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Control of the central chemoreflex by A5 noradrenergic neurons in rats.
Taxini CL, Takakura AC, Gargaglioni LH, Moreira TS (2011) Control of the central chemoreflex by A5 noradrenergic neurons in rats. Neuroscience 199:177-186. doi: 10.1016/j.neuroscience.2011.09.068
Summary: The A5 group of noradrenergic neurons in the ventrolateral pons is involved in the control of sympathetic and respiratory networks. Using anti-DBH-SAP (Cat. #IT-03) the authors eliminated TH+ neurons in order to clarify which aspects of respiration are modulated by A5 neurons. Rats received bilateral 4.2-ng injections of the toxin into the A5 region. The results suggest that A5 noradrenergic neurons are involved in control of mean arterial pressure, splanchnic sympathetic nerve activity, and phrenic nerve activity.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
MAP kinases couple hindbrain-derived catecholamine signals to hypothalamic adrenocortical control mechanisms during glycemia-related challenges.
Khan AM KKL, Sanchez-Watts, Ponzio TA, Kuzmiski JB, Bains JS, Watts AG (2011) MAP kinases couple hindbrain-derived catecholamine signals to hypothalamic adrenocortical control mechanisms during glycemia-related challenges. J Neurosci 31(50):18479-18491. doi: 10.1523/JNEUROSCI.4785-11.2011
Summary: This work uses in vivo and ex vivo techniques to clarify how hypothalamic afferent pathways use intracellular mechanisms to modulate glycemia related adrenocortical responses. Rats received 42 ng injections of anti-DBH-SAP (Cat. #IT-03) into the paraventricular nucleus of the hypothalamus. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The results establish a relationship between neurons from nutrient-sensing regions and intracellular mechanisms in hypothalamic corticotropin-releasing hormone neuroendocrine neurons.
Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)
Depletion of endogenous noradrenaline does not prevent spinal cord plasticity following peripheral nerve injury.
Hayashida K, Peters CM, Gutierrez S, Eisenach JC (2012) Depletion of endogenous noradrenaline does not prevent spinal cord plasticity following peripheral nerve injury. J Pain 13(1):49-57. doi: 10.1016/j.jpain.2011.09.009
Summary: The authors examined what involvement noradrenergic fibers in the spinal cord have in neuronal and glial plasticity associated with neuropathic pain states. Rats received 5 μg intrathecal injections of anti-DBH-SAP (Cat. #IT-03). Lesioned animals did not display altered mechanical withdrawal thresholds, but L5-L6 spinal nerve ligation in these animals caused enhanced mechanical hypersensitivity and analgesia induced by intrathecal clonidine. The data suggest that endogenous noradrenaline may play an inhibitory role on glial activation.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Redefining the components of central CO2 chemosensitivity – towards a better understanding of mechanism.
Huckstepp RT, Dale N (2011) Redefining the components of central CO2 chemosensitivity – towards a better understanding of mechanism. J Physiol 589(Pt 23):5561-5579. doi: 10.1113/jphysiol.2011.214759
Summary: This review discusses advances in the field of CO2 chemosensitivity over the past few years. Discussion of the role that locus coeruleus (LC) neurons play in this process describe the use of anti-DBH-SAP (Cat. #IT-03) to reduce the hypercapnic ventilatory response. Data from these and other experiments support a role of the LC in modulation of the ventilatory response to hypercapnia.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Norepinephrine denervation by dopamine beta-hydroxylase saporin impacts L-DOPA efficacy and side effects in a hemi-parkinsonian rat model
Bhide NS, Dickinson S, Feinberg E, Mohamed M, Dupre K, Eskow-Jaunarajs K, Lindenbach D, Ostock C, Bishop C (2011) Norepinephrine denervation by dopamine beta-hydroxylase saporin impacts L-DOPA efficacy and side effects in a hemi-parkinsonian rat model. Neuroscience 2011 Abstracts 883.20. Society for Neuroscience, Washington, DC.
