Number Of Noradrenergic Neurons Research Articles

Prenatal exposure to MDMA alters noradrenergic neurodevelopment in the rat

3,4-methylenedioxymethamphetamine (MDMA; ecstasy) binds with high affinity to the norepinephrine transporter (NET), making the noradrenergic system a potential target during fetal exposure. Recent data indicate that adult rats that had been prenatally exposed to MDMA display persistent deficits in working memory and attention; behaviors consistent with abnormal noradrenergic signaling in the forebrain. The present study was designed to investigate whether prenatal exposure to MDMA from embryonic days 14–20 affects the structure and/or function of the noradrenergic system of the rat on postnatal day 21. Offspring that were prenatally exposed to MDMA exhibited an increase in noradrenergic fiber density in the prelimbic region of the prefrontal cortex and the CA1 region of the hippocampus that was not accompanied by an increase in the number of noradrenergic neurons in the locus coeruleus. Direct tissue autoradiography using tritiated nisoxetine demonstrated that while NET binding was not altered in the prelimbic cortex, the dentate gyrus, or the locus coeruleus, it was increased in the CA1, CA2, and CA3 regions of the hippocampus. Basal levels of norepinephrine were increased in the prefrontal cortex and the nucleus accumbens of MDMA-exposed rats, as compared to saline-treated controls. These findings indicate that prenatal exposure to MDMA results in structural changes in the noradrenergic system as well as functional alterations in NE neurotransmission in structures that are critical in attentional processing.

Differential response of the central noradrenergic nervous system to the loss of locus coeruleus neurons in Parkinson's disease and Alzheimer's disease

In Parkinson's disease (PD), there is a significant loss of noradrenergic neurons in the locus coeruleus (LC) in addition to the loss of dopaminergic neurons in the substantia nigra (SN). The goal of this study was to determine if the surviving LC noradrenergic neurons in PD demonstrate compensatory changes in response to the neuronal loss, as observed in Alzheimer's disease (AD). Tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) mRNA expression in postmortem LC tissue of control and age-matched PD subjects demonstrated a significant reduction in the number of noradrenergic neurons in the LC of PD subjects. TH mRNA expression/neuron did not differ between control and PD subjects, but DBH mRNA expression/neuron was significantly elevated in PD subjects compared to control. This increase in DBH mRNA expression in PD subjects is not a response to neuronal loss because the amount of DBH mRNA expression/neuron in AD subjects was not significantly different from control. Norepinephrine transporter (NET) binding site concentration in the LC of PD subjects was significantly reduced over the cell body region as well as the peri-LC dendritic zone. In PD subjects, the loss of dendrites from surviving noradrenergic neurons was also apparent with TH-immunoreactivity (IR). This loss of LC dendritic innervation in PD subjects as measured by TH-IR was not due to LC neuronal loss because TH-IR in AD subjects was robust, despite a similar loss of LC neurons. These data suggest that there is a differential response of the noradrenergic nervous system in PD compared to AD in response to the loss of LC neurons.

The hyperalgesic effects induced by the injection of angiotensin II into the caudal ventrolateral medulla are mediated by the pontine A 5 noradrenergic cell group

The caudal ventrolateral medulla (CVLM) is a key component of the supraspinal pain modulatory system. Pain modulation from the CVLM is partially relayed by spinally projecting noradrenergic neurons of the pontine A 5 cell group, which leave collateral fibres at the CVLM. The injection of angiotensin II (Ang II) into the CVLM was recently shown to induce hyperalgesia mediated by angiotensin type 1 (AT 1) receptors, expressed by CVLM neurons that do not project to the spinal cord. The present study evaluates the effects of lesioning the noradrenergic pontine A 5 cell group by the retrograde transport of the selective toxin anti-dopamine β-hydroxylase-saporin (anti-DBH-SAP) from the CVLM in pain behavioural responses elicited by Ang II injection into the CVLM. The injection of anti-DBH-SAP induced neurodegeneration, identified by the marker Fluoro-Jade B, restricted to the A 5 noradrenergic cell group. These results were confirmed by the decrease in the number of noradrenergic neurons only in the A 5 group. Pain behavioural evaluation using the formalin test showed that Ang II injection into the CVLM induced hyperalgesia, which was partially prevented by lesion of the A 5 noradrenergic cell group with anti-DBH-SAP. Immunostaining of AT 1 receptors in CVLM neurons retrogradely labelled from the A 5 noradrenergic cell group showed that CVLM neurons that project to the A 5 express AT 1 receptors, indicating that Ang II can modulate directly the CVLM-A 5 connection. The results show that Ang II-induced hyperalgesia elicited from the CVLM is mediated by an indirect pathway relayed at the pontine noradrenergic A 5 group.

