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Fulltext Catecholaminergic neurons in the comissural region of the nucleus of the solitary tract modulate hyperosmolality-induced responses

Freiria-Oliveira AH, Blanch GT, Pedrino GR, Cravo SL, Murphy D, Menani JV, et al.

Am J Physiol Regul Integr Comp Physiol, 2015 Nov 01;309(9):R1082-91.
PMID: 26333788 DOI: 10.1152/ajpregu.00432.2014

Noradrenergic A2 neurons of the nucleus of the solitary tract (NTS) have been suggested to contribute to body fluid homeostasis and cardiovascular regulation. In the present study, we investigated the effects of lesions of A2 neurons of the commissural NTS (cNTS) on the c-Fos expression in neurons of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, arterial pressure, water intake, and urinary excretion in rats with plasma hyperosmolality produced by intragastric 2 M NaCl (2 ml/rat). Male Holtzman rats (280-320 g) received an injection of anti-dopamine-β-hydroxylase-saporin (12.6 ng/60 nl; cNTS/A2-lesion, n = 28) or immunoglobulin G (IgG)-saporin (12.6 ng/60 nl; sham, n = 24) into the cNTS. The cNTS/A2 lesions increased the number of neurons expressing c-Fos in the magnocellular PVN in rats treated with hypertonic NaCl (90 ± 13, vs. sham: 47 ± 20; n = 4), without changing the number of neurons expressing c-Fos in the parvocellular PVN or in the SON. Contrary to sham rats, intragastric 2 M NaCl also increased arterial pressure in cNTS/A2-lesioned rats (16 ± 3, vs. sham: 2 ± 2 mmHg 60 min after the intragastric load; n = 9), an effect blocked by the pretreatment with the vasopressin antagonist Manning compound (0 ± 3 mmHg; n = 10). In addition, cNTS/A2 lesions enhanced hyperosmolality-induced water intake (10.5 ± 1.4, vs. sham: 7.7 ± 0.8 ml/60 min; n = 8-10), without changing renal responses to hyperosmolality. The results suggest that inhibitory mechanisms dependent on cNTS/A2 neurons reduce water intake and vasopressin-dependent pressor response to an acute increase in plasma osmolality.

Matched MeSH terms: Solitary Nucleus/cytology; Solitary Nucleus/physiology*
Cardiovascular autonomic effects of transcutaneous auricular nerve stimulation via the tragus in the rat involve spinal cervical sensory afferent pathways

Mahadi KM, Lall VK, Deuchars SA, Deuchars J

Brain Stimul, 2019 05 06;12(5):1151-1158.
PMID: 31129152 DOI: 10.1016/j.brs.2019.05.002

BACKGROUND: Electrical stimulation on select areas of the external auricular dermatome influences the autonomic nervous system. It has been postulated that activation of the Auricular Branch of the Vagus Nerve (ABVN) mediates such autonomic changes. However, the underlying neural pathways mediating these effects are unknown and, further, our understanding of the anatomical distribution of the ABVN in the auricle has now been questioned.
OBJECTIVE: To investigate the effects of electrical stimulation of the tragus on autonomic outputs in the rat and probe the underlying neural pathways.
METHODS: Central neuronal projections from nerves innervating the external auricle were investigated by injections of the transganglionic tracer cholera toxin B chain (CTB) into the right tragus of Wistar rats. Physiological recordings of heart rate, perfusion pressure, respiratory rate and sympathetic nerve activity were made in an anaesthetic free Working Heart Brainstem Preparation (WHBP) of the rat and changes in response to electrical stimulation of the tragus analysed.
RESULTS: Neuronal tracing from the tragus revealed that the densest CTB labelling was within laminae III-IV of the dorsal horn of the upper cervical spinal cord, ipsilateral to the injection sites. In the medulla oblongata, CTB labelled afferents were observed in the paratrigeminal nucleus, spinal trigeminal tract and cuneate nucleus. Surprisingly, only sparse labelling was observed in the vagal afferent termination site, the nucleus tractus solitarius. Recordings made from rats at night time revealed more robust sympathetic activity in comparison to day time rats, thus subsequent experiments were conducted in rats at night time. Electrical stimulation was delivered across the tragus for 5 min. Direct recording from the sympathetic chain revealed a central sympathoinhibition by up to 36% following tragus stimulation. Sympathoinhibition remained following sectioning of the cervical vagus nerve ipsilateral to the stimulation site, but was attenuated by sectioning of the upper cervical afferent nerve roots.
CONCLUSIONS: Inhibition of the sympathetic nervous system activity upon electrical stimulation of the tragus in the rat is mediated at least in part through sensory afferent projections to the upper cervical spinal cord. This challenges the notion that tragal stimulation is mediated by the auricular branch of the vagus nerve and suggests that alternative mechanisms may be involved.

