sfn2009

Lima T-Z, Blanco MM, Bueno MA, Dos Santos Junior JG, Bargieri DY, Mello LE (2009) The influence of cholinergic degeneration on the progression of Alzheimer’s disease and its action in determining the outcome of lithium treatment. Neuroscience 2009 Abstracts 139.26/D36. Society for Neuroscience, Chicago, IL.

Summary: A substantial loss of cholinergic innervation in the hippocampus and cerebral cortex is universally accepted as a typical feature of Alzheimer’s disease (AD). Cholinergic deafferentation is an often, but not a constant phenomenon in AD and its contribution to the progression of disease is not completely understood. The present work was aimed to evaluate the effect of cholinergic deafferentation on cognitive decline and on Amyloid-b (A_) metabolism and how this outcome is modulated by lithium. To this end rats were subjected to neonatal intracerebroventricular injection of 192 IgG-saporin (an immunotoxin selective to cholinergic neurons). Three months after surgery animals were evaluated in Morris Water Maze (MWM) and then entered a three months long lithium (LiCl) or control treatment. At the end of treatment, animals were once again tested in MWM and their cerebral cortical A_ levels were measured. We found that working memory impairment arises earlier and it is also more severe than reference memory related deficits. The cognitive performance was only slightly influenced by LiCl treatment. Furthermore we found that the cholinergic denervation produced by neonatal IgG-sap infusion did not modify A_ levels or its aggregation state. Moreover lithium increased the levels of A_1-42 despite decreasing the amount of A_1-40, an effect that is dependent of cholinergic integrity. These data suggest that the contribution of cholinergic deafferentation, which occurs over the progression of disease, to the amyloigenesis is likely to be modest in AD brain. In addition the effects of lithium treatment presented here imply in avoiding its use as prophylactic propose for AD and in AD cases without marked cholinergic degeneration.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Wiley RG, Kline IV RH, Lemons LL (2009) Role of galanin receptor-expressing dorsal horn neurons in nocifensive reflex responses to heat. Neuroscience 2009 Abstracts 170.17/X19. Society for Neuroscience, Chicago, IL.

Summary: Spinal intrathecal (i.t.) galanin has been reported to be antinociceptive in some situations. Using lumbar i.t injections of galanin, coupled to the ribosomal inactivating peptide, saporin, to selectively destroy spinal dorsal horn cells that express galanin receptors, we sought to determine the role of galanin receptor-expressing dorsal horn neurons in reflex nocifensive hotplate behavior. Rats were injected into lumbar CSF with either 500 ng or 750 ng Gal-sap or saline, then tested over several weeks on the hotplate at 44o, 47o and 52oC. Gal-sap increased hindpaw withdrawal latencies only to 44oC and decreased the amount of responding on both 44o and 47oC hotplates. Morphine (5 mg/kg, s.c.) twenty minutes before 44°C hotplate testing slightly increased initial response latency and significantly decreased responding of the control rats. The antinociceptive effect of morphine in the Gal-sap rats was approximately additive with the antinociceptive effect of Gal-sap. Mustard oil applied to the dorsal hindpaws significantly increased responding on the 44°C hotplate in control rats, but produced less of an increase in Gal-sap rats. Topical capsaicin to hindpaw plantar skin reduced control, but not Gal-sap, responses on the 44°C hotplate. These results suggest a role for galanin receptor-expressing dorsal horn neurons in modulation of nociception that is unique, different from several other types of dorsal horn neurons and suggests a strategy for augmenting opiate drug effect.

Related Products: Galanin-SAP (Cat. #IT-34)

Sivasathiaseelan H, Nunan R, Zaben M, Shtaya A, Gray WP (2009) The role of microglia and neuropeptides in regulating hippocampal neurogenesis. Neuroscience 2009 Abstracts 31.26/B52. Society for Neuroscience, Chicago, IL.