Novelty-induced behavioral traits correlate with numbers of brainstem noradrenergic neurons and septal cholinergic neurons in C57BL/6J mice

It is generally accepted that different brain regions regulate specific behavioral responses and that structural alterations in these regions may affect behavior. We investigated whether inter-individual variability in novelty-induced behaviors in C57BL/6J mice correlates with numbers of noradrenergic neurons in the locus coeruleus and cholinergic neurons in the septum. We found that exploration of new stimuli correlated negatively with numbers of noradrenergic neurons, whereas anxiety correlated positively with numbers of cholinergic neurons. The observed correlations suggest physiologically plausible links between structure and function and indicate that precise morphological estimates can be predictive for behavioral responses.

ORIGINAL RESEARCH—BASIC SCIENCE: Effect of the Destruction of Cells Containing the Serotonin Reuptake Transporter on Urethrogenital Reflexes

ABSTRACT Introduction The urethrogenital (UG) reflex is an autonomic and somatic response that mimics some of the physiological changes seen during ejaculation. The UG reflex is tonically inhibited by neurons in the ventral medulla, an area containing serotonin neurons. Aim To examine the effect of lesions of brain neurons containing the serotonin reuptake transporter (SERT) on ejaculatory-like reflexes. Methods Anti-SERT saporin (80 nL, 1 mM) or saline was injected bilaterally into the ventrolateral medulla of male Sprague–Dawley rats. Ten to 18 days later, animals were deeply anesthetized and the presence of the UG reflex was examined before and after acute spinal cord transection (T9–10). Following the experiment the presence and number of serotonin and norepinephrine containing neurons (using tryptophan hydroxylase and dopamine beta-hydroxylase, respectively) was performed. Main Outcome Measures The UG reflex and cell counts. Results In saline-injected controls the UG reflex was not evoked in the anesthetized, intact preparation, indicating the presence of the supraspinal inhibition, as previously reported. Injection of anti-SERT saporin into the ventrolateral medulla allowed the UG reflex to be activated in the intact preparation, thus removed the inhibition. This was associated with a decrease in the number of serotonin neurons in the ventrolateral medulla and raphe. No change in the number of noradrenergic neurons was observed. Conclusion These studies suggest that ventral medullary neurons containing SERT are involved in the tonic inhibition of the UG reflex.

Absence of dopaminergic neuronal degeneration and oxidative damage in aged DJ-1-deficient mice

Parkinson's disease is the most common movement disorder characterized by dopaminergic dysfunction and degeneration. Loss-of-function mutations in the DJ-1 gene have been linked to autosomal recessive forms of early-onset familial Parkinson's disease. DJ-1 is thought to play roles in protection of cells against oxidative stress and in maintenance of the normal dopaminergic function in the nigrostriatal pathway. Here we investigate the consequence of both DJ-1 inactivation and aging in mice. We found that DJ-1-/- mice at the age of 24–27 months have normal numbers of dopaminergic neurons in the substantia nigra and normal levels of dopamine and its major metabolites in the striatum. The number of noradrenergic neurons in the locus coeruleus is also unchanged in DJ-1-/- mice. Moreover, there is no accumulation of oxidative damage or inclusion bodies in aged DJ-1-/- brains. Together, these results indicate that loss of DJ-1 function alone is insufficient to cause nigral degeneration and oxidative damage in the life span of mice.