Summary: Dopaminergic neurodegeneration in Parkinson’s disease (PD) is accompanied by concomitant loss in the norepinephrine (NE) system. The exact contribution of NE denervation in the development of PD remains elusive. Recently, we demonstrated that NE neurons may contribute to the efficacy and side effects of L-DOPA, however, to better mimic NE loss observed in PD we employed the selective NE neurotoxin dopamine beta hydroxylase saporin (DHB saporin) and evaluated its effects on the anti-parkinsonian efficacy of L-DOPA and the development & expression of L-DOPA induced dyskinesia (LID). To do so, hemiparkinsonian adult Sprague-Dawley rats were exposed to intraventricular injections of either vehicle or DHB saporin. Three weeks later, animals were primed with L-DOPA (4mg/kg) for days 1-7 and L-DOPA (12 mg/kg) for days 9-15. During this period animals were monitored for motor-performance, a marker for L-DOPA’s anti-parkinsonian efficacy, and dyskinesia measured using Abnormal Involuntary Movements (AIMs) scale. Further, sensitivity of primed animals to different doses of L-DOPA (ranging from 2 to 12 mg/kg) was assessed. Results indicate that NE denervation resulted in reduced anti-parkinsonian efficacy of L-DOPA, but not the development of dyskinesia. In fully primed rats, NE denervation attenuated dyskinetic responses to L-DOPA when compared to animals with an intact NE innervation. These findings suggest that the NE system significantly modulates the anti-parkinsonian effects of L-DOPA and the expression of LID and indicate the importance of understanding the mechanisms by which NE modifies basal ganglia function in PD.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Cardiovascular dysfunction and cardiac injury result from selective glial damage in the nucleus tractus solitarii
Talman WT, Nitschke Dragon D, Jones S, Moore SA, Lin L-H (2011) Cardiovascular dysfunction and cardiac injury result from selective glial damage in the nucleus tractus solitarii. Neuroscience 2011 Abstracts 664.14. Society for Neuroscience, Washington, DC.
Summary: In man, extensive CNS dysfunction as may occur after subarachnoid hemorrhage may lead to cardiac damage and cardiac arrhythmias. We have shown that highly selective and restricted lesions of the nucleus tractus solitarii (NTS) may lead to similar cardiac and cardiovascular compromise. For example, using conjugates including the cytotoxin saporin (SAP) to selectively damage NTS neurons that express NK1 receptors or those that express tyrosine hydroxylase (TH) leads to cardiac dysfunction and associated lability of arterial pressure. In continuing efforts to better characterize cellular changes produced by introducing into the NTS conjugates containing SAP, we have studied the effect of anti-dopamine-beta-hydroxylase (anti-DBH)-SAP, stabilized substance P (SSP)-SAP, SAP (unconjugated), blank-SAP (non-targeted peptide conjugate), IgG-SAP (non-targeted immunoglobulin conjugate), and 6-hydoxydopamine (6-OHDA) as a control without SAP injected into NTS. We assessed effects of the injected agents both on cellular markers [NMDAR1 (NMDA receptor subunit 1), GluR2 (AMPA receptor subunit 2), gamma-aminobutyric acid (GABA) receptor type a and b, neuronal nitirc oxide synthase (nNOS), TH, vesicular glutamate transporters (VGluTs), choline acetyl transferase (ChAT), glial fibrillary acidic protein (GFAP), connexin 43 (Cx43), DBH and protein gene product 9.5 (PGP 9.5)] and on cardiovascular and cardiac function. We have found that each compound containing SAP (including blank-SAP, IgG-SAP, unconjugated SAP) led to loss of GFAP and Cx43 immunofluorescent labeling in the NTS as well as lability of arterial pressure, cardiac arrhythmias, and cardiac myocytolysis. Those outcomes occurred despite neuronal specificity for each of the SAP conjugates. For example, anti-DBH-SAP led to a decrease in TH and DBH staining as well as a profound loss in GFAP and Cx43. In contrast, SSP-SAP led to loss of NK1 as well as GFAP, Cx43, and glutamate receptor markers but did not lead to loss of DBH or GABA. SSP-SAP also caused a loss in PGP9.5 which was not observed in all other agents. SAP and blank-SAP, on the other hand, led to loss of GFAP and Cx43 while 6-OHDA led to loss of TH and DBH, increased GFAP and decreased Cx-43. We are still investigating the effects of 6-OHDA on lability of arterial pressure and cardiac events but preliminary data suggest that, in doses used, it led to loss of TH and DBH but did not lead to either lability or cardiac events that were seen with each of the conjugates containing an SAP moiety. This study suggests that glial dysfunction may alone interefere with cardiovascular control through the NTS and may lead to cardiac damage and cardiovascular dysfunction.