Summary: Adult mammalian neurogenesis is evident in the hippocampal dentate gyrus where it plays a role in learning and memory and is implicated in the pathophysiology of several brain disorders. Microglia, the innate immune cells of the brain, have recently emerged as an important component of the neurogenic niche, however their role in the regulation of neurogenesis under physiological and pathophysiological conditions is a matter of debate. The aim of this study is to investigate the effect of microglia on hippocampal neurogenesis and to look at how vasoactive intestinal peptide (VIP), a potent immunomodulatory neuropeptide found in dentate gyrus interneurons, modulates the effects microglia have on neurogenesis. In this study, we have investigated the effect of microglial depletion (using MAC-SAP), microglial co-culture and addition of microglia-conditioned-medium on primary hippocampal cell cultures derived from post-natal rats. We have also looked at how pre-treatment of microglia with VIP alters their effect on hippocampal cultures. Bromodeoxyuridine was used as a marker of cell proliferation. Quantification of cell death was achieved using the nuclear stain 4′,6-diamidino-2-phenylindole and Propidium Iodide. Immunohistochemistry was used to phenotype cells for nestin, GFAP and Tuj1. We have shown that microglial depletion results in a reduction in the numbers of nestin, GFAP and Tuj1 expressing cells. This reduction has been shown to be attributable to a decrease in cell survival and proliferation. Conversely, co-culture of microglia with hippocampal neurons or addition of their conditioned medium results in increased cell survival and proliferation. Pre-treatment of microglia with VIP was shown to increase both their proliferative and trophic effect on hippocampal cultures. In conclusion, this study demonstrates that microglia induce proliferative and trophic effects on neural stem cells and immature neurons through the release of soluble factors. Furthermore, we provide evidence that VIP regulates the release of these soluble factors, thus identifying a novel neuro-immuno-neurogenic link.

Related Products: Mac-1-SAP rat (Cat. #IT-33)

Dinh TT, Huston NJ, Ritter S (2009) Caudal hindbrain catecholaminergic projection to the ventrolateral bed nucleus of the stria terminalis (vlBNST): Assessment of role in glucoprivic and CCK feeding responses and corticosterone secretion. Neuroscience 2009 Abstracts 87.16/CC80. Society for Neuroscience, Chicago, IL.

Summary: Catecholamine neurons in the caudal hindbrain provide a significant innervation of the vlBNST and some of these neurons co-innervate the paraventricular nucleus of the hypothalamus (PVH). We previously found that PVH injections of the retrogradely-transported immunotoxin, anti-dopamine beta hydroxylase (DBH) saporin (anti-DBH-sap), profoundly reduced feeding and corticosterone responses to glucoprivation, but did not alter CCK-induced satiety, which has been linked to catecholamine neurons in the A2 cell group. In this experiment, we examined the origin of the vlBNST/PVH catecholamine projection and assessed its role in responses to glucoprivation and CCK. Retrograde tracing from vlBNST and PVH revealed dually-projecting DBH-ir (norepinephrine or epinephrine) neurons primarily in A2, A1 and caudal C1, with a few cells also present in C2. Dually-projecting PNMT-ir (epinephrine) were also present in C1 and in small numbers in C2. Overall, the relative numbers of DBH- and PMNT-ir neurons with projections to both vlBNST and PVH and the locations of these triply-labeled neurons indicate that the dually-projecting neurons are predominantly noradrenergic. Injections of anti-DBH-sap into the vlBNST produced cell losses in the hindbrain that were anatomically consistent in distribution and number with the tracing results. This immunotoxin caused a loss of DBH neurons in the dorsal hindbrain that was concentrated in the A2 cell group (14.6 – 13.68 mm caudal to bregma), where a maximum of 50% of DBH neurons were lesioned: 50% loss at 14.6 mm caudal to bregma, 25% at 13.24 mm and 0% at 11.96 mm. In ventral hindbrain, loss of DBH cell bodies was predominantly in the A1 cell group (14.6 – 12.8 mm caudal to bregma), where a maximum of 60% of DBH-ir neurons were lesioned: 60% loss at 14.6 and 13.68 mm, 22% at 13.24 and and 0% at 12.8 mm. In the dorsal hindbrain nearly all cells retrogradely labeled from the vlBNST were ipsilateral and DBH-ir. In ventral hindbrain there was a significant contralateral projection to vlBNST that was not DBH-ir. Anti-DBH-sap lesions did not impair the feeding, blood glucose or corticosterone responses to 2-deoxy-D-glucose (250 mg/kg) and did not impair the suppression of feeding by CCK-8 (4 ug/kg), indicating that the catecholamine projection to the vlBNST, including the dually-projecting neurons that innervate both the vlBNST and the PVH, is not required for these responses.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Mcauley J, Stewart AL, Pang KCH (2009) Role of cholinergic NBM neurons in timing and divided attention. Neuroscience 2009 Abstracts 95.12/EE81. Society for Neuroscience, Chicago, IL.

