant to the outcomes in the current study, as our group demonstrated functional EWcp-Ucn1 interactions with these structures, 24 , 30 , 50 , 51 hinting at novel midbrain circuits linking the stress response to dysregulated drug-seeking. 22 , 23 , 52 …”

“…Here, we focused on the neuronal population within the ventromedial periaqueductal gray that comprises the centrally projecting Edinger–Westphal nucleus (EWcp). 17 EWcp neurons are proposed to interact with regions of the classic stress and addiction neurocircuits described above, 16 , 18 , 19 , 20 , 21 , 22 , 23 , 24 as well as the lateral septum, brainstem and spinal cord. 17 , 25 , 26 , 27 , 28 , 29 , 30 EWcp neurons are activated by stressors 31 and highly enriched in genes encoding neuropeptide transmitters: cocaine- and amphetamine-related transcript ( Cart );, cholecystokinin ( Cck ); nesfatin-1 ( Nucb2 ); pituitary adenylyl cyclase-activating polypeptide (PACAP, Adcyap1 ); and urocortin-1 (Ucn1, Ucn ).…”

Involvement of Centrally Projecting Edinger–Westphal Nucleus Neuropeptides in Actions of Addictive Drugs

“…A depletion of these dopaminergic terminals did not prevent lipopolysaccharide-induced c-Fos induction in the EWcp [94]. A subsequent study indicated this projection to the EWcp is inhibitory, such that inhibition of activity in the VTA resulted in c-Fos induction in the EWcp [95]. A systematic assessment of retrograde tracing from the EWcp in rats identified afferent neurons in the subfornical area, paraventricular nucleus of hypothalamus, arcuate nucleus, lateral hypothalamus, zona inserta, posterior hypothalamus, medial vestibular nucleus and cerebellar interpositus nucleus [92].…”