Related Products: Anti-DBH-SAP (Cat. #IT-03), SSP-SAP (Cat. #IT-11), Mouse IgG-SAP (Cat. #IT-18), Blank-SAP (Cat. #IT-21), Saporin (Cat. #PR-01)
Fourth ventricular glucosamine-induced feeding is catecholamine-dependent
Li AJ, Wang Q, Ritter S (2011) Fourth ventricular glucosamine-induced feeding is catecholamine-dependent. Neuroscience 2011 Abstracts 600.17. Society for Neuroscience, Washington, DC.
Summary: Glucokinase has been identified as a glucose-sensor for detecting glucose changes both in the brain and periphery. Previous reports have shown that lateral ventricular injection of a glucokinase inhibitor, glucosamine, stimulates glucoprivic feeding in rats. Other work has demonstrated involvement of hindbrain glucokinase in glucoregulation. Here we compared the effects of lateral (LV) and fourth ventricular (4V) injections of glucosamine on food intake in rats. We found that glucosamine injected into 4V (0, 0.2, 0.6, and 1.0 mg/rat) enhanced food intake in a dose-dependent manner and that LV and 4V injections were of similar potency. Glucosamine did not elevate blood glucose under the conditions of our test. We also found that enhancement of feeding by 4V glucosamine was abolished by medial hypothalamic injections of anti-dopamine beta hydroxylase saporin, a retrogradely transported catecholamine immunotoxin that selectively lesions norepinephrine and epinephrine neurons that innervate the injection site. Furthermore, 4V injection of glucosamine increased Fos expression in catecholamine populations responsible for key glucoregulatory responses. These results demonstrate that glucokinase in hindbrain catecholamine neurons is a mediator of food intake and possibly a transduction mechanism for stimulation of glucoregulatory feeding by these neurons.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
The effects of noradrenergic lesions to the orbitofrontal cortex on reversal learning
Bates AT, Duys AN, Miller CE, Miller R, Mcgaughy J (2011) The effects of noradrenergic lesions to the orbitofrontal cortex on reversal learning. Neuroscience 2011 Abstracts 296.03. Society for Neuroscience, Washington, DC.
Summary: Poor impulse control is one of the major symptoms of disorders such as attention deficit disorder and is hypothesized to result from dysfunction in the prefrontal cortex. Specifically the ability to inhibit responding to a previously reinforced stimulus as required in tests of reversal rely on the functional integrity of the orbitofrontal cortex. Previous work from our lab and others have shown that norepinephrine in the prelimbic cortex is necessary to perform attentional set shifting. Lesions to this region result in attentional set shifting impairments that can be remediated by the administration of a selective noradrenergic reuptake blocker. Though many studies have shown monoamine levels in the orbitofrontal cortex are critical to reversal learning, few studies have directly addressed the impact of norepinephrine depletion in the orbitofrontal cortex on reversal learning. In the present study, we assess the effects of noradrenergic deafferentation of the orbitofrontal cortex in the intra-dimensional/extra-dimensional set shifting task using adult male, Long-Evans hooded rats. Preliminary data support the hypothesis that norepinephrine in orbitofrontal cortex is critical to successful reversal learning as the lesioned animals required more trials to reach criterion performance on reversals than sham-lesioned rats. Performance on the ID and ED portions of the task were not impacted by lesion. After behavioral testing was completed, brains were processed to elucidate norepinephrine transporters (NET). Fiber density of NET positive fibers was assessed in the regions of the orbitofrontal, prelimbic, and cingulate cortices for all subjects. These findings point to the function of the noradrenergic system within the orbitofrontal cortex on mediating impulse control while leaving attentional set shifting performance intact.
Related Products: Anti-DBH-SAP (Cat. #IT-03)
Basal metabolic substrate utilization is altered by lesion of hindbrain catecholamine neurons that innervate the medial hypothalamus and substrate selection during glucoprivation is impaired.
Ritter S, Li A-J, Wang Q, Dinh TT (2011) Basal metabolic substrate utilization is altered by lesion of hindbrain catecholamine neurons that innervate the medial hypothalamus and substrate selection during glucoprivation is impaired. Neuroscience 2011 Abstracts 88.05. Society for Neuroscience, Washington, DC.
