targeted-toxins

Pacheco-Herrero M, Thyssen D, Ramos-Rodriguez J, Berrocoso E, Bacskai B, Garcia-Alloza M (2011) Rapid beta-amyloid deposition and behavioural impairment after cholinergic denervation in APPswe/PS1dE9. Neuroscience 2011 Abstracts 47.02. Society for Neuroscience, Washington, DC.

Summary: Alzheimer’s disease (AD) is the most common cause of dementia. Although the ultimate neurotoxic mechanisms are not known, extensive evidence supports the role of amyloid-beta (Aβ) deposition as senile plaques (SP) in the disease. On the other hand, neuronal loss is the pathological feature that best correlates with the duration and severity of the illness and specifically, cholinergic denervation of the basal forebrain seems to be a good predictor of clinical dementia in AD. A close relationship has been documented between Aβ deposition and neurodegeneration, however, whether specific neurodegeneration may lead to senile plaque deposition remains unclear. We addressed this by inducing selective cholinergic lesions in APPswe/PS1dE9 mice with murine p-75 saporin, an inmunotoxin that selectively removes cholinergic innervation. We performed intracerebroventricular murine p-75 lesions in animals with an incipient (~3 months) and robust (~7 months of age) Aβ deposition and removed ~50% of basal forebrain cholinergic innervation to cortex and hippocampus. Immediately after injections, cranial windows were implanted and Aβ deposition was monitored in vivo and in real time in the cortex using methoxy-XO4 and multiphoton microscopy. We observed increased SP deposition as soon as 1 week after the lesion. We further corroborated our in vivo data post-mortem, using anti- Aβ and anti-fibrils antibodies as well as thioflavin S staining, both in the cortex and the hippocampus. 7 days after the surgery, when the lesion is established, animals were tested in the new object discrimination and Morris water maze tests. We observed an early memory impairment in young lesioned mice (~3 months) and this effect worsened with age (~7 months of age), when Aβ deposition is more robust. Altogether, our data suggest that cholinergic denervation may contribute to the deposition of Aβ and synergistically contribute to the cognitive impairment observed in AD.

Related Products: mu p75-SAP (Cat. #IT-16)

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)

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)

Savage S, Kehr J, Olson L, Mattsson A (2011) Impaired social interaction and enhanced sensitivity to phencyclidine-induced deficits in novel object recognition in rats with cortical cholinergic denervation. Neuroscience 195:60-69. doi: 10.1016/j.neuroscience.2011.08.027

Summary: Forebrain cholinergic dysfunction is thought to be part of the pathophysiology of schizophrenia. The authors lesioned the cholinergic corticopetal projection of rats by infusing 0.081 µg of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis magnocellularis. The lesioned animals displayed a reduction in the duration of social interaction. When the lesioned animals were then given PCP, they were no longer able to recognize a novel object. The data suggest a role of cholinergic hypofunction in the cognitive symptoms of schizophrenia.

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

Abbott SB, Stornetta RL, Coates MB, Guyenet PG (2011) Phox2b-expressing neurons of the parafacial region regulate breathing rate, inspiration, and expiration in conscious rats. J Neurosci 31(45):16410-16422. doi: 10.1523/JNEUROSCI.3280-11.2011

Summary: Neurons in the retrotrapezoid nucleus (RTN) are involved in the CO2-dependent control of breathing in conscious and anesthetized rats. In this work the authors specifically examined Phox2b-expressing glutaminergic neurons in the RTN. Rats received 44 ng of DBH-SAP (Cat. #IT-03) into the lateral horn of the second thoracic segment in order to eliminate C1 neurons that project to the spinal cord. The data demonstrate regulation of lung ventilation by RTN-Phox2b neurons, and also that these neurons are not rhythmogenic in adults.

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

Croxson PL, Kyriazis DA, Baxter MG (2011) Cholinergic modulation of a specific memory function of prefrontal cortex. Nat Neurosci 14(12):1510-1512. doi: 10.1038/nn.2971

Summary: The authors investigated loss of acetylcholine in the large and highly differentiated PFC’s of rhesus monkeys. The monkeys received 80-92 20-ng injections of ME20.4-SAP (Cat. #IT-15) per hemisphere. Lesioned animals were severely impaired on tasks involving spatial working memory.

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

Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, Li QF, Jeffry J, Kim JY, Loh HH, Chen ZF (2011) Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 147(2):447-458. doi: 10.1016/j.cell.2011.08.043

Summary: Recent work has begun to define the different pathways used by itch and pain. This study was designed to investigate whether opioids cause the itch sensation by gastrin releasing peptide receptor activation. Mice received intrathecal injections of bombesin-SAP (Cat. #IT-40) in order to investigate the coexpression of various signaling molecules in the spinal cord. Blank-SAP (Cat. #IT-21) was used as a control. The data suggest that opioid-induced itch is independent of opioid analgesia, and is controlled through a mu-opioid receptor isoform.

Related Products: Bombesin-SAP (Cat. #IT-40), Blank-SAP (Cat. #IT-21)

King T, Porreca F (2011) Featured Article: Contribution of afferent pathways to nerve injury-induced spontaneous pain and evoked hypersensitivity. Targeting Trends 12(4)

Related Products: SSP-SAP (Cat. #IT-11), Blank-SAP (Cat. #IT-21)

Read the featured article in Targeting Trends.

See Also:

• King T et al. Contribution of afferent pathways to nerve injury-induced spontaneous pain and evoked hypersensitivity. Pain 152(9):1997-2005, 2011.

Pongratz G, Melzer M, Straub R (2012) The sympathetic nervous system stimulates anti-inflammatory B cells in collagen-type II-induced arthritis. Ann Rheum Dis 71(3):432-9. doi: 10.1136/ard.2011.153056

Summary: The sympathetic nervous system exerts anti-inflammatory effects on collagen-induced arthritis. To examine whether these effects are mediated by B-cells producing interleukin-10 (IL-10) the authors treated mice with 5 µg intraperitoneal injections of anti-DBH-SAP (Cat. #IT-03). The sympathectomy efficacy was assessed by analyzing norepinephrine levels in the spleen. The data suggest that increasing the number of IL-10 producing B cells can slow down arthritis progression.

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

Olarte-Sánchez CM, Valencia Torres L, Body S, Cassaday HJ, Bradshaw CM, Szabadi E (2012) Effect of orexin-B-saporin-induced lesions of the lateral hypothalamus on performance on a progressive ratio schedule. J Psychopharmacol 26(6):871-886. doi: 10.1177/0269881111409607

Summary: It has been suggested that orexigenic neurons in the hypothalamus consist of two anatomically distinct groups. The lateral hypothalamic area group (LHA), which modulates reinforcement mechanisms; and the dorsomedial hypothalamus and perifornical area group involved in regulation of stress and arousal. Rats received bilateral 15 ng injections of orexin-SAP (Cat. #IT-20) into the LHA. Results from a progressive ratio model indicate that the lesioned neurons control the motor component of food-reinforced responding.

Related Products: Orexin-B-SAP (Cat. #IT-20)