Augmentation of the noradrenergic system in alpha-2 adrenergic receptor deficient mice: anatomical changes associated with enhanced fear memory

We have investigated sensitivity to the conditioned fear procedure of mice is influenced by the genetic deletion of α 2A adrenoceptors (ARs). We observed a heightened freezing response in the discrete cue memory test in α 2A AR knockout (α 2A AR KO) mice and in D79N mice, a transgenic mouse strain with functionally impaired α 2A ARs. No significant differences in contextual memory were observed between control and α 2A AR KO or D79N mice suggesting a minimal role for the noradrenergic system in contextual memory. We speculated that the increased freezing response of the α 2A AR KO and D79N mice in the discrete cue setting was due to increased release of norepinephrine evoked by the unconditioned footshock stimulus. In α 2A AR KO mice we measured a doubling in the number of noradrenergic neurons in the locus coeruleus (LC) and a large increase in the cell volume of tyrosine hydroxylase positive neurons, likely due to selective preservation of large, multipolar neurons in the subcoeruleus. Hyperplasia of the noradrenergic neurons in the nucleus tractus solitarius, A5 and A7, was also observed. α 2A AR KO mice exhibit greater c-Fos expression in the LC compared to wild type mice suggesting that the LC neurons in the α 2A AR KO mice were spontaneously more active. This study suggests that α 2A ARs are involved in the development of the central noradrenergic system and raises the possibility that alterations in α 2A AR expression may contribute to variations in fear and stress responses.

Effects of β-amyloid protein on serotoninergic, noradrenergic, and cholinergic markers in neurons of the pontomesencephalic tegmentum in the rat

The effects on serotoninergic, noradrenergic and cholinergic markers on neurons of the pontomesencephalic tegmentum nuclei were studied in rats following local administration of fibrillar β-amyloid peptide (Aβ1–40) into the left retrosplenial cortex. Focal deposition of Aβ in the retrosplenial cortex resulted in a loss of serotoninergic neurons in the dorsal and median raphe nuclei. The dorsal raphe nucleus showed a statistically significant reduction of 31.7% in the number of serotoninergic neurons and a decrease (up to 17.38%) in neuronal density in comparison with the same parameters in uninjected controls. A statistically significant reduction of 50.3%, together with a significant decrease of 53.94% in the density of serotoninergic neurons, was also observed in the median raphe nucleus as compared with control animals. Furthermore, a significant reduction of 35.07% in the number of noradrenergic neurons as well as a statistically significant decrease of 56.55% in the density of dopamine-β-hydroxylase-immunoreactive neurons were also found in the locus coeruleus as compared with the corresponding hemisphere in uninjected controls. By contrast, a reduction of 24.37% in the number of choline acetyltransferase-positive neurons and a slight decrease (up to 22.28%) in the density of cholinergic neurons, which were not statistically significant, was observed in the laterodorsal tegmental nucleus in comparison with the same parameters in control animals. These results show that three different neurochemically defined populations of neurons in the pontomesencephalic tegmentum are affected by the neurotoxicity of Aβ in vivo and that Aβ might indirectly affect serotoninergic, noradrenergic and cholinergic innervation in the retrosplenial cortex.

Effects of Ethanol on Development of Locus Coeruleus Brain Stem Transplantsin oculo

In this investigation, we studied the effects of ethanol (EtOH) on the development of noradrenergic (NE) neurons of the locus coeruleus. Fetal brainstem tissue from embryonic days 15-17 was grafted into the anterior chamber of the eye of adult rats. Two different experimental groups were exposed to 16% EtOH in the drinking water during different developmental windows. The first group received EtOH 24 h after transplantation and during the whole experimental period of 7 weeks (continuous EtOH), and the second group only during the last 5 weeks of the experimental period (delayed EtOH). The control group received water ad libitum. After 7 weeks, all the animals were sacrificed and morphological evaluations were performed. Immunohistochemical analysis showed that axon bundle formation and NE fiber outgrowth into the host iris was significantly reduced in the continuous EtOH-treated group compared to controls. We also studied the morphology of TH-positive neurons and processes in the intraocular transplants. A significant decrease in TH-positive staining intensity was observed in the continuous EtOH-treated group compared to controls. Moreover, we found a significant decrease in cell size and neuronal survival in both EtOH-treated groups compared to controls. The present results suggest that chronic EtOH exposure during development leads to an altered axonal outgrowth and decreased cell sizes and number of NE neurons in intraocular brain stem grafts. Furthermore, we found that NE neurons are more sensitive to EtOH exposure during the last prenatal days and the first postnatal week of development, compared to a later developmental period.