Summary: Central injection of the targeted immunotoxin, anti-dopamine beta hydroxylase (DBH)-saporin (DSAP), retrogradely and selectively lesions norepinephrine (NE) and epinephrine (E) neurons with projections to the injection site. Previous work has shown that DSAP injections targeting the hypothalamic paraventricular nucleus eliminate key counterregulatory responses to acute glucose deficit, including feeding and corticosterone secretion. To examine the role of these NE an E neurons in metabolic control under basal conditions, we injected rats in the PVH with DSAP or control unconjugated saporin (SAP) and analyzed their metabolic profiles using metabolic chambers (Columbus Instruments). Rats were maintained on a standard pelleted rodent diet. We found that the respiratory exchange ratio (RER) was consistently elevated in DSAP rats across the entire circadian cycle under basal conditions, compared to the RER of SAP controls, indicating increased dependence on carbohydrate utilization. Metabolic rate and activity did not differ between groups. This result suggests a chronic enhancement of glucose mobilization or an impairment of the ability to mobilize fatty acids in the DSAP rats. We also found that when challenged by 2-deoxy-D-glucose induced glucoprivation, SAP controls exhibited a rapid decrease in RER, indicating a switch to fat metabolism, whereas DSAP rats did not exhibit this response. Together these results favor the possibility that a central mechanism for fat mobilization is impaired in DSAP rats and that this impairment is reflected under both basal and glucoprivic conditions. The previously reported observation that PVH DSAP-injected rats exhibit a slowly-developing obesity also supports this possibility. Additional findings suggest that this impairment may be due to the loss of NE/E control of corticosterone secretion in the DSAP rats.
Related Products: Anti-DBH-SAP (Cat. #IT-03), , Saporin (Cat. #PR-01)
Diminished norepinephrine release in the BSTv decreases anxiety but does not promote maternal behavior in nulliparous female rats.
Holschbach MA, Lonstein JS (2011) Diminished norepinephrine release in the BSTv decreases anxiety but does not promote maternal behavior in nulliparous female rats. Neuroscience 2011 Abstracts 86.06. Society for Neuroscience, Washington, DC.
Summary: Postpartum caregiving heavily depends on both increased motivation to interact with offspring and decreased emotional reactivity. The early postpartum period is associated with reduced anxiety in mammals, which may promote contact with potentially anxiogenic young. The ventral bed nucleus of the stria terminalis (BSTv) is associated with both anxiety and maternal behaviors in laboratory rats and may be a site of integration for mediating tradeoffs between mothering and emotional reactivity. Our laboratory has previously shown that increasing norepinphrine (NE) release in the BSTv of postpartum rats via infusion of an autoreceptor antagonist increases dams’ anxiety behaviors to levels seen in untreated virgin rats. Interestingly, this treatment also disrupts maternal retrieval of pups (Smith and Lonstein, SFN 2009). Unlike postpartum rats, nulliparous females are not spontaneously maternal, and we hypothesized that if NE release in the BSTv disrupts maternal behaviors even in highly motivated postpartum rats, it may greatly hinder expression of maternal behaviors in virgins. To investigate whether depleting NE input to the BSTv is sufficient to reduce anxiety and promote maternal behavior in virgin female rats we injected an antiserum- based neurotoxin selective for noradrenergic fibers and cells (anti-dopamine beta-hydroxylase-saporin; anti-DBH-SAP; 50 mg/side), into the BSTv of ovariectomized virgin female rats. Two weeks later, we examined females’ anxiety behavior in an elevated plus maze and the next day began a maternal sensitization procedure. We placed three recently fed pups into each animal’s homecage and observed behavior for the following fifteen minutes each day until rats exhibited full maternal behavior (i.e. retrieved all three pups to a common nest site and hovered over them) during three consecutive tests. Histological analysis of the brains confirmed that anti-DBH-SAP greatly reduced NE fiber content in the BSTv. Compared to control animals injected with artificial CSF, animals injected with anti-DBH-SAP showed reduced anxiety in an elevated plus maze. Anti-DBH-SAP did not, however, reduce the latency to show full maternal behavior. Thus, although reduced anxiety permits or promotes expression of maternal behaviors in already motivated postpartum rats, reducing BSTv-mediated anxiety is not sufficient to facilitate maternal responsiveness without otherwise activating maternal motivational systems.
Related Products: Anti-DBH-SAP (Cat. #IT-03)