Matched MeSH terms: Solitary Nucleus/physiology
Fulltext Docking based screening and molecular dynamics simulations to identify potential selective PDE4B inhibitor

Al-Nema M, Gaurav A, Lee VS

Heliyon, 2020 Sep;6(9):e04856.
PMID: 32984588 DOI: 10.1016/j.heliyon.2020.e04856

Inhibition of phosphodiesterase 4 (PDE4) is a promising therapeutic approach for the treatment of inflammatory pulmonary disorders, i.e. asthma and chronic obstructive pulmonary disease. However, the treatment with non-selective PDE4 inhibitors is associated with side effects such as nausea and vomiting. Among the subtypes of PDE4 inhibited by these inhibitors, PDE4B is expressed in immune, inflammatory and airway smooth muscle cells, whereas, PDE4D is expressed in the area postrema and nucleus of the solitary tract. Thus, PDE4D inhibition is responsible for the emetic response. In this regard, a selective PDE4B inhibitor is expected to be a potential drug candidate for the treatment of inflammatory pulmonary disorders. Therefore, a shared feature pharmacophore model was developed and used as a query for the virtual screening of Maybridge and SPECS databases. A number of filters were applied to ensure only compounds with drug-like properties were selected. Accordingly, nine compounds have been identified as final hits, where HTS04529 showed the highest affinity and selectivity for PDE4B over PDE4D in molecular docking. The docked complexes of HTS04529 with PDE4B and PDE4D were subjected to molecular dynamics simulations for 100ns to assess their binding stability. The results showed that HTS04529 was bound tightly to PDE4B and formed a more stable complex with it than with PDE4D.

Matched MeSH terms: Solitary Nucleus
Fulltext 5α-Reduced neurosteroids sex-dependently reverse central prenatal programming of neuroendocrine stress responses in rats

Brunton PJ, Donadio MV, Yao ST, Greenwood M, Seckl JR, Murphy D, et al.

J Neurosci, 2015 Jan 14;35(2):666-77.
PMID: 25589761 DOI: 10.1523/JNEUROSCI.5104-13.2015

Maternal social stress during late pregnancy programs hypothalamo-pituitary-adrenal (HPA) axis hyper-responsiveness to stressors, such that adult prenatally stressed (PNS) offspring display exaggerated HPA axis responses to a physical stressor (systemic interleukin-1β; IL-1β) in adulthood, compared with controls. IL-1β acts via a noradrenergic relay from the nucleus tractus solitarii (NTS) to corticotropin releasing hormone neurons in the paraventricular nucleus (PVN). Neurosteroids can reduce HPA axis responses, so allopregnanolone and 3β-androstanediol (3β-diol; 5α-reduced metabolites of progesterone and testosterone, respectively) were given subacutely (over 24 h) to PNS rats to seek reversal of the "programmed" hyper-responsive HPA phenotype. Allopregnanolone attenuated ACTH responses to IL-1β (500 ng/kg, i.v.) in PNS females, but not in PNS males. However, 3β-diol normalized HPA axis responses to IL-1β in PNS males. Impaired testosterone and progesterone metabolism or increased secretion in PNS rats was indicated by greater plasma testosterone and progesterone concentrations in male and female PNS rats, respectively. Deficits in central neurosteroid production were indicated by reduced 5α-reductase mRNA levels in both male and female PNS offspring in the NTS, and in the PVN in males. In PNS females, adenovirus-mediated gene transfer was used to upregulate expression of 5α-reductase and 3α-hydroxysteroid dehydrogenase mRNAs in the NTS, and this normalized hyperactive HPA axis responses to IL-1β. Thus, downregulation of neurosteroid production in the brain may underlie HPA axis hyper-responsiveness in prenatally programmed offspring, and administration of 5α-reduced steroids acutely to PNS rats overrides programming of hyperactive HPA axis responses to immune challenge in a sex-dependent manner.

Matched MeSH terms: Solitary Nucleus/drug effects; Solitary Nucleus/growth & development; Solitary Nucleus/metabolism