Effect of guanethidine on dopamine in small intensely fluorescent cells of the superior cervical ganglion of the rat

To determine the portion of ganglionic dopamine stored in the small intensely fluorescent (SIF) cells of the superior cervical ganglion, rats were treated chronically with the neurotoxin guanethidine (50 mg/kg i.p. daily for 6, 13 or 18 days) which destroys noradrenergic neurons. The guanethidine effect was assessed in the ganglion using biochemistry of dopamine and norepinephrine and immunocytochemistry of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). After 18 days of treatment, the ganglionic norepinephrine content was reduced by 80%, but the dopamine content was reduced by only 20%. Morphologic analysis of ganglia stained to distinguish noradrenergic neurons (TH positive, DBH positive) and SIF cells (TH positive, DBH negative) indicated that guanethidine treatment reduced the number of noradrenergic neurons by 70%, dropping from 19413 +/- 1402 to 6515 +/- 1296 per ganglion, but increased the number of dopaminergic SIF cells by 80% from 578 +/- 150 to 1056 +/- 151 per ganglion. Based on these findings, it is concluded that a substantial portion of the dopamine in the rat superior cervical ganglion is located outside the noradrenergic neurons, i.e. in the SIF cells. Extrapolating the data obtained using guanethidine versus control rat leads to infer that although the proportion of SIF cells in the superior cervical ganglion is small (3 +/- 1% of the SIF and noradrenergic neurons combined), about 40% of the total ganglionic dopamine resides in SIF cells, with the remainder serving as precursor in noradrenergic neurons.

Increased number of locus ceruleus noradrenergic neurons in the convulsive mutant quaking mouse

Noradrenergic cell bodies in the locus ceruleus of the convulsive mutant quaking mouse and the control of the same strain were visualized using histofluorescence and tyrosine hydroxylase-like immunoreactivity. Cell counts performed with the two techniques gave closely similar results within each strain, indicating a 50% increase in the number of noradrenergic neurons in the midportion of the mutants' locus ceruleus when compared to the controls. This result gives histological support to the increased noradrenergic neurotransmission previously described in the brain of this mutant. Thus, the abnormally high activity of the noradrenergic system appears to be a primary effect of the mutation, associated with the convulsions of this animal model of epilepsy.

Positive control of target cerebellar cells on norepinephrine uptake in embryonic brainstem cultures in serum-free medium

Brainstem cells from 15-day-old mouse embryos (E 15) grown for 8–10 days in dissociated primary cell culture in serum-free medium show high affinity uptake for [ 3H]norepinephrine (NE) that is specifically inhibited by desmethylimipramine (DMI), and also show high affinity binding for [ 3H]DMI. Brainstem cell uptake capacity for NE is increased at least 2-fold when cocultured with target cerebellar or striatal cells of the same embryonic age. The stimulation exerted by the cerebellum appears to be developmentally regulated since more mature cerebella (from 16–17-day-old embryos) exerted a greater stimulation than younger structures (from 14–15-day-old embryos). This stimulatory effect is also correlated with the number of available target sites since increasing the amount of cerebellar cells result in an increased stimulation of uptake capacity. The high affinity binding for [ 3H]DMI is also enhanced in coculture. The number of noradrenergic neurons, detected by autoradiography, remains unchanged in coculture indicating that added cerebellar cells did not take up NE, suggesting that the number of uptake sites per noradrenergic neuron is increased in the presence of target cells. These results indicate that interactions between afferent and target neurons, which normally take place during in vivo development, also occur in vitro and may result in a modification of neurotransmitter uptake in the afferent neuron.