Summary: The nucleus basalis magnocellularis (NBM) provides cholinergic and GABAergic innervation to the neocortex. In previous studies, non-selective lesions of the NBM using ibotenic acid impaired interval timing and divided attention. Rats with NBM damage produced rightward shifts in peak times, demonstrating overproduction (underestimation) of time. Additionally, NBM damage impaired the ability to divide attention when timing two intervals simultaneously. Damage of the frontal cortex produced similar impairments in timing and divided attention as NBM damage, suggesting the NBM projections to frontal cortex were critical. Currently, the NBM neurons responsible for modulating timing and attention are unknown. The present study will determine the importance of cholinergic NBM neurons in timing and attention using the selective immunotoxin 192-IgG saporin (192-SAP). Sixteen Sprague Dawley rats were first trained on a peak-interval (PI) procedure using fixed-intervals of 12 s and 24 s paired with light and tone stimuli, respectively. During this phase, only one stimulus was presented during a trial (focused attention). Following the initial phase of training, rats were trained on a divided attention version of the peak-interval procedure, in which 2 stimuli were presented simultaneously in a trial and rats timed both intervals in parallel. Rats were administered 192-SAP into the NBM (n = 10) or given SHAM surgeries (n = 6). Following surgery, 192-SAP rats produced a leftward shift in timing with increased variability compared to SHAM rats. These changes in timing were observed in both focused and divided attention conditions, but the effects were larger in divided attention conditions than in focused attention conditions. Results implicate the cholinergic NBM neurons in the modulation of interval timing and divided attention. Current work is verifying the selectivity and efficacy of the 192-SAP administration. Additional studies will examine the role of GABAergic NBM neurons in interval timing and divided attention.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Croxson PL, Baxter MG (2009) Multiple neuromodulator depletion interacts with fornix transection to impair episodic memory in monkeys. Neuroscience 2009 Abstracts 98.4/EE128. Society for Neuroscience, Chicago, IL.

Summary: Acetylcholine may play an important role in some aspects of cognitive function, and in particular in episodic memory. However, the role of other neuromodulatory (NM) substances, such as noradrenaline, dopamine, and serotonin, in episodic memory is less well-defined. We tested monkeys on a model of episodic memory in monkeys and carried out specific depletions of different neuromodulators within inferotemporal cortex (IT). Six rhesus macaque monkeys (five male) were trained on an object-in-place scene learning task that models key features of human episodic memory, because learning occurs rapidly (often in a single trial) in the contaxt of unique background scenes. After preoperative testing three monkeys were given injections into IT of the immunotoxin ME20.4-saporin interleaved with injections of 6-hydroxydopamine and 5,7-dihydroxytryptamine. This resulted in depletion of acetylcholine, dopamine, noradrenaline and serotonin throughout IT (group NM+ACh). Three monkeys received the same treatment but omitting the ME20.4-saporin, thus depleting dopamine, noradrenaline and serotonin, but sparing acetylcholine (group NM). Neither group of monkeys (NM+ACh or NM) were impaired in postoperative scene learning. We found previously that addition of fornix transection to depletion of ACh from IT severely impaired scene learning relative to fornix transection alone (Browning et al. 2009, Cerebral Cortex). Therefore we gave each monkey in groups NM and NM+ACh a bilateral fornix transection and performed a further postoperative performance test. As expected, monkeys in group NM+ACh were severely impaired in scene learning following fornix transection. However, monkeys in group NM were also severely impaired in scene learning following fornix transection, despite having no visible damage to cholinergic innervation. Depletion of cholinergic, dopaminergic, adrenergic and serotoninergic innervation of inferotemporal cortex, therefore, is not sufficient to impair monkeys’ performance on an episodic memory task. Furthermore, there is a synergistic interaction between the NM depletion and fornix transection in this task, like that between ACh depletion and fornix transection. This may be due to a general reduction in cortical function after NM depletion, albeit not sufficient to cause episodic memory impairment on its own, which exacerbates the effect of fornix transection. It may point to one or more of these neuromodulators having a role in post-lesion plasticity, a role that is also played by ACh. Importantly, these data suggest that intact cholinergic innervation is not sufficient for post-lesion plasticity.

Related Products: ME20.4-SAP (Cat. #IT-15)